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Archive for the ‘Imaging-based Cancer Patient Management’ Category


cancerandoncologyseriesccover

Series C: e-Books on Cancer & Oncology

Series C Content Consultant: Larry H. Bernstein, MD, FCAP

 

VOLUME ONE 

Cancer Biology and Genomics

for

Disease Diagnosis

2015

http://www.amazon.com/dp/B013RVYR2K

Stephen J. Williams, PhD, Senior Editor

sjwilliamspa@comcast.net

Tilda Barliya, PhD, Editor

tildabarliya@gmail.com

Ritu Saxena, PhD, Editor

ritu.uab@gmail.com

Leaders in Pharmaceutical Business Intelligence 

Part I

Historical Perspective of Cancer Demographics, Etiology, and Progress in Research

Chapter 1:  The Occurrence of Cancer in World Populations

1.1   Understanding Cancer

Prabodh Kandala, PhD

1.2  Cancer Metastasis

Tilda Barliya, PhD

1.3      2013 Perspective on “War on Cancer” on December 23, 1971

Aviva Lev-Ari, PhD, RN

1.4   Global Burden of Cancer Treatment & Women Health: Market Access & Cost Concerns

Aviva Lev-Ari, PhD, RN

1.5    The Importance of Cancer Prevention Programs: New Perspectives for Fighting Cancer

Ziv Raviv, PhD

1.6      The “Cancer establishments” examined by James Watson, co-discoverer of DNA w/Crick, 4/1953,  

Larry H Bernstein, MD, FCAP

1.7      New Ecosystem of Cancer Research: Cross Institutional Team Science

Aviva Lev-Ari, PhD, RN

1.8       Cancer Innovations from across the Web

Larry H Bernstein, MD, FCAP

1.9         Exploring the role of vitamin C in Cancer therapy

Ritu Saxena PhD

1.10        Relation of Diet and Cancer

Sudipta Saha, PhD

1.11      Association between Non-melanoma Skin Cancer and subsequent Primary Cancers in White Population 

Aviva Lev-Ari, PhD, RN

1.12       Men With Prostate Cancer More Likely to Die from Other Causes

Prabodh Kandala, PhD

1.13      Battle of Steve Jobs and Ralph Steinman with Pancreatic Cancer: How we Lost

Ritu Saxena, PhD

Chapter 2.  Rapid Scientific Advances Changes Our View on How Cancer Forms

2.1     All Cancer Cells Are Not Created Equal: Some Cell Types Control Continued Tumor Growth, Others Prepare the Way for Metastasis 

Prabodh Kandala, PhD

2.2      Hold on. Mutations in Cancer do Good

Prabodh Kandala, PhD

2.3       Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?

Larry H Bernstein, MD, FCAP

2.4          Naked Mole Rats Cancer-Free

Larry H Bernstein, MD, FCAP

2.5           Zebrafish—Susceptible to Cancer

Larry H Bernstein, MD, FCAP

2.6         Demythologizing Sharks, Cancer, and Shark Fins,

Larry H Bernstein, MD, FCAP

2.7       Tumor Cells’ Inner Workings Predict Cancer Progression

Prabodh Kandala, PhD

2.8      In Focus: Identity of Cancer Stem Cells

Ritu Saxena, PhD

2.9      In Focus: Circulating Tumor Cells

Ritu Saxena, PhD

2.10     Rewriting the Mathematics of Tumor Growth; Teams Use Math Models to Sort Drivers from Passengers 

Stephen J. Williams, PhD

2.11     Role of Primary Cilia in Ovarian Cancer

Aashir Awan, PhD

Chapter 3:  A Genetic Basis and Genetic Complexity of Cancer Emerges

3.1       The Binding of Oligonucleotides in DNA and 3-D Lattice Structures

Larry H Bernstein, MD, FCAP

3.2      How Mobile Elements in “Junk” DNA Promote Cancer. Part 1: Transposon-mediated Tumorigenesis. 

Stephen J. Williams, PhD

3.3      DNA: One Man’s Trash is another Man’s Treasure, but there is no JUNK after all

Demet Sag, PhD

3.4 Issues of Tumor Heterogeneity

3.4.1    Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

Stephen J. Williams, PhD

3.4.2       Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn

Stephen J. Williams, PhD

3.5        arrayMap: Genomic Feature Mining of Cancer Entities of Copy Number Abnormalities (CNAs) Data

Aviva Lev-Ari, PhD, RN

3.6        HBV and HCV-associated Liver Cancer: Important Insights from the Genome

Ritu Saxena, PhD

3.7      Salivary Gland Cancer – Adenoid Cystic Carcinoma: Mutation Patterns: Exome- and Genome-Sequencing @ Memorial Sloan-Kettering Cancer Center

Aviva Lev-Ari, PhD, RN

3.8         Gastric Cancer: Whole-genome Reconstruction and Mutational Signatures

Aviva Lev-Ari, PhD, RN

3.9        Missing Gene may Drive more than a quarter of Breast Cancers

Aviva Lev-Ari, PhD, RN

3.10     Critical Gene in Calcium Reabsorption: Variants in the KCNJ and SLC12A1 genes – Calcium Intake and Cancer Protection

