Tackling Tumors with Small RNAs Derived from Transfer RNA

Only approximately 1% of the human genome is made up of genes that encode proteins. Our understanding of the rest of our genome is scant: it is — for the most part — a world undiscovered. (It is also true that the function of many genes is not understood, even though this minuscule portion of the…

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Tackling Tumors with Small RNAs Derived from Transfer RNA

Only approximately 1% of the human genome is made up of genes that encode proteins. Our understanding of the rest of our genome is scant: it is — for the most part — a world undiscovered. (It is also true that the function of many genes is not understood, even though this minuscule portion of the…

https://ift.tt/2I7jFJc

Sex, Body Image, and Relationships: A BRIGHTLIGHT Workshop on Information and Support Needs of Adolescents and Young Adults

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


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Sex, Body Image, and Relationships: A BRIGHTLIGHT Workshop on Information and Support Needs of Adolescents and Young Adults

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


https://ift.tt/2K7SL4w

A comprehensive analysis of clinical trials including both immunotherapy and radiation therapy

Abstract

Purpose

Radiation therapy (RT) may work synergistically with cancer immunotherapies but clinical trial data is needed to validate this paradigm. We isolated the portfolio of trials that investigate the primary immunomodulatory properties of RT and examined recent trends in clinical trials that combine immunotherapy and RT (ITRT).

Methods

We queried clinicaltrials.gov for trials initiated since 2002 using both radiation and immunotherapy as mandated interventions. We designated the trials that examine the specific aspects of RT or its abscopal properties as "Primary RT Immunomodulation" trials. Chi-squared analysis determined differences between primary RT immunomodulation trials and those that incorporate RT as a secondary intervention. Joinpoint regression modeling determined the rate of change of the introduction of new trials over time.

Results

One hundred and ninety trials met inclusion criteria. Targeted immunostimulatory agents, including checkpoint inhibitors, were the most common immunotherapy (n = 79 [41.6%]). Sixty-six (34.7%) trials included RT as the primary intervention, with 50 (75.6%) of these utilizing stereotactic body radiation (SBRT). All ITRT trials increased at a rate of 14.8% per year. Primary RT immunomodulation trials increased at a rate of 26.8% per year. Primary RT immunomodulation trials were more likely to utilize targeted immunostimulatory agents (p < 0.01), and SBRT (p < 0.01), and more likely to involve metastatic sites (p < 0.01). The number of ITRT studies increased drastically in the latest two years of the study.

Conclusion

The number of new ITRT clinical trials is increasing rapidly. This increase in quantity may improve the clinical application of the immunomodulatory properties of RT.

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Cancers, Vol. 10, Pages 141: Role of the Bone Microenvironment in the Development of Painful Complications of Skeletal Metastases

Cancers, Vol. 10, Pages 141: Role of the Bone Microenvironment in the Development of Painful Complications of Skeletal Metastases

Cancers doi: 10.3390/cancers10050141

Authors: Sun H. Park Matthew R. Eber D. Brooke Widner Yusuke Shiozawa

Cancer-induced bone pain (CIBP) is the most common and painful complication in patients with bone metastases. It causes a significant reduction in patient quality of life. Available analgesic treatments for CIBP, such as opioids that target the central nervous system, come with severe side effects as well as the risk of abuse and addiction. Therefore, alternative treatments for CIBP are desperately needed. Although the exact mechanisms of CIBP have not been fully elucidated, recent studies using preclinical models have demonstrated the role of the bone marrow microenvironment (e.g., osteoclasts, osteoblasts, macrophages, mast cells, mesenchymal stem cells, and fibroblasts) in CIBP development. Several clinical trials have been performed based on these findings. CIBP is a complex and challenging condition that currently has no standard effective treatments other than opioids. Further studies are clearly warranted to better understand this painful condition and develop more effective and safer targeted therapies.

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Cancers, Vol. 10, Pages 141: Role of the Bone Microenvironment in the Development of Painful Complications of Skeletal Metastases

Cancers, Vol. 10, Pages 141: Role of the Bone Microenvironment in the Development of Painful Complications of Skeletal Metastases

Cancers doi: 10.3390/cancers10050141

Authors: Sun H. Park Matthew R. Eber D. Brooke Widner Yusuke Shiozawa

Cancer-induced bone pain (CIBP) is the most common and painful complication in patients with bone metastases. It causes a significant reduction in patient quality of life. Available analgesic treatments for CIBP, such as opioids that target the central nervous system, come with severe side effects as well as the risk of abuse and addiction. Therefore, alternative treatments for CIBP are desperately needed. Although the exact mechanisms of CIBP have not been fully elucidated, recent studies using preclinical models have demonstrated the role of the bone marrow microenvironment (e.g., osteoclasts, osteoblasts, macrophages, mast cells, mesenchymal stem cells, and fibroblasts) in CIBP development. Several clinical trials have been performed based on these findings. CIBP is a complex and challenging condition that currently has no standard effective treatments other than opioids. Further studies are clearly warranted to better understand this painful condition and develop more effective and safer targeted therapies.

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Preclinical development of a bispecific antibody that safely and effectively targets CD19 and CD47 for the treatment of B cell lymphoma and leukemia

CD47, a ubiquitously expressed innate immune checkpoint receptor that serves as a universal "don't eat me" signal of phagocytosis, is often up-regulated by hematological and solid cancers to evade immune surveillance. Development of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hemotoxicity including anemia. To overcome such liabilities, we have developed a fully human bispecific antibody, NI-1701, designed to co-engage CD47 and CD19 selectively on B cells. NI-1701 demonstrates favorable elimination kinetics with no deleterious effects seen on hematological parameters following single or multiple administrations to non-human primates. Potent in vitro and in vivo activity is induced by NI-1701 to kill cancer cells across a plethora of B cell malignancies and control tumor growth in xenograft mouse models. The mechanism affording maximal tumor growth inhibition by NI-1701 is dependent on the co-engagement of CD47/CD19 on B cells inducing potent antibody dependent cellular phagocytosis of the targeted cells. NI-1701-induced control of tumor growth in immunodeficient NOD/SCID mice was more effective than that achieved with the anti-CD20 targeted antibody, rituximab. Interestingly, a synergistic effect was seen when tumor-implanted mice were co-administered NI-1701 and rituximab leading to significantly improved tumor growth inhibition and regression in some animals. We describe herein, a novel bispecific antibody approach aimed at sensitizing B cells to become more readily phagocytosed and eliminated thus offering an alternative or adjunct therapeutic option to patients with B cell malignancies refractory/resistant to anti-CD20 targeted therapy.

https://ift.tt/2I3j3bC

Preclinical development of a bispecific antibody that safely and effectively targets CD19 and CD47 for the treatment of B cell lymphoma and leukemia

CD47, a ubiquitously expressed innate immune checkpoint receptor that serves as a universal "don't eat me" signal of phagocytosis, is often up-regulated by hematological and solid cancers to evade immune surveillance. Development of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hemotoxicity including anemia. To overcome such liabilities, we have developed a fully human bispecific antibody, NI-1701, designed to co-engage CD47 and CD19 selectively on B cells. NI-1701 demonstrates favorable elimination kinetics with no deleterious effects seen on hematological parameters following single or multiple administrations to non-human primates. Potent in vitro and in vivo activity is induced by NI-1701 to kill cancer cells across a plethora of B cell malignancies and control tumor growth in xenograft mouse models. The mechanism affording maximal tumor growth inhibition by NI-1701 is dependent on the co-engagement of CD47/CD19 on B cells inducing potent antibody dependent cellular phagocytosis of the targeted cells. NI-1701-induced control of tumor growth in immunodeficient NOD/SCID mice was more effective than that achieved with the anti-CD20 targeted antibody, rituximab. Interestingly, a synergistic effect was seen when tumor-implanted mice were co-administered NI-1701 and rituximab leading to significantly improved tumor growth inhibition and regression in some animals. We describe herein, a novel bispecific antibody approach aimed at sensitizing B cells to become more readily phagocytosed and eliminated thus offering an alternative or adjunct therapeutic option to patients with B cell malignancies refractory/resistant to anti-CD20 targeted therapy.

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Sociodemographic variation in the use of chemotherapy and radiotherapy in patients with stage IV lung, oesophageal, stomach and pancreatic cancer: evidence from population-based data in England during 2013–2014

Sociodemographic variation in the use of chemotherapy and radiotherapy in patients with stage IV lung, oesophageal, stomach and pancreatic cancer: evidence from population-based data in England during 2013–2014

Sociodemographic variation in the use of chemotherapy and radiotherapy in patients with stage IV lung, oesophageal, stomach and pancreatic cancer: evidence from population-based data in England during 2013–2014, Published online: 10 May 2018; doi:10.1038/s41416-018-0028-7

Sociodemographic variation in the use of chemotherapy and radiotherapy in patients with stage IV lung, oesophageal, stomach and pancreatic cancer: evidence from population-based data in England during 2013–2014

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When it comes to genomic analysis of tumours, don't buy in bulk

When it comes to genomic analysis of tumours, don't buy in bulk

When it comes to genomic analysis of tumours, don't buy in bulk, Published online: 10 May 2018; doi:10.1038/s41416-018-0096-8

When it comes to genomic analysis of tumours, don't buy in bulk

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Sociodemographic variation in the use of chemotherapy and radiotherapy in patients with stage IV lung, oesophageal, stomach and pancreatic cancer: evidence from population-based data in England during 2013–2014

Sociodemographic variation in the use of chemotherapy and radiotherapy in patients with stage IV lung, oesophageal, stomach and pancreatic cancer: evidence from population-based data in England during 2013–2014

Sociodemographic variation in the use of chemotherapy and radiotherapy in patients with stage IV lung, oesophageal, stomach and pancreatic cancer: evidence from population-based data in England during 2013–2014, Published online: 10 May 2018; doi:10.1038/s41416-018-0028-7

Sociodemographic variation in the use of chemotherapy and radiotherapy in patients with stage IV lung, oesophageal, stomach and pancreatic cancer: evidence from population-based data in England during 2013–2014

https://ift.tt/2I6x8Fr

When it comes to genomic analysis of tumours, don't buy in bulk

When it comes to genomic analysis of tumours, don't buy in bulk

When it comes to genomic analysis of tumours, don't buy in bulk, Published online: 10 May 2018; doi:10.1038/s41416-018-0096-8