Aviva Lev-Ari,PhD, RN

Chapter 4: How Epigenetic and Metabolic Factors Affect Tumor Growth

4.1    Epigenetics

4.1.1     The Magic of the Pandora’s Box : Epigenetics and Stemness with Long non-coding RNAs (lincRNA)

Demet Sag, PhD, CRA, GCP

4.1.2     Stomach Cancer Subtypes Methylation-based identified by Singapore-Led Team

Aviva Lev-Ari, PhD, RN

4.1.3     The Underappreciated EpiGenome

Demet Sag, Ph.D., CRA, GCP

4.1.4     Differentiation Therapy – Epigenetics Tackles Solid Tumors

Stephen J. Williams, PhD

4.1.5      “The SILENCE of the Lambs” Introducing The Power of Uncoded RNA

Demet Sag, Ph.D., CRA, GCP

4.1.6      DNA Methyltransferases – Implications to Epigenetic Regulation and Cancer Therapy Targeting: James Shen, PhD

Aviva Lev-Ari, PhD, RN

4.2   Metabolism

4.2.1      Mitochondria and Cancer: An overview of mechanisms

Ritu Saxena, PhD

4.2.2     Bioenergetic Mechanism: The Inverse Association of Cancer and Alzheimer’s

Aviva Lev-Ari, PhD, RN

4.2.3      Crucial role of Nitric Oxide in Cancer

Ritu Saxena, PhD

4.2.4      Nitric Oxide Mitigates Sensitivity of Melanoma Cells to Cisplatin

Stephen J. Williams, PhD

4.2.5      Increased risks of obesity and cancer, Decreased risk of type 2 diabetes: The role of Tumor-suppressor phosphatase and tensin homologue (PTEN)

Aviva Lev-Ari, PhD, RN

4.2.6      Lipid Profile, Saturated Fats, Raman Spectrosopy, Cancer Cytology

Larry H Bernstein, MD, FCAP

4.3     Other Factors Affecting Tumor Growth

4.3.1      Squeezing Ovarian Cancer Cells to Predict Metastatic Potential: Cell Stiffness as Possible Biomarker

Prabodh Kandala, PhD

4.3.2      Prostate Cancer: Androgen-driven “Pathomechanism” in Early-onset Forms of the Disease

Aviva Lev-Ari, PhD, RN

Chapter 5: Advances in Breast and Gastrointestinal Cancer Research Supports Hope for Cure

5.1 Breast Cancer

5.1.1      Cell Movement Provides Clues to Aggressive Breast Cancer

Prabodh Kandala, PhD

5.1.2    Identifying Aggressive Breast Cancers by Interpreting the Mathematical Patterns in the Cancer Genome

Prabodh Kandala, PhD

5.1.3  Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment

Aviva Lev-Ari, PhD, RN

5.1.4       BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

Sudipta Saha, PhD

5.1.5      Breast Cancer and Mitochondrial Mutations

Larry H Bernstein, MD, FCAP

5.1.6      MIT Scientists Identified Gene that Controls Aggressiveness in Breast Cancer Cells

Aviva Lev-Ari PhD RN

5.1.7       “The Molecular pathology of Breast Cancer Progression”

Tilda Barliya, PhD

5.1.8       In focus: Triple Negative Breast Cancer

Ritu Saxena, PhD

5.1.9       Automated Breast Ultrasound System (‘ABUS’) for full breast scanning: The beginning of structuring a solution for an acute need!

Dror Nir, PhD

5.1.10       State of the art in oncologic imaging of breast.

Dror Nir, PhD

 

5.2 Gastrointestinal Cancer

5.2.1         Colon Cancer

Tilda Barliya, PhD

5.2.2      PIK3CA mutation in Colorectal Cancer may serve as a Predictive Molecular Biomarker for adjuvant Aspirin therapy

Aviva Lev-Ari, PhD, RN

5.2.3     State of the art in oncologic imaging of colorectal cancers.

Dror Nir, PhD

5.2.4     Pancreatic Cancer: Genetics, Genomics and Immunotherapy

Tilda Barliya, PhD

5.2.5     Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed

Aviva Lev-Ari, PhD, RN

Part II

Advent of Translational Medicine, “omics”, and Personalized Medicine Ushers in New Paradigms in Cancer Treatment and Advances in Drug Development

Chapter 6:  Treatment Strategies

6.1 Marketed and Novel Drugs

Breast Cancer                                   

6.1.1     Treatment for Metastatic HER2 Breast Cancer

Larry H Bernstein MD, FCAP

6.1.2          Aspirin a Day Tied to Lower Cancer Mortality

Aviva Lev-Ari, PhD, RN

6.1.3       New Anti-Cancer Drug Developed

Prabodh Kandala, Ph.D.

6.1.4         Pfizer’s Kidney Cancer Drug Sutent Effectively caused REMISSION to Adult Acute Lymphoblastic Leukemia (ALL)

Aviva Lev-Ari ,PhD, RN

6.1.5     “To Die or Not To Die” – Time and Order of Combination drugs for Triple Negative Breast Cancer cells: A Systems Level Analysis

Anamika Sarkar, PhD. and Ritu Saxena, PhD

Melanoma

6.1.6    “Thymosin alpha1 and melanoma”

Tilda Barliya, PhD

Leukemia

6.1.7    Acute Lymphoblastic Leukemia and Bone Marrow Transplantation

Tilda Barliya PhD

6.2 Natural agents

Prostate Cancer                 

6.2.1      Scientists use natural agents for prostate cancer bone metastasis treatment

Ritu Saxena, PhD

Breast Cancer

6.2.2        Marijuana Compound Shows Promise In Fighting Breast Cancer

Prabodh Kandala, PhD

Ovarian Cancer                  

6.2.3        Dimming ovarian cancer growth

Prabodh Kandala, PhD

6.3 Potential Therapeutic Agents

Gastric Cancer                 

6.3.1       β Integrin emerges as an important player in mitochondrial dysfunction associated Gastric Cancer

Ritu Saxena, PhD

6.3.2      Arthritis, Cancer: New Screening Technique Yields Elusive Compounds to Block Immune-Regulating Enzyme

Prabodh Kandala, PhD

Pancreatic Cancer                                   

6.3.3    Usp9x: Promising therapeutic target for pancreatic cancer

Ritu Saxena, PhD

Breast Cancer                 

6.3.4       Breast Cancer, drug resistance, and biopharmaceutical targets

Larry H Bernstein, MD, FCAP

Prostate Cancer

6.3.5        Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition

Stephen J. Williams, PhD

Glioblastoma

6.3.6      Gamma Linolenic Acid (GLA) as a Therapeutic tool in the Management of Glioblastoma

Raphael Nir, PhD, MSM, MSc

6.3.7   Akt inhibition for cancer treatment, where do we stand today?

Ziv Raviv, PhD

Chapter 7:  Personalized Medicine and Targeted Therapy

7.1.1        Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders

Aviva Lev-Ari, PhD, RN

7.1.2      Personalized medicine-based cure for cancer might not be far away

Ritu Saxena, PhD

7.1.3      Personalized medicine gearing up to tackle cancer

Ritu Saxena, PhD

7.1.4       Cancer Screening at Sourasky Medical Center Cancer Prevention Center in Tel-Aviv

Ziv Raviv, PhD

7.1.5       Inspiration From Dr. Maureen Cronin’s Achievements in Applying Genomic Sequencing to Cancer Diagnostics

Aviva Lev-Ari, PhD, RN

7.1.6       Personalized Medicine: Cancer Cell Biology and Minimally Invasive Surgery (MIS)

Aviva Lev-Ari, PhD, RN

7.2 Personalized Medicine and Genomics

7.2.1       Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Aviva Lev-Ari, PhD, RN

7.2.2       Whole exome somatic mutations analysis of malignant melanoma contributes to the development of personalized cancer therapy for this disease

Ziv Raviv, PhD

7.2.3       Genotype-based Analysis for Cancer Therapy using Large-scale Data Modeling: Nayoung Kim, PhD(c)

Aviva Lev-Ari, PhD, RN

7.2.4         Cancer Genomic Precision Therapy: Digitized Tumor’s Genome (WGSA) Compared with Genome-native Germ Line: Flash-frozen specimen and Formalin-fixed paraffin-embedded Specimen Needed

Aviva Lev-Ari, PhD, RN

7.2.5         LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment: Part 2

Aviva Lev-Ari, PhD, RN

7.2.6       Ethical Concerns in Personalized Medicine: BRCA1/2 Testing in Minors and Communication of Breast Cancer Risk

Stephen J. Williams, PhD

7.3  Personalized Medicine and Targeted Therapy

7.3.1     The Development of siRNA-Based Therapies for Cancer

Ziv Raviv, PhD

7.3.2       mRNA interference with cancer expression

Larry H Bernstein, MD, FCAP

7.3.3       CD47: Target Therapy for Cancer

Tilda Barliya, PhD

7.3.4      Targeting Mitochondrial-bound Hexokinase for Cancer Therapy

Ziv Raviv, PhD

7.3.5       GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”

Aviva Lev-Ari, PhD, RN

7.3.6         Personalized Pancreatic Cancer Treatment Option

Aviva Lev-Ari, PhD, RN

7.3.7        New scheme to routinely test patients for inherited cancer genes

Stephen J. Williams, PhD

7.3.8        Targeting Untargetable Proto-Oncogenes

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

7.3.9        The Future of Translational Medicine with Smart Diagnostics and Therapies: PharmacoGenomics 

Demet Sag, PhD

7.4 Personalized Medicine in Specific Cancers

7.4.1      Personalized medicine and Colon cancer

Tilda Barliya, PhD

7.4.2      Comprehensive Genomic Characterization of Squamous Cell Lung Cancers

Aviva Lev-Ari, PhD, RN

7.4.3        Targeted Tumor-Penetrating siRNA Nanocomplexes for Credentialing the Ovarian Cancer Oncogene ID4

Sudipta Saha, PhD

7.4.4        Cancer and Bone: low magnitude vibrations help mitigate bone loss

Ritu Saxena, PhD

7.4.5         New Prostate Cancer Screening Guidelines Face a Tough Sell, Study Suggests

Prabodh Kandala, PhD

Part III

Translational Medicine, Genomics, and New Technologies Converge to Improve Early Detection

Diagnosis, Detection And Biomarkers

Chapter 8:  Diagnosis Diagnosis: Prostate Cancer

8.1        Prostate Cancer Molecular Diagnostic Market – the Players are: SRI Int’l, Genomic Health w/Cleveland Clinic, Myriad Genetics w/UCSF, GenomeDx and BioTheranostics