When it comes to genomic analysis of tumours, don't buy in bulk

https://ift.tt/2ruK1P4

FDA's Approval of the First Biosimilar to Bevacizumab

Passage of the Biologics Price Competition and Innovation Act of 2009 created an abbreviated licensure pathway for biosimilar products. The Food and Drug Administration approved ABP215 (MVASI, bevacizumab-awwb, Amgen) as a biosimilar to US-licensed Avastin (bevacizumab, Genentech) based on an extensive comparative analytical characterization, data obtained in a pharmacokinetic similarity study in healthy subjects, and a comparative clinical study in patients with non-small cell lung cancer. The totality of the evidence for biosimilarity supported extrapolation of the data to support licensure as a biosimilar for other approved indications of US-licensed Avastin, without the need of additional clinical studies.

https://ift.tt/2rz2E3u

PTPN12/PTP-PEST Regulates Phosphorylation-Dependent Ubiquitination and Stability of Focal Adhesion Substrates in Invasive Glioblastoma Cells

Glioblastoma (GBM) is an invasive brain cancer with tumor cells that disperse from the primary mass, escaping surgical resection and invariably giving rise to lethal recurrent lesions. Here we report that PTP-PEST, a cytoplasmic protein tyrosine phosphatase, controls GBM cell invasion by physically bridging the focal adhesion protein Crk-associated substrate (Cas) to valosin containing protein (Vcp), an ATP-dependent protein segregase that selectively extracts ubiquitinated proteins from multiprotein complexes and targets them for degradation via the ubiquitin proteasome system. Both Cas and Vcp are substrates for PTP-PEST, with the phosphorylation status of tyrosine 805 (Y805) in Vcp impacting affinity for Cas in focal adhesions and controlling ubiquitination levels and protein stability. Perturbing PTP-PEST-mediated phosphorylation of Cas and Vcp led to alterations in GBM cell invasive growth in vitro and in pre-clinical mouse models. Collectively, these data reveal a novel regulatory mechanism involving PTP-PEST, Vcp, and Cas that dynamically balances phosphorylation-dependent ubiquitination of key focal proteins involved in GBM cell invasion.

https://ift.tt/2IaEYd5

FDA's Approval of the First Biosimilar to Bevacizumab

Passage of the Biologics Price Competition and Innovation Act of 2009 created an abbreviated licensure pathway for biosimilar products. The Food and Drug Administration approved ABP215 (MVASI, bevacizumab-awwb, Amgen) as a biosimilar to US-licensed Avastin (bevacizumab, Genentech) based on an extensive comparative analytical characterization, data obtained in a pharmacokinetic similarity study in healthy subjects, and a comparative clinical study in patients with non-small cell lung cancer. The totality of the evidence for biosimilarity supported extrapolation of the data to support licensure as a biosimilar for other approved indications of US-licensed Avastin, without the need of additional clinical studies.

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PTPN12/PTP-PEST Regulates Phosphorylation-Dependent Ubiquitination and Stability of Focal Adhesion Substrates in Invasive Glioblastoma Cells

Glioblastoma (GBM) is an invasive brain cancer with tumor cells that disperse from the primary mass, escaping surgical resection and invariably giving rise to lethal recurrent lesions. Here we report that PTP-PEST, a cytoplasmic protein tyrosine phosphatase, controls GBM cell invasion by physically bridging the focal adhesion protein Crk-associated substrate (Cas) to valosin containing protein (Vcp), an ATP-dependent protein segregase that selectively extracts ubiquitinated proteins from multiprotein complexes and targets them for degradation via the ubiquitin proteasome system. Both Cas and Vcp are substrates for PTP-PEST, with the phosphorylation status of tyrosine 805 (Y805) in Vcp impacting affinity for Cas in focal adhesions and controlling ubiquitination levels and protein stability. Perturbing PTP-PEST-mediated phosphorylation of Cas and Vcp led to alterations in GBM cell invasive growth in vitro and in pre-clinical mouse models. Collectively, these data reveal a novel regulatory mechanism involving PTP-PEST, Vcp, and Cas that dynamically balances phosphorylation-dependent ubiquitination of key focal proteins involved in GBM cell invasion.

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CONTRA: Postoperative Epiduralanalgesie – der Goldstandard?

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 246-251
DOI: 10.1055/s-0043-104667

Die Epiduralanalgesie (EDA) kann nicht für alle Eingriffe mit mittelstarkem bis starkem Schmerzniveau der Goldstandard der Therapie sein. Die EDA ist der PCA (patientenkontrollierte Analgesie) und den oralen Analgetika in Bezug auf Reduktion der postoperativen Schmerzintensität überlegen [1]. Mögliche schwerwiegende Komplikationen sowie die höheren Kosten der EDA erfordern aber eine sorgfältige, evidenzbasierte operationsspezifische Abwägung.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2K7N7iJ

Spinalanästhesie bei Sectio: hyperbares oder isobares Bupivacain?

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 230-231
DOI: 10.1055/a-0588-2078

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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https://ift.tt/2wu6Ibb

Die Bedeutung der Hämolyse in Anästhesie und Intensivmedizin

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 296-305
DOI: 10.1055/s-0043-121622

Die intravasale Hämolyse mit erhöhten Plasmakonzentrationen von zellfreiem Hämoglobin tritt nicht nur bei hämolytischen Erkrankungen auf – sie ist auch bei der Transfusion von Blutkonserven sowie bei Patienten mit ARDS, Sepsis oder kardiopulmonalem Bypass für den Krankheitsverlauf von Bedeutung. Dieser Beitrag möchte den klinisch tätigen Anästhesisten für die Relevanz der Hämolyse sowie deren Prävention und Früherkennung sensibilisieren.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2wr2Yah

Intensivmedizin: Dysphagie nach Intensivbeatmung

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 231-232
DOI: 10.1055/a-0589-4882

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text

https://ift.tt/2ryFoUb

Patientenkontrollierte Analgesie: Methoden, Handhabung und Ausbaufähigkeit

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 270-280
DOI: 10.1055/s-0043-104665

Eine nebenwirkungsarme und patientenadaptierte Schmerztherapie ist integraler Bestandteil aller multimodalen Behandlungskonzepte, die eine schnelle und komplikationsfreie Erholung nach operativen Eingriffen ermöglichen sollen. Die patientenkontrollierte Analgesie (PCA) bietet dabei eine etablierte und sichere Option für eine individuell angepasste Schmerztherapie, die – richtig genutzt – ein hohes Maß an Patientenzufriedenheit garantiert.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2K4Us2L

Opioid-Missbrauch bei chronischen Schmerzen: Messinstrumente zur Risikoeinschätzung

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 232-234
DOI: 10.1055/a-0588-2062

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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https://ift.tt/2K945NW

Neurologisches Defizit nach intraoperativem anaphylaktischen Schock

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 314-316
DOI: 10.1055/a-0592-8364

Schlichtungsstellen für Arzthaftpflichtfragen bieten Patienten, Ärzten und Versicherern eine Möglichkeit, Arzthaftungsstreitigkeiten außergerichtlich zu klären. In der Rubrik „Fälle der Schlichtungsstelle" stellen wir abgeschlossene Fälle aus der Schlichtungsstelle für Arzthaftpflichtfragen der norddeutschen Ärztekammern vor.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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https://ift.tt/2wsIpKr

Intraoperative Anaphylaxie: Nach Behandlung kann die OP meist weitergehen

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 234-234
DOI: 10.1055/a-0588-2034

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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https://ift.tt/2rwjzob

Periphere Regionalanästhesie ohne Komplikationen – Ein Traum wird wahr?!

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 252-268
DOI: 10.1055/s-0043-104664

Periphere Regionalanästhesieverfahren sind relativ sichere Verfahren der klinischen Anästhesie – dennoch können typische, meist transiente und selten sogar persistierende Komplikationen auftreten. Neben allgemeinen Komplikationen und Strategien zur Risikoreduktion widmet sich dieser Artikel akzidentellen Mitblockaden anderer nervaler Strukturen am Beispiel des Plexus brachialis. Ein Ausblick in die Zukunft informiert über selektivere Blockaden.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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https://ift.tt/2rwfArS

Postoperative Schmerztherapie: Wie gehtʼs uns denn heute?

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 235-236
DOI: 10.1055/a-0588-5760

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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https://ift.tt/2wsIr51

Organisation der perioperativen Schmerztherapie

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 282-294
DOI: 10.1055/s-0043-104671

Organisatorische Aspekte der postoperativen Schmerztherapie werden oft vernachlässigt – dabei sind sie ebenso wichtig wie Details zu pharmakologischen oder regionalanalgetischen Verfahren. Anhand virtueller Fragen und Erfahrungen eines Assistenzarztes beleuchten wir in diesem Artikel die „Organisation der perioperativen Schmerztherapie": Schmerzerfassung und Dokumentation, Patienteninformation und -edukation, Aufgaben eines Akutschmerzdienstes.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2rvmAVE

PRO: Epiduralanalgesie – Goldstandard bei abdominalen und thorakalen Eingriffen

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 237-244
DOI: 10.1055/s-0043-104668

Die Kombination aus thorakaler Epiduralanalgesie (TEA) und Allgemeinanästhesie hat sich bei großen abdominellen und thorakalen Operationen aufgrund der ausgezeichneten Analgesiequalität bewährt 1. Komplikationen sind selten, aber potenziell schwerwiegend – sie müssen rasch erkannt und therapiert werden. Daher sollte die TEA in ein den gesamten perioperativen Verlauf umfassendes Konzept integriert sein, wie es in diesem Beitrag vorgestellt wird.
[...]

Georg Thieme Verlag KG Stuttgart · New York

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Transfusion in der Herzchirurgie: liberal oder restriktiv?