Aviva Lev-Ari PhD RN

8.2         Today’s fundamental challenge in Prostate cancer screening

Dror Nir, PhD

Diagnosis & Guidance: Prostate Cancer

8.3      Prostate Cancers Plunged After USPSTF Guidance, Will It Happen Again?

Aviva Lev-Ari, PhD, RN

Diagnosis, Guidance and Market Aspects: Prostate Cancer

8.4       New Prostate Cancer Screening Guidelines Face a Tough Sell, Study Suggests

Prabodh Kandala, PhD

Diagnossis: Lung Cancer

8.5      Diagnosing lung cancer in exhaled breath using gold nanoparticles

Tilda Barliya PhD

Chapter 9:  Detection

Detection: Prostate Cancer

9.1     Early Detection of Prostate Cancer: American Urological Association (AUA) Guideline

Dror Nir, PhD

Detection: Breast & Ovarian Cancer

9.2       Testing for Multiple Genetic Mutations via NGS for Patients: Very Strong Family History of Breast & Ovarian Cancer, Diagnosed at Young Ages, & Negative on BRCA Test

Aviva Lev-Ari, PhD, RN

Detection: Aggressive Prostate Cancer

9.3     A Blood Test to Identify Aggressive Prostate Cancer: a Discovery @ SRI International, Menlo Park, CA

Aviva Lev-Ari, PhD, RN

Diagnostic Markers & Screening as Diagnosis Method

9.4      Combining Nanotube Technology and Genetically Engineered Antibodies to Detect Prostate Cancer Biomarkers

Stephen J. Williams, PhD

Detection: Ovarian Cancer

9.5      Warning signs may lead to better early detection of ovarian cancer

Prabodh Kandala, PhD

9.6       Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-guided intervention?

Dror Nir, PhD

Chapter 10:  Biomarkers

                                                Biomarkers: Pancreatic Cancer

10.1        Mesothelin: An early detection biomarker for cancer (By Jack Andraka)

Tilda Barliya, PhD

Biomarkers: All Types of Cancer, Genomics and Histology

10.2                  Stanniocalcin: A Cancer Biomarker

Aashir Awan, PhD

10.3         Breast Cancer: Genomic Profiling to Predict Survival: Combination of Histopathology and Gene Expression Analysis

Aviva Lev-Ari, PhD, RN

Biomarkers: Pancreatic Cancer

10.4         Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University

Aviva Lev-Ari, PhD, RN

10.5     Early Biomarker for Pancreatic Cancer Identified

Prabodh Kandala, PhD

Biomarkers: Head and Neck Cancer

10.6        Head and Neck Cancer Studies Suggest Alternative Markers More Prognostically Useful than HPV DNA Testing

Aviva Lev-Ari, PhD, RN

10.7      Opens Exome Service for Rare Diseases & Advanced Cancer @Mayo Clinic’s OncoSpire

Aviva Lev-Ari, PhD, RN

Diagnostic Markers and Screening as Diagnosis Methods

10.8         In Search of Clarity on Prostate Cancer Screening, Post-Surgical Followup, and Prediction of Long Term Remission

Larry H Bernstein, MD, FCAP

Chapter 11  Imaging In Cancer

11.1  Introduction by Dror Nir, PhD

11.2  Ultrasound

11.2.1        2013 – YEAR OF THE ULTRASOUND

Dror Nir, PhD

11.2.2      Imaging: seeing or imagining? (Part 1)

Dror Nir, PhD

11.2.3        Early Detection of Prostate Cancer: American Urological Association (AUA) Guideline

Dror Nir, PhD

11.2.4        Today’s fundamental challenge in Prostate cancer screening

Dror Nir, PhD

11.2.5       State of the art in oncologic imaging of Prostate

Dror Nir, PhD

11.2.6        From AUA 2013: “HistoScanning”- aided template biopsies for patients with previous negative TRUS biopsies

Dror Nir, PhD

11.2.7     On the road to improve prostate biopsy

Dror Nir, PhD

11.2.8       Ultrasound imaging as an instrument for measuring tissue elasticity: “Shear-wave Elastography” VS. “Strain-Imaging”

Dror Nir, PhD

11.2.9       What could transform an underdog into a winner?

Dror Nir, PhD

11.2.10        Ultrasound-based Screening for Ovarian Cancer

Dror Nir, PhD

11.2.11        Imaging Guided Cancer-Therapy – a Discipline in Need of Guidance

Dror Nir, PhD

11.3   MRI & PET/MRI

11.3.1     Introducing smart-imaging into radiologists’ daily practice

Dror Nir, PhD

11.3.2     Imaging: seeing or imagining? (Part 2)

[Part 1 is included in the ultrasound section above]

Dror Nir, PhD

11.3.3    Imaging-guided biopsies: Is there a preferred strategy to choose?

Dror Nir, PhD

11.3.4     New clinical results support Imaging-guidance for targeted prostate biopsy

Dror Nir, PhD

11.3.5      Whole-body imaging as cancer screening tool; answering an unmet clinical need?

Dror Nir, PhD

11.3.6        State of the art in oncologic imaging of Lymphoma

Dror Nir, PhD

11.3.7      A corner in the medical imaging’s ECO system

Dror Nir, PhD

11.4  CT, Mammography & PET/CT 

11.4.1      Causes and imaging features of false positives and false negatives on 18F-PET/CT in oncologic imaging

Dror Nir, PhD

11.4.2     Minimally invasive image-guided therapy for inoperable hepatocellular carcinoma

Dror Nir, PhD

11.4.3        Improving Mammography-based imaging for better treatment planning

Dror Nir, PhD

11.4.4       Closing the Mammography gap

Dror Nir, PhD

11.4.5       State of the art in oncologic imaging of lungs

Dror Nir, PhD

11.4.6       Ovarian Cancer and fluorescence-guided surgery: A report

Tilda Barliya, PhD

11.5  Optical Coherent Tomography (OCT)

11.5.1       Optical Coherent Tomography – emerging technology in cancer patient management

Dror Nir, PhD

11.5.2     New Imaging device bears a promise for better quality control of breast-cancer lumpectomies – considering the cost impact

Dror Nir, PhD

11.5.3        Virtual Biopsy – is it possible?

Dror Nir, PhD

11.5.4      New development in measuring mechanical properties of tissue

Dror Nir, PhD

Chapter 12. Nanotechnology Imparts New Advances in Cancer Treatment,  Detection, and Imaging  

12.1     DNA Nanotechnology

Tilda Barliya, PhD

12.2     Nanotechnology, personalized medicine and DNA sequencing

Tilda Barliya, PhD       

12.3     Nanotech Therapy for Breast Cancer

Tilda Barliya, PhD

12.4     Prostate Cancer and Nanotecnology

Tilda Barliya, PhD

12.5     Nanotechnology: Detecting and Treating metastatic cancer in the lymph node

Tilda Barliya, PhD

12.6     Nanotechnology Tackles Brain Cancer

Tilda Barliya, PhD

12.7     Lung Cancer (NSCLC), drug administration and nanotechnology

Tilda Barliya, PhD

Volume Epilogue by Larry H. Bernstein, MD, FACP

Epilogue: Envisioning New Insights in Cancer Translational Biology

Larry H. Berstein, MD, FACP

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Almudena’s Story:  A Life of Hope, Rejuvenation and Strength

Author: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

Patient had ovarian clear cell adenocarcinomas (OCCAs) and underwent a complete hysterectomy at age 52. Interview was conducted 15 months’ post-surgery. Earlier in life, patient had thyroid cancer and removal of her thyroid gland and all the lymph nodes in her neck.

 

Almudena Seeder-Alonso, originally from Madrid, Spain, and now living in Amsterdam, The Netherlands, with her Dutch husband, René, is the eternal optimist, embracing life, reinventing herself, and looking for opportunity in every moment. She is an influential blogger of international relations issues, a career professional in human resources management in both corporate and consulting businesses in Legal, Accounting and Technology, and a lawyer and political scientist with an advanced degree in international relations who is also pursuing a Ph.D. in international relations and diplomacy. And she speaks four languages fluently – Spanish, Dutch, Portuguese and English.

Her story is one of hope, rejuvenation and strength that defines her effervescent personality. One year ago, a routine gynecology exam changed her outlook and perspective on life. She would have never thought that her diagnosis would be ovarian carcinoma of the clear cell, the most aggressive form of cancer.

 

Image SOURCE: Photographs courtesy of Almudena Seeder-Alonso. Top Left: Almudena’s parents, María and Angel, and sister, Cristina, and her husband. Top Right: Almudena during chemotherapy last summer (2015). Middle: Almudena attending a wedding in Asturias (northwest Spain – May 2016), Almudena and René in Comporta, Portugal (Summer 2014) and in New York (April 2014). Below left: Almudena in New York (April 2014). Below Right: Almudena’s sisters, María and Cristina with nephew, Jaime (May 2016). 

A Small Cyst Turns Into Diagnosis of Ovarian Cancer

In early 2015, Almudena visited her gynecologist in Amsterdam for a regular, yearly appointment.

“I was feeling fine. I had no physical complaints, except for my monthly periods which were heavy. I didn’t think much about it. During my examination, my doctor told me that she found a small cyst on my right ovary and we would just observe it to make sure it was not growing.”

Almudena went back to her gynecologist at the OLVG (Onze Lieve Vrouw Gasthuis https://www.olvg.nl/) in Amsterdam twice over the next month to monitor the cyst, only to find that the cyst was growing slightly. Her gynecologist recommended blood tests, an ultrasound, and a specimen of the cyst to be removed through a laparoscopy, a procedure requiring small incisions made below the navel using specialized tools.

“The pathology report said that the cyst was an aggressive cancer, called ovarian carcinoma of the clear cell. I remember sitting in my doctor’s office once she told me the results of the test, and I got very quiet. I could not believe that this was happening to me. While I was meeting with the doctor, I called my husband to let the doctor inform him about the situation. I was listening to this conversation but from far away. He immediately left his meeting with his client (he is one of two founding partners of SeederdeBoer, a Dutch Consulting & Technology firm), to come home. I left the doctor’s office, went home and cried in my husband’s arms.”

Almudena then called her parents, María and Angel, and her two sisters, María and Cristina who live in Madrid, to tell them the news.

“My Mother was very emotional when she heard about my diagnosis. My Father, who is a quiet man by nature, asked me, ‘How could this be happening to you again?’ I did not have an answer for him.”

Almudena’s father was referring to his daughter’s diagnosis of thyroid cancer in her late 20s.