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 229-230
DOI: 10.1055/a-0589-4915

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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https://ift.tt/2ru9Kr4

Kasuistik: Opioidtherapie bei chronischem Rückenschmerz

Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 306-313
DOI: 10.1055/s-0043-115205

Ein 76-jähriger stellt sich mit chronischen lumbalen Rückenschmerzen vor, die trotz hochdosierter Opioidtherapie nicht suffizient behandelt sind. Nach Ausschluss spezifischer Ursachen konnte im Rahmen eines multimodalen tagesklinischen Behandlungsprogramms für Senioren die Opioidtagesdosis von 480 mg auf 28 mg Morphinäquivalent und die initiale hohe Schmerzintensität von 7 auf 4 Punkte auf einer numerischen Rangskala erfolgreich reduziert werden.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

https://ift.tt/2rwx07P

Tyrosine kinase inhibitors for brain metastases in HER2-positive breast cancer

Publication date: Available online 9 May 2018
Source:Cancer Treatment Reviews
Author(s): Renata Duchnowska, Sibylle Loibl, Jacek Jassem
Approximately 30–50% of advanced HER2-positive breast cancer patients will develop central nervous system (CNS) metastases, with an annual risk of around 10%, and a half of them will die from brain progression. An increased risk of brain metastases is also seen in patients with early HER2-positive breast cancer administered curative therapy. Brain metastases in HER2-positive breast cancer patients usually constitute the first site of recurrence. The administration of anti-HER2 monoclonal antibodies, trastuzumab and pertuzumab, considerably delays the onset of symptomatic brain disease: however, the limited penetration of these compounds into the CNS hinders their efficacy. The small-molecule tyrosine kinase inhibitors of epidermal growth factor receptors family have established activity in HER2-positive breast cancer in both advanced disease and neoadjuvant setting. Favorable physico-chemical properties of these compounds allow them for a more efficient penetration through the blood-brain barrier, and hold the promise for more effective prevention and treatment of brain metastases. In this article we review the role of currently available or investigational HER2 tyrosine kinase inhibitors: lapatinib, neratinib, afatinib and tucatinib in the treatment of brain metastases in HER2-positive breast cancer patients.



https://ift.tt/2FZlDtm

Sociodemographic variation in the use of chemotherapy and radiotherapy in patients with stage IV lung, oesophageal, stomach and pancreatic cancer: evidence from population-based data in England during 2013–2014

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Sociodemographic variation in the use of chemotherapy and radiotherapy in patients with stage IV lung, oesophageal, stomach and pancreatic cancer: evidence from population-based data in England during 2013–2014

https://ift.tt/2K88L6N

When it comes to genomic analysis of tumours, don't buy in bulk

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When it comes to genomic analysis of tumours, don't buy in bulk

https://ift.tt/2KaumeF

Respiratory motion-resolved, self-gated 4D-MRI using Rotating Cartesian K-space (ROCK): Initial clinical experience on an MRI-guided radiotherapy system

To optimize and evaluate the respiratory motion-resolved, self-gated 4D-MRI using Rotating Cartesian K-space (ROCK-4D-MRI) method in a 0.35 T MRI-guided radiotherapy (MRgRT) system.

https://ift.tt/2jJ2VgL

Rescue procedure for an electrical storm using robotic non-invasive cardiac radio-ablation

Stereotactic body radiotherapy (SBRT) is an emerging non-invasive treatment in the management of ventricular tachycardia (VT). We report here an intensive care patient suffering from an electrical storm due to incessant VT, unresponsive to catheter ablation and anti-arrhythmic drugs, showing an immediate and durable response to electrophysiology-guided cardiac SBRT.

https://ift.tt/2FZl1nF

Development of quality indicators to monitor radiotherapy care for men with prostate cancer: A modified Delphi method

Quality indicators (QIs) have been developed for many aspects of prostate cancer care, but are under-developed with regard to radiotherapy treatment. We aimed to develop a valid, relevant and feasible set of core QIs to measure quality of radiotherapy care in men with prostate cancer.

https://ift.tt/2KPtGfW

Real-time navigation system for sentinel lymph node biopsy in breast cancer patients using projection mapping with indocyanine green fluorescence

Abstract

Background

Inability to visualize indocyanine green fluorescence images in the surgical field limits the application of current near-infrared fluorescence imaging (NIR) systems for real-time navigation during sentinel lymph node (SLN) biopsy in breast cancer patients. The aim of this study was to evaluate the usefulness of the Medical Imaging Projection System (MIPS), which uses active projection mapping, for SLN biopsy.

Methods

A total of 56 patients (59 procedures) underwent SLN biopsy using the MIPS between March 2016 and November 2017. After SLN biopsy using the MIPS, residual SLNs were removed using a conventional NIR camera and/or radioisotope method. The primary endpoint of this study was identification rate of SLNs using the MIPS.

Results

In all procedures, at least one SLN was detected by the MIPS, giving an SLN identification rate of 100% [95% confidence interval (CI) 94–100%]. SLN biopsy was successfully performed without operating lights in all procedures. In total, 3 positive SLNs were excised using MIPS, but were not included in the additional SLNs excised by other methods. The median number of SLNs excised using the MIPS was 3 (range 1–7). Of procedures performed after preoperative systemic therapy, the median number of SLNs excised using the MIPS was 3 (range 2–6).

Conclusions

The MIPS is effective in detecting SLNs in patients with breast cancer, providing continuous and accurate projection of fluorescence signals in the surgical field, without need for operating lights, and could be useful in real-time navigation surgery for SLN biopsy.

https://ift.tt/2rwZeis

Current status of enhanced recovery after surgery (ERAS) protocol in gastrointestinal surgery

Abstract

Enhanced Recovery After Surgery (ERAS) is an evidence-based paradigm shift in perioperative care, proven to lower both recovery time and postoperative complication rates. The role of ERAS in several surgical disciplines was reviewed. In colorectal surgery, ERAS protocol is currently well established as the best care. In gastric surgery, 2014 saw an establishment of ERAS protocol for gastrectomies with resulting meta-analysis showing ERAS effectiveness. ERAS has also been shown to be beneficial in liver surgery with many centers starting implementation. The advantages of ERAS in pancreatic surgery have been strongly established, but there is still a need for large-scale, multicenter randomized trials. Barriers to implementation were analyzed, with recent studies concluding that successful implementation requires a multidisciplinary team, a willingness to change and a clear understanding of the protocol. Additionally, the difficulty in accomplishing necessary compliance to all protocol items calls for new implementation strategies. ERAS success in different patient populations was analyzed, and it was found that in the elderly population, ERAS shortened the length of hospitalization and did not lead to a higher risk of postoperative complications or readmissions. ERAS utilization in the emergency setting is possible and effective; however, certain changes to the protocol may need to be adapted. Therefore, further research is needed. There remains insufficient evidence on whether ERAS actually improves patients' course in the long term. However, since most centers started to implement ERAS protocol less than 5 years ago, more data are expected.

https://ift.tt/2wqwL2N

Current status of enhanced recovery after surgery (ERAS) protocol in gastrointestinal surgery

Abstract

Enhanced Recovery After Surgery (ERAS) is an evidence-based paradigm shift in perioperative care, proven to lower both recovery time and postoperative complication rates. The role of ERAS in several surgical disciplines was reviewed. In colorectal surgery, ERAS protocol is currently well established as the best care. In gastric surgery, 2014 saw an establishment of ERAS protocol for gastrectomies with resulting meta-analysis showing ERAS effectiveness. ERAS has also been shown to be beneficial in liver surgery with many centers starting implementation. The advantages of ERAS in pancreatic surgery have been strongly established, but there is still a need for large-scale, multicenter randomized trials. Barriers to implementation were analyzed, with recent studies concluding that successful implementation requires a multidisciplinary team, a willingness to change and a clear understanding of the protocol. Additionally, the difficulty in accomplishing necessary compliance to all protocol items calls for new implementation strategies. ERAS success in different patient populations was analyzed, and it was found that in the elderly population, ERAS shortened the length of hospitalization and did not lead to a higher risk of postoperative complications or readmissions. ERAS utilization in the emergency setting is possible and effective; however, certain changes to the protocol may need to be adapted. Therefore, further research is needed. There remains insufficient evidence on whether ERAS actually improves patients' course in the long term. However, since most centers started to implement ERAS protocol less than 5 years ago, more data are expected.

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Correction to: Secondary B-cell lymphoma associated with the Epstein-Barr virus in chronic lymphocytic leukemia patients

The article Secondary B-cell lymphoma associated with the Epstein-Barr virus in chronic lymphocytic leukemia patients.

https://ift.tt/2I2b5zv

Immature teratoma mimicking pulmonary stenosis: a case report

Immature teratoma in a mediastinal location is a rare disease that might present as a valve pathology. Germ cell tumors with mediastinal locations account for up to 6% of immature teratoma cases. We present a ...

https://ift.tt/2G02Y0y

Asymptomatic recurrence detection and cost-effectiveness in urothelial carcinoma

Abstract

For the management of muscle-invasive bladder cancer or upper tract urothelial carcinoma, the set guidelines recommend regular surveillance after radical cystectomy or radical nephroureterectomy. However, the prognostic benefit of regular oncological surveillance remains controversial in the absence of prospective studies although several retrospective studies with relatively large sample sizes have demonstrated the association between asymptomatic recurrence and better oncological outcomes. Seven out of eight studies reported that patients diagnosed with symptomatic recurrence showed significantly poorer prognosis in comparison to those diagnosed with asymptomatic recurrence. However, potential lead-time and length-time biases prevent the determination of any benefit of regular surveillance. In addition, an optimal surveillance protocol has yet to be established because conventional pathology-based protocols cannot identify the heterogenetic tumor biology of urothelial carcinoma, such as rapid- or slow-growing form of the disease. Several studies suggest that conventional pathology-based surveillance resulted in reduced cost-effectiveness. Recurrence risk-score stratified surveillance protocol including clinical and pathological factors may improve cost-effectiveness. The establishment of optimal risk stratification and surveillance strategies are required to improve the efficacy of regular oncological surveillance. Well-planned prospective studies are necessary to address the prognostic benefit of regular oncological surveillance and shared decision making.

https://ift.tt/2rrKLUi

PDXliver: a database of liver cancer patient derived xenograft mouse models

Abstract

Background

Liver cancer is the second leading cause of cancer-related deaths and characterized by heterogeneity and drug resistance. Patient-derived xenograft (PDX) models have been widely used in cancer research because they reproduce the characteristics of original tumors. However, the current studies of liver cancer PDX mice are scattered and the number of available PDX models are too small to represent the heterogeneity of liver cancer patients. To improve this situation and to complement available PDX models related resources, here we constructed a comprehensive database, PDXliver, to integrate and analyze liver cancer PDX models.

Description

Currently, PDXliver contains 116 PDX models from Chinese liver cancer patients, 51 of them were established by the in-house PDX platform and others were curated from the public literatures. These models are annotated with complete information, including clinical characteristics of patients, genome-wide expression profiles, germline variations, somatic mutations and copy number alterations. Analysis of expression subtypes and mutated genes show that PDXliver represents the diversity of human patients. Another feature of PDXliver is storing drug response data of PDX mice, which makes it possible to explore the association between molecular profiles and drug sensitivity. All data can be accessed via the Browse and Search pages. Additionally, two tools are provided to interactively visualize the omics data of selected PDXs or to compare two groups of PDXs.

Conclusion

As far as we known, PDXliver is the first public database of liver cancer PDX models. We hope that this comprehensive resource will accelerate the utility of PDX models and facilitate liver cancer research. The PDXliver database is freely available online at: http://www.picb.ac.cn/PDXliver/

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XPF polymorphism toward lung cancer susceptibility and survival in patients treated with platinum-based chemotherapy

Future Oncology, Ahead of Print.


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Temozolomide rechallenge in recurrent glioblastoma: when is it useful?

Future Oncology, Ahead of Print.


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Recent breakthroughs in metastatic uveal melanoma: a cause for optimism?

Future Oncology, Ahead of Print.


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Corrigendum

Future Oncology, Ahead of Print.


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Overexpression of Fn14 in gliomas: tumor progression and poor prognosis

Future Oncology, Ahead of Print.


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CXCL12 and CXCR4 polymorphisms and expressions in peripheral blood from patients of hepatocellular carcinoma

Future Oncology, Ahead of Print.


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Diagnostic serum vitamin D level is not a reliable prognostic factor for resectable breast cancer

Future Oncology, Ahead of Print.


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Phase II study of adjuvant chemotherapy with S1 plus oxaliplatin for Chinese patients with gastric cancer

Abstract

Background

S-1 plus oxaliplatin(SOX) has been demonstrated to be effective and well tolerated for patients with metastatic gastric cancer. We conducted this phase II study to evaluate the feasibility of SOX as adjuvant chemotherapy for gastric cancer after curative resection.

Methods

Adjuvant chemotherapy consisted of six to eight cycles of S-1 plus oxaliplatin. Oxaliplatin was administered intravenously at a dose of 130 mg/m² on day 1. S-1 was administered orally at a dose of 70 mg/m² daily from day 1 to 14 of a 3-week cycle. A total of 58 patients were enrolled in this study. The primary end point of the trial was the treatment completion rate for six cycles. Secondary endpoints were safety, 1-year and 3-year of disease free survival (DFS) and overall survival (OS).

Results

A total of 58 patients were enrolled and 54 patients have been analysed. The completion rate of six cycles was 72.2%. Grade 4 toxicities included neutropenia (1.9%) and thrombocytopenia (3.7%). Grade 3 toxicities included leukopenia (5.6%), neutropenia (24.1%), thrombocytopenia (13.0%), nausea (7.4%), vomiting 13.0%), and diarrhea (13.0%). There was no grade 3 or higher peripheral sensory neuropathy and treatment-related death. The median follow-up time was 42.4 months. 1-year and 3-year DFS rate were 85.2 and 75.9%, respectively.1-year and 3-year OS were 98.1 and 85.2%, respectively.

Conclusion

Adjuvant chemotherapy for GC with S-1 plus oxaliplatin is safe and feasible in Chinese patients. The optimal dose of oxaliplatin and optimal cycles of treatment still need to be further investigated.

Trial registration

clinicaltrials.gov identifier NCT01542294. Trial registration date: 03/02/2012.

https://ift.tt/2ryheIz

Clinical decision making in cancer care: a review of current and future roles of patient age

Abstract

Background

Patient age is among the most controversial patient characteristics in clinical decision making. In personalized cancer medicine it is important to understand how individual characteristics do affect practice and how to appropriately incorporate such factors into decision making. Some argue that using age in decision making is unethical, and how patient age should guide cancer care is unsettled. This article provides an overview of the use of age in clinical decision making and discusses how age can be relevant in the context of personalized medicine.

Methods

We conducted a scoping review, searching Pubmed for English references published between 1985 and May 2017. References concerning cancer, with patients above the age of 18 and that discussed age in relation to diagnostic or treatment decisions were included. References that were non-medical or concerning patients below the age of 18, and references that were case reports, ongoing studies or opinion pieces were excluded. Additional references were collected through snowballing and from selected reports, guidelines and articles.

Results

Three hundred and forty-seven relevant references were identified. Patient age can have many and diverse roles in clinical decision making: Contextual roles linked to access (age influences how fast patients are referred to specialized care) and incidence (association between increasing age and increasing incidence rates for cancer); patient-relevant roles linked to physiology (age-related changes in drug metabolism) and comorbidity (association between increasing age and increasing number of comorbidities); and roles related to interventions, such as treatment (older patients receive substandard care) and outcome (survival varies by age).

Conclusions

Patient age is integrated into cancer care decision making in a range of ways that makes it difficult to claim age-neutrality. Acknowledging this and being more transparent about the use of age in decision making are likely to promote better clinical decisions, irrespective of one's normative viewpoint. This overview also provides a starting point for future discussions on the appropriate role of age in cancer care decision making, which we see as crucial for harnessing the full potential of personalized medicine.

https://ift.tt/2KJ418J

PDXliver: a database of liver cancer patient derived xenograft mouse models

Abstract

Background

Liver cancer is the second leading cause of cancer-related deaths and characterized by heterogeneity and drug resistance. Patient-derived xenograft (PDX) models have been widely used in cancer research because they reproduce the characteristics of original tumors. However, the current studies of liver cancer PDX mice are scattered and the number of available PDX models are too small to represent the heterogeneity of liver cancer patients. To improve this situation and to complement available PDX models related resources, here we constructed a comprehensive database, PDXliver, to integrate and analyze liver cancer PDX models.

Description

Currently, PDXliver contains 116 PDX models from Chinese liver cancer patients, 51 of them were established by the in-house PDX platform and others were curated from the public literatures. These models are annotated with complete information, including clinical characteristics of patients, genome-wide expression profiles, germline variations, somatic mutations and copy number alterations. Analysis of expression subtypes and mutated genes show that PDXliver represents the diversity of human patients. Another feature of PDXliver is storing drug response data of PDX mice, which makes it possible to explore the association between molecular profiles and drug sensitivity. All data can be accessed via the Browse and Search pages. Additionally, two tools are provided to interactively visualize the omics data of selected PDXs or to compare two groups of PDXs.

Conclusion

As far as we known, PDXliver is the first public database of liver cancer PDX models. We hope that this comprehensive resource will accelerate the utility of PDX models and facilitate liver cancer research. The PDXliver database is freely available online at: http://www.picb.ac.cn/PDXliver/

https://ift.tt/2rxHsL9

XPF polymorphism toward lung cancer susceptibility and survival in patients treated with platinum-based chemotherapy

Future Oncology, Ahead of Print.


https://ift.tt/2IbOxIo

Temozolomide rechallenge in recurrent glioblastoma: when is it useful?

Future Oncology, Ahead of Print.


https://ift.tt/2ruEvfs

Recent breakthroughs in metastatic uveal melanoma: a cause for optimism?

Future Oncology, Ahead of Print.


https://ift.tt/2I6taII

Corrigendum

Future Oncology, Ahead of Print.


https://ift.tt/2jIBkME

Overexpression of Fn14 in gliomas: tumor progression and poor prognosis

Future Oncology, Ahead of Print.


https://ift.tt/2IbOiNu

CXCL12 and CXCR4 polymorphisms and expressions in peripheral blood from patients of hepatocellular carcinoma

Future Oncology, Ahead of Print.


https://ift.tt/2ruEc4i

Diagnostic serum vitamin D level is not a reliable prognostic factor for resectable breast cancer

Future Oncology, Ahead of Print.


https://ift.tt/2I8DMH5

Optimal collimator rotation based on the outline of multiple brain targets in VMAT

The aim of this study was to investigate the dosimetric quality in volumetric modulated arc therapy (VMAT) plans with optimal collimator angles that can represent the outline of multiple brain targets.

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Re-irradiation in lung disease by SBRT: a retrospective, single institutional study

The loco regional relapse is frequent in the lung disease. The aim of this study was to evaluate the outcomes of re-irradiation by SBRT in terms of Local Control (LC) and toxicities.

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Co-expression of NGF and PD-L1 on tumor-associated immune cells in the microenvironment of Merkel cell carcinoma

Abstract

Purpose

Merkel cell carcinoma (MCC) is a malignant neuroendocrine skin tumor with known viral association. The microenvironment and its interaction with the tumor via the programmed cell death protein 1 (PD-1) pathway are crucial for response to anti-PD-1/anti-PD-L1 treatments. However, not all patients respond, which is suggestive of additional mechanisms for tumor growth and/or persistence. We previously detected tropomyosin receptor kinase A (TrkA) expression on MCC tumor cells and, therefore, gained interest in the expression of its ligand nerve growth factor (NGF).

Methods

Thirty-nine patients from our department were studied for immunohistochemical NGF, PD-1, and PD-L1 expression and clinico-pathological correlation.

Results

PD-L1 was expressed on the tumor cells in 42%. In 95%, PD-L1 expression was also found on CD68+ spindle cells at the tumor border, which co-expressed NGF in 71%. 66% contained PD-1+ tumor infiltrating lymphocytes. PD-1, PD-L1, and NGF expression seems to correlate with a worse outcome.

Conclusions

The present study shows that PD-L1 and NGF are co-expressed on spindle cells in the microenvironment. The expression of NGF might be a link of the microenvironment to the TrkA-positive tumor cells. Whether this mechanism is critical for tumor growth and lack of response to anti-PD-1/L1 treatment has to be investigated in further studies.