Diagnosis of Thyroid Cancer As A Young Woman

When Almudena was 27 years old, she was diagnosed with follicular thyroid cancer, a slow-growing, highly treatable type of cancer that forms in follicular cells in the thyroid gland. After a 12-hour surgery to remove the gland through a procedure called a full thyroidectomy, she also needed radiation therapy. Many years later, she is feeling fine and continues to be on thyroid medication for the rest of her life.

“I was not aware at that young age of the scope of the diagnosis, but my life really changed. I was kind of a party animal at the end of the 1980s, and I did not have any amount of energy for that anymore. I needed several months to get back into shape as the scar from the surgery was a large one on the right side of my neck. I could not use my right arm and hand properly for months, even writing was complicated. The worst news came later when I could not get pregnant given the situation that many of my eggs were gone because of radiation. At that moment, egg freezing technology was not as advanced as it is today; it was not normal to freeze eggs for a later time. That was really painful, as I could not become a mother, even after four in vitro fertilization (IVF) cycles.”

According to the National Cancer Institute’s web site, thyroid cancer is a disease in which malignant cancer cells form in the tissues of the thyroid gland. The thyroid is a gland at the base of the throat near the trachea (windpipe). It is shaped like a butterfly, with a right lobe and a left lobe. The isthmus, a thin piece of tissue, connects the two lobes. A healthy thyroid is a little larger than a quarter coin. It usually cannot be felt through the skin. The thyroid uses iodine, a mineral found in some foods and in iodized salt, to help make several hormones. Thyroid hormones control heart rate, body temperature, and how quickly food is changed into energy (metabolism) as well as, it controls the amount of calcium in the blood.  http://www.cancer.gov/types/thyroid/patient/thyroid-treatment-pdq

Ovarian Cancer Diagnosis Continues

Almudena then spoke with her physicians in Madrid, as that is where she grew up, to get a second opinion about her ovarian carcinoma diagnosis. The physicians knew her history well and they told her that they did not believe that the follicular thyroid cancer was directly related to the ovarian cancer.

“My local gynecologist in Amsterdam then referred me to a specialist, Dr. J. van der Velden, a gynecologist/oncologist at the Amsterdam Medisch Centrum (AMC), http://www.cgoa.nl/page/view/name/34-wie-we-zijn, one of the top university hospitals in The Netherlands for this surgery and treatment. My husband, René, and I met with Dr. van der Velden, and he told us that my cancer was a fast-spreading condition and I needed to have it removed immediately. He answered our questions, calmed my fears and said he would do everything to help me.

“I have an open attitude towards people so it was easy to create a good connection with the doctors and medical personnel, which I consider very fundamental in such a process. I talked to them about my concerns or doubts and shared my worries about the process that I was going through. I have to say that all of them were wonderful in every aspect!”

Dr. van der Velden explained to Almudena that as clear cell is an aggressive form of ovarian cancer, it would need to be treated that way. One month later, Almudena underwent a procedure called open surgery, rather than laparoscopic surgery, requiring an incision large enough for the doctor to see the cyst and surrounding tissue.

“My incision from the surgery is a constant reminder of the struggle I went through. The cyst, which was 3cm, was a solid mass on my right ovary. It had adhered itself to the ovary and had to be broken to be removed, so some cells spilled out into my reproductive organs, namely, in my uterus and fallopian tubes. During this surgery, which was a complete hysterectomy, the doctor took additional tissue samples of my reproductive organs to be analyzed by pathology. Weeks later, he found no other metastases or extra cancer cells.”

http://www.mountsinai.org/patient-care/health-library/treatments-and-procedures/ovarian-cyst-removal-open-surgery

https://www.amc.nl/web/Het-AMC/Organisatie/Academisch-Medisch-Centrum.htm

The Process of Healing Begins

One month later, Almudena’s body was still recovering from the operation. Now, she had to start chemotherapy back at the OLVG.

“The doctor, Dr. W. Terpstra, hematologist/oncologist instructed me that I would be going through six full cycles of chemotherapy, which means full doses of carboplatin & paclitaxel every 21 days. At first, I felt reasonably good, then as each week progressed, I became more and more tired, nauseous, and just feeling terrible. I was not sleeping well and even lost the sensation of my fingers and toes as chemo attacks the nerves, too. Then, I started losing my eyelashes and hair so I shaved my long, flowing hair and wore a scarf wrapped around my head.”

Almudena would report to the hospital for her weekly chemotherapy session, starting at 9am and leaving at 6pm. The medical team would put her in a room with a full-size bed so she can relax during the infusion. Her husband, two sisters and some close friends would take turns accompanying her during this time, as she had a nurturing and caring support network.

“I could not have gone through this condition without my family and friends. It tests your relationships and shows you who your friends really are.”

The chemotherapy affected Almudena’s red blood cell count halfway through the process and she felt weak and tired.

“Anemia is normal during this time, but always being tired made me concentrate and focus on things less. I would watch a movie or read a book through the chemo session, and then I would fall asleep quickly.”

After Almudena finished the complete cycle of chemotherapy infusions, she had a follow-up appointment with her doctor, which included blood work, CT scan, and other diagnostic tests.

“My doctor said the tests results were very good. Now, I see him every three months for a routine visit. That was such a wonderful report to hear.

“During this process I learned to love myself, and pampered myself and my body. I learned to improve in terms of beauty, even in the worst circumstances. I wanted to feel beautiful and attractive for myself and for my close family. After three chemo cycles, I started even to think about how my new hair style would be in the moment that I finished chemo.”