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Assessing the kidney function parameters glomerular filtration rate and effective renal plasma flow with dynamic FDG-PET/MRI in healthy subjects

Abstract

Background

A method was developed to assess the kidney parameters glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) from 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) concentration behavior in kidneys, measured with positron emission tomography (PET) scans.

Twenty-four healthy adult subjects prospectively underwent dynamic simultaneous PET/magnetic resonance imaging (MRI) examination. Time activity curves (TACs) were obtained from the dynamic PET series, with the guidance of MR information. Patlak analysis was performed to determine the GFR, and based on integrals, ERPF was calculated. Results were compared to intra-individually obtained reference values determined from venous blood samples.

Results

Total kidney GFR and ERPF as estimated by dynamic PET/MRI were highly correlated to their reference values (r = 0.88/p < 0.0001 and r = 0.82/p < 0.0001, respectively) with no significant difference between their means.

Conclusions

The study is a proof of concept that GFR and ERPF can be assessed with dynamic FDG PET/MRI scans in healthy kidneys. This has advantages for patients getting a routine scan, where additional examinations for kidney function estimation could be avoided. Further studies are required for transferring this PET/MRI method to PET/CT applications.

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SPIN1, negatively regulated by miR-148/152, enhances Adriamycin resistance via upregulating drug metabolizing enzymes and transporter in breast cancer

Abstract

Background

Spindlin1 (SPIN1), a protein highly expressed in several human cancers, has been correlated with tumorigenesis and development. Alterations of drug metabolizing enzymes and drug transporters are major determinants of chemoresistance in tumor cells. However, whether the metabolizing enzymes and transporters are under the control of SPIN1 in breast cancer chemoresistance has not yet been defined.

Methods

SPIN1 expression in breast cancer cells and tissues was detected by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Chemosensitivity assays in vitro and in vivo were performed to determine the effect of SPIN1 on Adriamycin resistance. Downstream effectors of SPIN1 were screened by microarray and confirmed by qRT-PCR and Western blot. Luciferase assay and Western blot were used to identify miRNAs regulating SPIN1.

Results

We showed that SPIN1 was significantly elevated in drug-resistant breast cancer cell lines and tissues, compared with the chemosensitive ones. SPIN1 enhanced Adriamycin resistance of breast cancer cells in vitro, and downregulation of SPIN1 by miRNA could decrease Adriamycin resistance in vivo. Mechanistically, drug metabolizing enzymes and transporter CYP2C8, UGT2B4, UGT2B17 and ABCB4 were proven to be downstream effectors of SPIN1. Notably, SPIN1 was identified as a direct target of the miR-148/152 family (miR-148a-3p, miR-148b-3p and miR-152-3p). As expected, miR-148a-3p, miR-148b-3p or miR-152-3p could increase Adriamycin sensitivity in breast cancer cells in vitro. Moreover, high expression of SPIN1 or low expression of the miR-148/152 family predicted poorer survival in breast cancer patients.

Conclusions

Our results establish that SPIN1, negatively regulated by the miR-148/152 family, enhances Adriamycin resistance in breast cancer via upregulating the expression of drug metabolizing enzymes and drug transporter.

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The dysregulation of tRNAs and tRNA derivatives in cancer

Abstract

Transfer RNAs (tRNAs), traditionally considered to participate in protein translation, were interspersed in the entire genome. Recent studies suggested that dysregulation was observed in not only tRNAs, but also tRNA derivatives generated by the specific cleavage of pre- and mature tRNAs in the progression of cancer. Accumulating evidence had identified that certain tRNAs and tRNA derivatives were involved in proliferation, metastasis and invasiveness of cancer cell, as well as tumor growth and angiogenesis in several malignant human tumors. This paper reviews the importance of the dysregulation of tRNAs and tRNA derivatives during the development of cancer, such as breast cancer, lung cancer, and melanoma, aiming at a better understanding of the tumorigenesis and providing new ideas for the treatment of these cancers.

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Optimal collimator rotation based on the outline of multiple brain targets in VMAT

The aim of this study was to investigate the dosimetric quality in volumetric modulated arc therapy (VMAT) plans with optimal collimator angles that can represent the outline of multiple brain targets.

https://ift.tt/2FYuQlC

Re-irradiation in lung disease by SBRT: a retrospective, single institutional study

The loco regional relapse is frequent in the lung disease. The aim of this study was to evaluate the outcomes of re-irradiation by SBRT in terms of Local Control (LC) and toxicities.

https://ift.tt/2KJ1efL

Co-expression of NGF and PD-L1 on tumor-associated immune cells in the microenvironment of Merkel cell carcinoma

Abstract

Purpose

Merkel cell carcinoma (MCC) is a malignant neuroendocrine skin tumor with known viral association. The microenvironment and its interaction with the tumor via the programmed cell death protein 1 (PD-1) pathway are crucial for response to anti-PD-1/anti-PD-L1 treatments. However, not all patients respond, which is suggestive of additional mechanisms for tumor growth and/or persistence. We previously detected tropomyosin receptor kinase A (TrkA) expression on MCC tumor cells and, therefore, gained interest in the expression of its ligand nerve growth factor (NGF).

Methods

Thirty-nine patients from our department were studied for immunohistochemical NGF, PD-1, and PD-L1 expression and clinico-pathological correlation.

Results

PD-L1 was expressed on the tumor cells in 42%. In 95%, PD-L1 expression was also found on CD68+ spindle cells at the tumor border, which co-expressed NGF in 71%. 66% contained PD-1+ tumor infiltrating lymphocytes. PD-1, PD-L1, and NGF expression seems to correlate with a worse outcome.

Conclusions

The present study shows that PD-L1 and NGF are co-expressed on spindle cells in the microenvironment. The expression of NGF might be a link of the microenvironment to the TrkA-positive tumor cells. Whether this mechanism is critical for tumor growth and lack of response to anti-PD-1/L1 treatment has to be investigated in further studies.

https://ift.tt/2K9JAAP

Assessing the kidney function parameters glomerular filtration rate and effective renal plasma flow with dynamic FDG-PET/MRI in healthy subjects

Abstract

Background

A method was developed to assess the kidney parameters glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) from 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) concentration behavior in kidneys, measured with positron emission tomography (PET) scans.

Twenty-four healthy adult subjects prospectively underwent dynamic simultaneous PET/magnetic resonance imaging (MRI) examination. Time activity curves (TACs) were obtained from the dynamic PET series, with the guidance of MR information. Patlak analysis was performed to determine the GFR, and based on integrals, ERPF was calculated. Results were compared to intra-individually obtained reference values determined from venous blood samples.

Results

Total kidney GFR and ERPF as estimated by dynamic PET/MRI were highly correlated to their reference values (r = 0.88/p < 0.0001 and r = 0.82/p < 0.0001, respectively) with no significant difference between their means.

Conclusions

The study is a proof of concept that GFR and ERPF can be assessed with dynamic FDG PET/MRI scans in healthy kidneys. This has advantages for patients getting a routine scan, where additional examinations for kidney function estimation could be avoided. Further studies are required for transferring this PET/MRI method to PET/CT applications.

https://ift.tt/2I2GQs3

SPIN1, negatively regulated by miR-148/152, enhances Adriamycin resistance via upregulating drug metabolizing enzymes and transporter in breast cancer

Abstract

Background

Spindlin1 (SPIN1), a protein highly expressed in several human cancers, has been correlated with tumorigenesis and development. Alterations of drug metabolizing enzymes and drug transporters are major determinants of chemoresistance in tumor cells. However, whether the metabolizing enzymes and transporters are under the control of SPIN1 in breast cancer chemoresistance has not yet been defined.

Methods

SPIN1 expression in breast cancer cells and tissues was detected by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Chemosensitivity assays in vitro and in vivo were performed to determine the effect of SPIN1 on Adriamycin resistance. Downstream effectors of SPIN1 were screened by microarray and confirmed by qRT-PCR and Western blot. Luciferase assay and Western blot were used to identify miRNAs regulating SPIN1.

Results

We showed that SPIN1 was significantly elevated in drug-resistant breast cancer cell lines and tissues, compared with the chemosensitive ones. SPIN1 enhanced Adriamycin resistance of breast cancer cells in vitro, and downregulation of SPIN1 by miRNA could decrease Adriamycin resistance in vivo. Mechanistically, drug metabolizing enzymes and transporter CYP2C8, UGT2B4, UGT2B17 and ABCB4 were proven to be downstream effectors of SPIN1. Notably, SPIN1 was identified as a direct target of the miR-148/152 family (miR-148a-3p, miR-148b-3p and miR-152-3p). As expected, miR-148a-3p, miR-148b-3p or miR-152-3p could increase Adriamycin sensitivity in breast cancer cells in vitro. Moreover, high expression of SPIN1 or low expression of the miR-148/152 family predicted poorer survival in breast cancer patients.

Conclusions

Our results establish that SPIN1, negatively regulated by the miR-148/152 family, enhances Adriamycin resistance in breast cancer via upregulating the expression of drug metabolizing enzymes and drug transporter.

https://ift.tt/2KMvgiI

The dysregulation of tRNAs and tRNA derivatives in cancer

Abstract

Transfer RNAs (tRNAs), traditionally considered to participate in protein translation, were interspersed in the entire genome. Recent studies suggested that dysregulation was observed in not only tRNAs, but also tRNA derivatives generated by the specific cleavage of pre- and mature tRNAs in the progression of cancer. Accumulating evidence had identified that certain tRNAs and tRNA derivatives were involved in proliferation, metastasis and invasiveness of cancer cell, as well as tumor growth and angiogenesis in several malignant human tumors. This paper reviews the importance of the dysregulation of tRNAs and tRNA derivatives during the development of cancer, such as breast cancer, lung cancer, and melanoma, aiming at a better understanding of the tumorigenesis and providing new ideas for the treatment of these cancers.

https://ift.tt/2rxn39d

Salvage therapy outcomes for atypical meningioma

Abstract

Atypical menginomas demonstrate increased clinical aggressiveness characterized by recurrence and diminished survival. The optimal management of atypical meningioma in the recurrent setting is especially not well defined. To characterize outcomes following salvage treatment of recurrent atypical meningioma and to identify risk factors for further recurrence. Retrospective chart review was performed on 65 patients who underwent salvage treatment of atypical meningioma at a single institution. Data were analyzed using the Kaplan–Meier method and Cox proportional hazards modeling. Sixty-five patients with recurrent atypical meningioma and median imaging follow-up of 4.0 years (range 1.9–6.6 years) underwent 62 surgeries and 114 radiation treatments (RT) for salvage therapy. Salvage modality was surgery (21%), surgery/RT (25%), or RT alone (54%), associated with 2 year local freedom from recurrence (LFFR) of 36, 59, and 73%, respectively (P = 0.01). Twenty percent of patients experienced CTCAE grade ≥ 3 toxicity with salvage therapy. Thirty-nine percent of patients experienced ≥ 3 recurrences. The median disease-free survival intervals after first and second salvage treatments were 2.9 and 1.3 years, respectively. On univariate Cox analysis, prior subtotal resection, prior RT, tumor diameter > 2.5 cm, and multifocal local recurrence were associated with recurrence after salvage therapy. On multivariate logistic regression, only multifocal local recurrence was associated with further recurrence. Recurrent atypical meningioma is clinically and pathologically more aggressive than primary atypical meningioma, and the likelihood of durable local control with salvage therapy is lower. Future efforts should identify patients at risk of recurrence, and aggressive upfront treatment should be employed.

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Hormone receptors status: a strong determinant of the kinetics of brain metastases occurrence compared with HER2 status in breast cancer

Abstract

Breast cancer (BC) metastatic behavior varies according to the hormone receptors (HR) and HER2 statuses. Indeed, patients with triple-negative (TN) and HER2+ tumors are at higher risk of brain metastases (BM). The objective of this multinational cohort was to evaluate BM kinetics depending on the BC subtype. We retrospectively analyzed a series of BC patients with BM diagnosed in four European institutions (1996–2016). The delay between BC and BM diagnoses (BM-free survival) according to tumor biology was estimated with the Kaplan–Meier method. A multivariate analysis was performed using the Cox proportional hazards regression model. 649 women were included: 32.0% HER2−/HR+, 24.8% TN, 22.2% HER2+/HR− and 21.0% HER2+/HR+ tumors. Median age at BM diagnosis was 56 (25–85). In univariate analysis, BM-free survival differed depending on tumor biology: HER2−/HR+ 5.3 years (95% CI 4.6–5.9), HER2+/HR+ 4.4 years (95% CI 3.4–5.2), HER2+/HR− 2.6 years (95% CI 2.2–3.1) and TN 2.2 years (95% CI 1.9–2.7) (p < 0.001). It was significantly different between HR+ and HR- tumors (5.0 vs. 2.5 years, p < 0.001), and between HER2+ and HER2− tumors (3.2 vs. 3.8 years, p = 0.039). In multivariate analysis, estrogen-receptors (ER) and progesterone-receptors (PR) negativity, but not HER2 status, were independently associated with BM-free survival (hazard ratio = 1.36 for ER, p = 0.013, 1.31 for PR, p = 0.021, and 1.01 for HER2+ vs. HER2− tumors, p = 0.880). HR− and HER2+ tumors are overrepresented in BC patients with BM, supporting a higher risk of BM in these biological subtypes. HR status, but not HER2 status, impacts the kinetics of BM occurrence.

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The utility of “low current” stimulation threshold of intraoperative electromyography monitoring in predicting facial nerve function outcome after vestibular schwannoma surgery: a prospective cohort study of 103 large tumors

Abstract

To investigate the predictive utility of stimulation threshold (ST) of intraoperative electromyography monitoring for facial nerve (FN) outcomes among vestibular schwannoma (VS) patients postoperatively. The authors enrolled 103 unilateral VS patients who underwent surgical resection into a prospective cohort observational study from January 2013 to April 2015 in our hospital. ST values were used to categorize 81 patients into the "low current" (ST ≤ 0.05 mA) group and 22 patients into the control (ST > 0.05 mA) group. The FN function outcomes were summarized and correlated with these two groups at 1, 3, 6, and 12 months after surgery. Binary regression analysis revealed that the percentage of "good" FN outcome, defined by House-Brackmann (HB) classification of facial function (I–II), in the "low current" group was significantly higher than that of the control group (42.0 vs. 4.5% at 1 month, P = 0.015; 64.2 vs. 31.8% at 3 months, P = 0.024; 72.8 vs. 40.9% at 6 months, P = 0.021; 84.0 vs. 45.5% at 12 months, P = 0.002). Ordinal regression analysis showed that the distribution of HB scores was shifted in a favorable direction in the "low current" group at 1, 3, 6, and 12 months postoperatively. For patients with HB IV at the first month postoperative period, the recovery rate of the "low current" group was significantly higher than that of control group (P = 0.003). "Low current" can predict FN function outcomes better and has faster recovery rates than that of the control group.

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Diagnosis of non-osseous spinal metastatic disease: the role of PET/CT and PET/MRI

Abstract

The spine is the third most common site for distant metastasis in cancer patients with approximately 70% of patients with metastatic cancer having spinal involvement. Positron emission tomography (PET), combined with computed tomography (CT) or magnetic resonance imaging (MRI), has been deeply integrated in modern clinical oncology as a pivotal component of the diagnostic work-up of patients with cancer. PET is able to diagnose several neoplastic processes before any detectable morphological changes can be identified by anatomic imaging modalities alone. In this review, we discuss the role of PET/CT and PET/MRI in the diagnostic management of non-osseous metastatic disease of the spinal canal. While sometimes subtle, recognizing such disease on FDG PET/CT and PET/MRI imaging done routinely in cancer patients can guide treatment strategies to potentially prevent irreversible neurological damage.

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Surgical treatment of large vestibular schwannomas in patients with neurofibromatosis type 2: outcomes on facial nerve function and hearing preservation

Abstract

Surgical treatment of vestibular schwannoma (VS) in patients with neurofibromatosis type 2 (NF2) along with functional preservation of cranial nerves is challenging. The aim of this study was to analyze the outcomes of hearing and facial nerve function in patients with NF2 who underwent large-size VS (> 2 cm) surgery. From 2006 to 2016, one hundred and forty NF2 patients were included with 149 large-size VS resections using retrosigmoid approach. Hearing function was classified according to the American Academy of Otolaryngology–Head and Neck Surgery (AAO–HNS) criteria. Preoperative and one-year postoperative facial nerve function were both assessed using the House–Brackmann (H–B) grading scale. A multivariate logistic regression was performed to identify preoperative predictors for facial function outcomes. No operative death we noted. Total tumor removal was achieved in 82.6% of the operated VSs. The anatomical integrity of the facial nerve was preserved in 67.8% of surgeries. Good facial nerve function (H–B Grades I–III) was maintained in 49.6% of patients at 12 months after surgery. Tumor size larger than 3 cm and preoperative facial weakness related with worse outcome of facial nerve function (P < 0.001; for both). Hearing preservation surgeries were attempted in 31 ears. Class B or C hearing according to the AAO–HNS criteria was maintained in 7 ears (22.5%), and measurable hearing was maintained 11 ears (35.5%). It is challenging to maintain hearing and facial nerve function in NF2 patients with large VSs. Early surgical intervention is an appropriate choice to decrease the risk of neurological functions deficit.

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Validation of the Chowdhury overall survival score in patients with melanoma brain metastasis treated with Gamma Knife Radiosurgery

Abstract

Melanoma brain metastases (MBM) are common in patients with stage IV disease. For Gamma Knife radiosurgery (GKRS) on MBM, risk scores such as RPA and melanoma-GPA aid to identify prognostic subgroups. This study aimed to validate the overall survival (OS) risk score developed by Chowdhury et al. in our center's patient cohort. A total of 104 MBM patients were treated with GKRS between 1/1/2002 and 31/12/2014 in our institution. Patients were categorized according to RPA, melanoma-GPA and Chowdhury OS score. The Kaplan–Meier method was used to estimate overall survival, and predicted survival probabilities were calculated for calibration. Cox proportional hazards regressions were performed to identify additional risk factors. Overall, median follow-up time was 80 months, while median OS (mOS) after GKRS was 6 months. Stratified according to the Chowdhury OS score, mOS in the high, medium and low risk group was 3.4, 7.1, and 10.0 months, respectively. The addition of other patient or disease characteristics to the Chowdhury OS model did not improve its performance. The C-index of the melanoma-GPA was 0.46 while the Chowdhury OS had an index of 0.67. In comparison with the RPA and melanoma-GPA, the Chowdhury OS score more accurately distinguished between separate risk groups among patients with MBM treated with GKRS. Contrary to the original study by Chowdhury, follow-up time was sufficient here for the low-risk group to reach the mOS time of 10 months.

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Cost-effectiveness of the long-term use of temozolomide for treating newly diagnosed glioblastoma in Germany

Abstract

Concomitant radiochemotherapy followed by six cycles of temozolomide (= short term) is considered as standard therapy for adults with newly diagnosed glioblastoma. In contrast, open-end administration of temozolomide until progression (= long-term) is proposed by some authors as a viable alternative. We aimed to determine the cost-effectiveness of long-term temozolomide therapy for patients newly diagnosed with glioblastoma compared to standard therapy. A Markov model was constructed to compare medical costs and clinical outcomes for both therapy types over a time horizon of 60 months. Transition probabilities for standard therapy were calculated from randomized controlled trial data by Stupp et al. The data for long-term temozolomide therapy was collected by matching a cohort treated in the Department of Neurosurgery at Jena University Hospital. Health utilities were obtained from a previous cost utility study. The cost perspective was based on health insurance. The base case analysis showed a median overall survival of 17.1 months and a median progression-free survival of 7.4 months for patients in the long-term temozolomide therapy arm. The cost-effectiveness analysis using all base case parameters in a time-dependent Markov model resulted in an incremental effectiveness of 0.022 quality-adjusted life-years (QALYs). The incremental cost-effectiveness ratio (ICER) was €351,909/QALY. Sensitivity analyses showed that parameters with the most influence on ICER were the health state utility of progression in both therapy arms. Although open-ended temozolomide therapy is very expensive, the ICER of this therapy is comparable to that of the standard temozolomide therapy for patients newly diagnosed with glioblastoma.