Ovarian Carcinoma Pathophysiology Facts

According to published studies, ovarian clear cell adenocarcinomas (OCCAs) account for less than 5 percent of all ovarian malignancies, and 3.7–12.1 percent of all epithelial ovarian carcinomas. By contrast, early‐stage clear cell ovarian cancer carries a relatively good prognosis. When compared with their serous counterparts, a greater proportion of OCCA tumors present as early‐stage (I–II) tumors, are often associated with a large pelvic mass, which may account for their earlier diagnosis, and rarely occur bilaterally. Very little is known about the pathobiology of OCCA. Between 5 percent and 10 percent of ovarian cancers are associated with endometriotic lesions in which there is a predominance of clear and endometrioid cell subtypes, suggesting that both tumor types may arise in endometriosis. http://www.cancer.gov/types/ovarian/hp/ovarian-epithelial-treatment-pdq

The National Cancer Institute’s web site offers these statistics. In most families affected with the breast and ovarian cancer syndrome or site-specific ovarian cancer, genetic linkage has been found to the BRCA1 locus on chromosome 17q21. BRCA2, also responsible for some instances of inherited ovarian and breast cancer, has been mapped by genetic linkage to chromosome 13q12. The lifetime risk for developing ovarian cancer in patients harboring germline mutations in BRCA1 is substantially increased over that of the general population. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2001101/

Words Of Wisdom

“Throughout this journey, I found myself again in some way and found my strength as well. When it seemed I could not stand it anymore, either physically and mentally, I realized that I could.

“At the beginning of my diagnosis, I asked myself, ‘Why me?’, and I then changed it to, ‘Why not me?’ I discovered that I have the same opportunities as anyone who becomes ill. The important perspective to have is not whining and dwelling on my bad luck. The important thing is to heal, survive, and recover my life, which is very good!

“I learned the real value and importance of things: to differentiate and give real meaning and value to the care and support of my husband, René, who was always there for me, and my parents and sisters, who came to Amsterdam very often during the process. I also made sure that René was well-supported and accompanied by my family.  René was feeling terrible for me, but he never showed it — and I learned this fact after I was starting to be back on track.”

Almudena’s Life Today

“At a significant moment in my life during my cancer diagnosis and after a long professional life in many corporate and consulting business in several countries, I decided to re-invent myself and start a new career, this time, in the battle of the opinions. I always liked foreign affairs and diplomacy, so why not share my thoughts and write about current international issues.”

That’s when Almudena started a blog to discuss relevant international political issues with her background specialization in International Relations, International Politics, International Law and Governance.

“I consider myself politically liberal and have been influenced by J.S. Mill and A. Tocqueville’s tradition of thought, as well as their ethical conception of the defense of freedom. This is what I try to capture in my political approach and in this blog. http://almudenas.website/index.php/about-me/

“Regarding my profession, I have already reinvented myself, leaving the corporate life with all that is included regarding life’s standards, and do what really makes me happy, which I´m doing right now. It seems after all, looking back with perspective, I did the right thing.

“I am grateful for my life and never take anything for granted. I am the happiest when I am doing things that please me or give me the utmost satisfaction. I now have balance in my personal and professional life, something that I’ve never had before. My husband, René, likes it too and I have his full support.”

She recently ‘liked’ this saying on LinkedIn, the professional network site, ‘I never lose. I either win or learn,’ which was attributed to Nelson Mandela, the deceased South African anti-apartheid revolutionary, politician and philanthropist.

Almudena’s life continues on a path of balance, richness and thankfulness for the person she is and the many blessings she continues to have along the way.

Editor’s note:

We would like to thank Gabriela Contreras, a global communications consultant and patient advocate, for the tremendous help and support she provided in locating and scheduling time to talk with Almudena Seeder-Alonso.

Almudena Seeder-Alonso provided her permission to publish this interview on August 10, 2016.

REFERENCES/SOURCES

http://www.nytimes.com/2016/07/31/health/harnessing-the-immune-system-to-fight-cancer.html?_r=0

http://www.sharecancersupport.org/share-new/support/stories/linda_clear_cell_ovarian_cancer/

http://www.cancer.gov/types/thyroid/patient/thyroid-treatment-pdq

http://almudenas.website/index.php/about-me/

http://www.cancer.gov/types/ovarian/hp/ovarian-epithelial-treatment-pdq

http://www.cgoa.nl/page/view/name/34-wie-we-zijn

http://www.mountsinai.org/patient-care/health-library/treatments-and-procedures/ovarian-cyst-removal-open-surgery

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2001101/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2001101/

Other related articles on the link between Ovarian Cancer and Thyroid Cancer:

https://www.whatnext.com/questions/is-there-a-link-between-ovarian-and-thyroid-cancer

Other related articles/information:

https://www.olvg.nl/

https://www.amc.nl/web/Het-AMC/Organisatie/Academisch-Medisch-Centrum.htm

 

Other related articles on Ovarian Cancer and Thyroid Cancer were published in this Open Access Online Scientific Journal include the following: 

Ovarian Cancer (N = 285)