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Salvage therapy outcomes for atypical meningioma

Abstract

Atypical menginomas demonstrate increased clinical aggressiveness characterized by recurrence and diminished survival. The optimal management of atypical meningioma in the recurrent setting is especially not well defined. To characterize outcomes following salvage treatment of recurrent atypical meningioma and to identify risk factors for further recurrence. Retrospective chart review was performed on 65 patients who underwent salvage treatment of atypical meningioma at a single institution. Data were analyzed using the Kaplan–Meier method and Cox proportional hazards modeling. Sixty-five patients with recurrent atypical meningioma and median imaging follow-up of 4.0 years (range 1.9–6.6 years) underwent 62 surgeries and 114 radiation treatments (RT) for salvage therapy. Salvage modality was surgery (21%), surgery/RT (25%), or RT alone (54%), associated with 2 year local freedom from recurrence (LFFR) of 36, 59, and 73%, respectively (P = 0.01). Twenty percent of patients experienced CTCAE grade ≥ 3 toxicity with salvage therapy. Thirty-nine percent of patients experienced ≥ 3 recurrences. The median disease-free survival intervals after first and second salvage treatments were 2.9 and 1.3 years, respectively. On univariate Cox analysis, prior subtotal resection, prior RT, tumor diameter > 2.5 cm, and multifocal local recurrence were associated with recurrence after salvage therapy. On multivariate logistic regression, only multifocal local recurrence was associated with further recurrence. Recurrent atypical meningioma is clinically and pathologically more aggressive than primary atypical meningioma, and the likelihood of durable local control with salvage therapy is lower. Future efforts should identify patients at risk of recurrence, and aggressive upfront treatment should be employed.

https://ift.tt/2Iaz4bE

Hormone receptors status: a strong determinant of the kinetics of brain metastases occurrence compared with HER2 status in breast cancer

Abstract

Breast cancer (BC) metastatic behavior varies according to the hormone receptors (HR) and HER2 statuses. Indeed, patients with triple-negative (TN) and HER2+ tumors are at higher risk of brain metastases (BM). The objective of this multinational cohort was to evaluate BM kinetics depending on the BC subtype. We retrospectively analyzed a series of BC patients with BM diagnosed in four European institutions (1996–2016). The delay between BC and BM diagnoses (BM-free survival) according to tumor biology was estimated with the Kaplan–Meier method. A multivariate analysis was performed using the Cox proportional hazards regression model. 649 women were included: 32.0% HER2−/HR+, 24.8% TN, 22.2% HER2+/HR− and 21.0% HER2+/HR+ tumors. Median age at BM diagnosis was 56 (25–85). In univariate analysis, BM-free survival differed depending on tumor biology: HER2−/HR+ 5.3 years (95% CI 4.6–5.9), HER2+/HR+ 4.4 years (95% CI 3.4–5.2), HER2+/HR− 2.6 years (95% CI 2.2–3.1) and TN 2.2 years (95% CI 1.9–2.7) (p < 0.001). It was significantly different between HR+ and HR- tumors (5.0 vs. 2.5 years, p < 0.001), and between HER2+ and HER2− tumors (3.2 vs. 3.8 years, p = 0.039). In multivariate analysis, estrogen-receptors (ER) and progesterone-receptors (PR) negativity, but not HER2 status, were independently associated with BM-free survival (hazard ratio = 1.36 for ER, p = 0.013, 1.31 for PR, p = 0.021, and 1.01 for HER2+ vs. HER2− tumors, p = 0.880). HR− and HER2+ tumors are overrepresented in BC patients with BM, supporting a higher risk of BM in these biological subtypes. HR status, but not HER2 status, impacts the kinetics of BM occurrence.

https://ift.tt/2ruCAqX

The utility of “low current” stimulation threshold of intraoperative electromyography monitoring in predicting facial nerve function outcome after vestibular schwannoma surgery: a prospective cohort study of 103 large tumors

Abstract

To investigate the predictive utility of stimulation threshold (ST) of intraoperative electromyography monitoring for facial nerve (FN) outcomes among vestibular schwannoma (VS) patients postoperatively. The authors enrolled 103 unilateral VS patients who underwent surgical resection into a prospective cohort observational study from January 2013 to April 2015 in our hospital. ST values were used to categorize 81 patients into the "low current" (ST ≤ 0.05 mA) group and 22 patients into the control (ST > 0.05 mA) group. The FN function outcomes were summarized and correlated with these two groups at 1, 3, 6, and 12 months after surgery. Binary regression analysis revealed that the percentage of "good" FN outcome, defined by House-Brackmann (HB) classification of facial function (I–II), in the "low current" group was significantly higher than that of the control group (42.0 vs. 4.5% at 1 month, P = 0.015; 64.2 vs. 31.8% at 3 months, P = 0.024; 72.8 vs. 40.9% at 6 months, P = 0.021; 84.0 vs. 45.5% at 12 months, P = 0.002). Ordinal regression analysis showed that the distribution of HB scores was shifted in a favorable direction in the "low current" group at 1, 3, 6, and 12 months postoperatively. For patients with HB IV at the first month postoperative period, the recovery rate of the "low current" group was significantly higher than that of control group (P = 0.003). "Low current" can predict FN function outcomes better and has faster recovery rates than that of the control group.

https://ift.tt/2IbCpXS

Diagnosis of non-osseous spinal metastatic disease: the role of PET/CT and PET/MRI

Abstract

The spine is the third most common site for distant metastasis in cancer patients with approximately 70% of patients with metastatic cancer having spinal involvement. Positron emission tomography (PET), combined with computed tomography (CT) or magnetic resonance imaging (MRI), has been deeply integrated in modern clinical oncology as a pivotal component of the diagnostic work-up of patients with cancer. PET is able to diagnose several neoplastic processes before any detectable morphological changes can be identified by anatomic imaging modalities alone. In this review, we discuss the role of PET/CT and PET/MRI in the diagnostic management of non-osseous metastatic disease of the spinal canal. While sometimes subtle, recognizing such disease on FDG PET/CT and PET/MRI imaging done routinely in cancer patients can guide treatment strategies to potentially prevent irreversible neurological damage.

https://ift.tt/2jJ70BF

Surgical treatment of large vestibular schwannomas in patients with neurofibromatosis type 2: outcomes on facial nerve function and hearing preservation

Abstract

Surgical treatment of vestibular schwannoma (VS) in patients with neurofibromatosis type 2 (NF2) along with functional preservation of cranial nerves is challenging. The aim of this study was to analyze the outcomes of hearing and facial nerve function in patients with NF2 who underwent large-size VS (> 2 cm) surgery. From 2006 to 2016, one hundred and forty NF2 patients were included with 149 large-size VS resections using retrosigmoid approach. Hearing function was classified according to the American Academy of Otolaryngology–Head and Neck Surgery (AAO–HNS) criteria. Preoperative and one-year postoperative facial nerve function were both assessed using the House–Brackmann (H–B) grading scale. A multivariate logistic regression was performed to identify preoperative predictors for facial function outcomes. No operative death we noted. Total tumor removal was achieved in 82.6% of the operated VSs. The anatomical integrity of the facial nerve was preserved in 67.8% of surgeries. Good facial nerve function (H–B Grades I–III) was maintained in 49.6% of patients at 12 months after surgery. Tumor size larger than 3 cm and preoperative facial weakness related with worse outcome of facial nerve function (P < 0.001; for both). Hearing preservation surgeries were attempted in 31 ears. Class B or C hearing according to the AAO–HNS criteria was maintained in 7 ears (22.5%), and measurable hearing was maintained 11 ears (35.5%). It is challenging to maintain hearing and facial nerve function in NF2 patients with large VSs. Early surgical intervention is an appropriate choice to decrease the risk of neurological functions deficit.

https://ift.tt/2I8qr1t

Validation of the Chowdhury overall survival score in patients with melanoma brain metastasis treated with Gamma Knife Radiosurgery

Abstract

Melanoma brain metastases (MBM) are common in patients with stage IV disease. For Gamma Knife radiosurgery (GKRS) on MBM, risk scores such as RPA and melanoma-GPA aid to identify prognostic subgroups. This study aimed to validate the overall survival (OS) risk score developed by Chowdhury et al. in our center's patient cohort. A total of 104 MBM patients were treated with GKRS between 1/1/2002 and 31/12/2014 in our institution. Patients were categorized according to RPA, melanoma-GPA and Chowdhury OS score. The Kaplan–Meier method was used to estimate overall survival, and predicted survival probabilities were calculated for calibration. Cox proportional hazards regressions were performed to identify additional risk factors. Overall, median follow-up time was 80 months, while median OS (mOS) after GKRS was 6 months. Stratified according to the Chowdhury OS score, mOS in the high, medium and low risk group was 3.4, 7.1, and 10.0 months, respectively. The addition of other patient or disease characteristics to the Chowdhury OS model did not improve its performance. The C-index of the melanoma-GPA was 0.46 while the Chowdhury OS had an index of 0.67. In comparison with the RPA and melanoma-GPA, the Chowdhury OS score more accurately distinguished between separate risk groups among patients with MBM treated with GKRS. Contrary to the original study by Chowdhury, follow-up time was sufficient here for the low-risk group to reach the mOS time of 10 months.

https://ift.tt/2rv6xY2

Cost-effectiveness of the long-term use of temozolomide for treating newly diagnosed glioblastoma in Germany

Abstract

Concomitant radiochemotherapy followed by six cycles of temozolomide (= short term) is considered as standard therapy for adults with newly diagnosed glioblastoma. In contrast, open-end administration of temozolomide until progression (= long-term) is proposed by some authors as a viable alternative. We aimed to determine the cost-effectiveness of long-term temozolomide therapy for patients newly diagnosed with glioblastoma compared to standard therapy. A Markov model was constructed to compare medical costs and clinical outcomes for both therapy types over a time horizon of 60 months. Transition probabilities for standard therapy were calculated from randomized controlled trial data by Stupp et al. The data for long-term temozolomide therapy was collected by matching a cohort treated in the Department of Neurosurgery at Jena University Hospital. Health utilities were obtained from a previous cost utility study. The cost perspective was based on health insurance. The base case analysis showed a median overall survival of 17.1 months and a median progression-free survival of 7.4 months for patients in the long-term temozolomide therapy arm. The cost-effectiveness analysis using all base case parameters in a time-dependent Markov model resulted in an incremental effectiveness of 0.022 quality-adjusted life-years (QALYs). The incremental cost-effectiveness ratio (ICER) was €351,909/QALY. Sensitivity analyses showed that parameters with the most influence on ICER were the health state utility of progression in both therapy arms. Although open-ended temozolomide therapy is very expensive, the ICER of this therapy is comparable to that of the standard temozolomide therapy for patients newly diagnosed with glioblastoma.

https://ift.tt/2I7dvc0

A robust response to combination immune checkpoint inhibitor therapy in HPV-related small cell cancer: a case report

Abstract

Background

Human papillomavirus-related small cell carcinoma of the head and neck is an extremely rare, aggressive subtype with poor outcomes. Therapeutic options are limited and are largely adopted from small cell lung cancer treatment paradigms.

Case presentation

This report describes a 69-year old male who was diagnosed of HPV-related oropharyngeal cancer with mixed small cell and squamous cell pathology which was clinically aggressive and progressed through multimodal platinum-based therapies. Upon manifestation of worsening metastatic disease, the patient was initiated on a combination of ipilimumab and nivolumab. Within 2 months of starting immunotherapy, a robust partial response was observed. During the treatment course, the patient developed immune-related adverse effects including new diabetes mellitus, colitis, and hypothyroidism. The disease-specific survival was 26 months.

Conclusion

Combination immunotherapy may be an attractive option for HPV-related small cell head and neck cancers resistant to other treatment modalities and thus warrants further evaluation.

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Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden

Abstract

Background

Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma.

Methods

Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8⁺ T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario.

Results

PD-L1 positivity ≥1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity.

Conclusions

In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden.

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A robust response to combination immune checkpoint inhibitor therapy in HPV-related small cell cancer: a case report

Abstract

Background

Human papillomavirus-related small cell carcinoma of the head and neck is an extremely rare, aggressive subtype with poor outcomes. Therapeutic options are limited and are largely adopted from small cell lung cancer treatment paradigms.

Case presentation

This report describes a 69-year old male who was diagnosed of HPV-related oropharyngeal cancer with mixed small cell and squamous cell pathology which was clinically aggressive and progressed through multimodal platinum-based therapies. Upon manifestation of worsening metastatic disease, the patient was initiated on a combination of ipilimumab and nivolumab. Within 2 months of starting immunotherapy, a robust partial response was observed. During the treatment course, the patient developed immune-related adverse effects including new diabetes mellitus, colitis, and hypothyroidism. The disease-specific survival was 26 months.

Conclusion

Combination immunotherapy may be an attractive option for HPV-related small cell head and neck cancers resistant to other treatment modalities and thus warrants further evaluation.

https://ift.tt/2FZsbbl

Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden

Abstract

Background

Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma.

Methods

Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8⁺ T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario.

Results

PD-L1 positivity ≥1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity.

Conclusions

In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden.

https://ift.tt/2ItKrPt

Associations of dietary intake and supplement use with post-therapy cognitive recovery in breast cancer survivors

Abstract

Purpose

Cognitive impairment induced by cancer therapy is common and can be long lasting after completion of therapy. Little is known on factors that influence recovery from the impairment. We evaluated the associations of dietary intake and supplement use with post-therapy cognitive recovery in a large cohort of breast cancer survivors.

Methods

This study included 1047 breast cancer patients aged 20–75 who were recruited to the Shanghai Breast Cancer Survival Study between 2002 and 2006 at approximately 6.5 months post-cancer diagnosis. Two cognitive assessments covering immediate memory, delayed memory, verbal fluency, and attention, were conducted at 18 and 36 months post-diagnosis. We used food frequency questionnaire to collect information on their dietary intake and supplement use between 18 and 36 months post-diagnosis. Linear regression models were used to examine the associations of dietary intake and supplement use with mean cognitive scores at 36 months post-diagnosis and with differences in cognitive scores between 18 and 36 months post-diagnosis.

Results

Higher vegetable, fruit and fish intake, supplementation with vitamin B and vitamin E, and tea drinking were associated with higher cognitive scores, while alcohol drinking was associated with lower cognitive scores at 36 months post-diagnosis. Vegetable intake was positively associated with improvement in verbal fluency, while tea drinking and fish oil supplementation were associated with greater improvements in delayed memory between 18 and 36 months post-diagnosis.

Conclusions

Our results indicate that higher vegetable intake, tea drinking, and fish oil supplementation may help post-therapy cognitive recovery for cancer patients.

https://ift.tt/2FYtuYh

Unmasking of intracranial metastatic melanoma during ipilimumab/nivolumab therapy: case report and literature review

Abstract

Background

While data from several studies over the last decade has demonstrated that introduction of immunologic checkpoint blockage therapy with anti-CTLA-4/PD-1 drugs leads to improved survival in metastatic melanoma patients, relatively little is known about brain-specific therapeutic response and adverse events in the context of immunotherapeutic treatment of intracranial disease. Here we report two independent cases of new intracranial metastases presenting after initiation of combined checkpoint blockade Ipilimumab and Nivolumab for recurrent metastatic melanoma in the context of positive systemic disease response.

Case presentation

Case #1: A 43-year-old Caucasian male with Stage III melanoma of the left knee had subsequent nodal, hepatic and osseous metastases and was started on ipilimumab/nivolumab. He developed an intractable headache one week later. MRI revealed new enhancing and hemorrhagic brain metastases. After 6 weeks of immunotherapy, there was interval hemorrhage of a dominant intracranial lesion but substantial improvement in systemic metastatic disease. Durable, near complete intracranial and systemic response was achieved after completion of both induction and maintenance immunotherapy.

Case #2: A 58-year old Caucasian woman with stage II melanoma of the right index finger developed cutaneous, pulmonary and hepatic metastases within 4 months of adjuvant radiation. Although combined checkpoint blockade resulted in improvement in both cutaneous and systemic disease, brain MR performed for eye discomfort demonstrated new enhancing and hemorrhagic brain metastases. Serial MR imaging five months later revealed only a solitary focus of brain enhancement with continued improved systemic disease.

Conclusions

These cases raise the question of whether the initial immune activation and modulation of the blood brain barrier by Ipilimumab/Nivolumab somehow "unmasks" previously clinically silent metastatic disease, rather than representing new or progressive metastatic disease. An overview of currently available literature discussing the role of immune checkpoint blockade in the treatment of intracranial metastatic melanoma will be provided, as well as discussion highlighting the need for future work elucidating the response of brain metastases to anti-CTLA/PD-1 drugs and documentation of brain-specific adverse events.

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Predictors of adverse pathologic features after radical prostatectomy in low-risk prostate cancer

Abstract

Background

Prostate-specific antigen (PSA) screening more frequently detects early stage prostate cancer (PC). However, adverse pathologic features (APFs) after radical prostatectomy (RP) in low-risk PC occur. Previous related studies had utilized outdated staging criteria or small sample cohorts. In this study, we analyzed predictors of APFs after RP in low-risk PC using classification under the current criteria.

Materials and methods

We retrospectively reviewed medical records of 546 low-risk PC patients who had undergone RP. Low-risk PC was defined as PC with clinical T1–T2a, Gleason score ≤ 6, and PSA levels < 10 ng/mL. Clinical and pathological parameters were analyzed to predict APFs. APFs were defined as extracapsular extension (ECE), seminal vesicle invasion (SVI), or positive surgical margins (PSM). We analyzed our data using univariable and multivariable logistic regression analyses, as well as receiver operator characteristics to predict APFs.

Results

Among 546 patients, ECE, SVI, and PSM were present in 199 (36.4%), 8 (1.5%), and 179 cases (32.8%), respectively. PSM had a significant correlation with preoperative high PSA levels and number of positive cores obtained. ECE/SVI was also significantly correlated with PSA levels and number of positive cores. As a result, presence of APFs after RP was associated with high PSA levels and large number of positive cores. PSA > 4.5 ng/mL and number of positive cores > 2 in low-risk PC were significantly associated with APFs, and suggested as cut-off values for predicting APFs.

Conclusions

PSA > 4.5 ng/mL and number of positive cores > 2 in low-risk PC were associated with presence of APFs and patients with such records should be considered carefully to provide active surveillance.

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18 FDG-PET-CT identifies histopathological non-responders after neoadjuvant chemotherapy in locally advanced gastric and cardia cancer: cohort study

Abstract

Background

Pathologic response to neoadjuvant chemotherapy (neoCTX) is a prognostic factor in many cancer types, and early prediction would help to modify treatment. In patients with gastric and esophagogastric junction (AEG) cancer, the accuracy of FDG PET-CT to predict early pathologic response after neoadjuvant chemotherapy (neoCTX) is currently not known.

Methods

From a consecutive cohort of 72 patients, 44 patients with resectable, locally-advanced gastric cancer or AEG Siewert type II and III received neoCTX after primary staging with endoscopic ultrasound, PET-CT and laparoscopy. Overall, 14 patients did not show FDG uptake, and the remaining 30 were restaged by PET-CT 14 days after the first cycle of neoCTX. Metabolic response was defined as decrease of tumor standardized uptake value (SUV) by ≥35%. Major pathologic regression was defined as less than 10% residual tumor cells.

Results

Metabolic response after neoCTX was detected in 20/30 (66.7%), and non-response in 10/30 (33.3%) patients. Among metabolic responders, n = 10 (50%) showed major and n = 10 (50%) minor pathologic regression. In non-responders, n = 9 (90%) had minor and 1 (10%) a major pathologic regression. This resulted in a sensitivity of 90.9%, specificity 47.3%, positive predictive value 50%, negative predictive value 90% and accuracy of 63.3%.

Conclusion

Response PET-CT after the first cycle of neoCTX does not accurately predict overall pathologic response. However, PET-CT reliably detects non-responders, and identifies patients who should either immediately proceed to resection or receive a modified multimodality therapy.

Trial registration

The trial was registered and approved by local ethics committee PB_2016–00769.

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