2015

A Curated History of the Science Behind the Ovarian Cancer β-Blocker Trial

Model mimicking clinical profile of patients with ovarian cancer @ Yale School of Medicine

https://pharmaceuticalintelligence.com/2015/09/26/model-mimicking-clinical-profile-of-patients-with-ovarian-cancer-yale-school-of-medicine/

2014

Preclinical study identifies ‘master’ proto-oncogene that regulates stress-induced ovarian cancer metastasis | MD Anderson Cancer Center

https://pharmaceuticalintelligence.com/2014/08/15/preclinical-study-identifies-master-proto-oncogene-that-regulates-stress-induced-ovarian-cancer-metastasis-md-anderson-cancer-center/

Good and Bad News Reported for Ovarian Cancer Therapy

https://pharmaceuticalintelligence.com/2014/07/01/good-and-bad-news-reported-for-ovarian-cancer-therapy-2/

Efficacy of Ovariectomy in Presence of BRCA1 vs BRCA2 and the Risk for Ovarian Cancer

https://pharmaceuticalintelligence.com/2014/02/25/efficacy-of-ovariectomy-in-presence-of-brca1-vs-brca2-and-the-risk-for-ovarian-cancer/

 

And 
 
Thyroid Cancer (N = 124)
2015
Experience with Thyroid Cancer

 

2012

Thyroid Cancer: The Evolution of Treatment Options

https://pharmaceuticalintelligence.com/2012/08/19/thyroid-cancer-the-evolution-of-treatment-options/

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CancerBase.org – The Global HUB for Diagnoses, Genomes, Pathology Images: A Real-time Diagnosis and Therapy Mapping Service for Cancer Patients – Anonymized Medical Records accessible to anyone on Earth

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 10/29/2019

Pan-cancer computational histopathology reveals mutations, tumor composition and prognosis

Yu Fu1, Alexander W Jung1, Ramon Viñas Torne1, Santiago Gonzalez1,2, Harald Vöhringer1, Mercedes Jimenez-Linan3, Luiza Moore3,4, and Moritz Gerstung#1,5 # to whom correspondence should be addressed 1) European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK. 2) Current affiliation: Institute for Research in Biomedicine (IRB Barcelona), Parc Científic de Barcelona, Barcelona, Spain. 3) Department of Pathology, Addenbrooke’s Hospital, Cambridge, UK. 4) Wellcome Sanger Institute, Hinxton, UK 5) European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany.

Correspondence:

Dr Moritz Gerstung European Molecular Biology Laboratory European Bioinformatics Institute (EMBL-EBI) Hinxton, CB10 1SA UK. Tel: +44 (0) 1223 494636 E-mail: moritz.gerstung@ebi.ac.uk

Abstract

Pan-cancer computational histopathology reveals mutations, tumor composition and prognosis

Here we use deep transfer learning to quantify histopathological patterns across 17,396 H&E stained histopathology image slides from 28 cancer types and correlate these with underlying genomic and transcriptomic data. Pan-cancer computational histopathology (PC-CHiP) classifies the tissue origin across organ sites and provides highly accurate, spatially resolved tumor and normal distinction within a given slide. The learned computational histopathological features correlate with a large range of recurrent genetic aberrations, including whole genome duplications (WGDs), arm-level copy number gains and losses, focal amplifications and deletions as well as driver gene mutations within a range of cancer types. WGDs can be predicted in 25/27 cancer types (mean AUC=0.79) including those that were not part of model training. Similarly, we observe associations with 25% of mRNA transcript levels, which enables to learn and localise histopathological patterns of molecularly defined cell types on each slide. Lastly, we find that computational histopathology provides prognostic information augmenting histopathological subtyping and grading in the majority of cancers assessed, which pinpoints prognostically relevant areas such as necrosis or infiltrating lymphocytes on each tumour section. Taken together, these findings highlight the large potential of PC-CHiP to discover new molecular and prognostic associations, which can augment diagnostic workflows and lay out a rationale for integrating molecular and histopathological data.

https://www.biorxiv.org/content/10.1101/813543v1

 

Key points

● Pan-cancer computational histopathology analysis with deep learning extracts histopathological patterns and accurately discriminates 28 cancer and 14 normal tissue types

● Computational histopathology predicts whole genome duplications, focal amplifications and deletions, as well as driver gene mutations

● Wide-spread correlations with gene expression indicative of immune infiltration and proliferation

● Prognostic information augments conventional grading and histopathology subtyping in the majority of cancers

 

Discussion

Here we presented PC-CHiP, a pan-cancer transfer learning approach to extract computational histopathological features across 42 cancer and normal tissue types and their genomic, molecular and prognostic associations. Histopathological features, originally derived to classify different tissues, contained rich histologic and morphological signals predictive of a range of genomic and transcriptomic changes as well as survival. This shows that computer vision not only has the capacity to highly accurately reproduce predefined tissue labels, but also that this quantifies diverse histological patterns, which are predictive of a broad range of genomic and molecular traits, which were not part of the original training task. As the predictions are exclusively based on standard H&E-stained tissue sections, our analysis highlights the high potential of computational histopathology to digitally augment existing histopathological workflows. The strongest genomic associations were found for whole genome duplications, which can in part be explained by nuclear enlargement and increased nuclear intensities, but seemingly also stems from tumour grade and other histomorphological patterns contained in the high-dimensional computational histopathological features. Further, we observed associations with a range of chromosomal gains and losses, focal deletions and amplifications as well as driver gene mutations across a number of cancer types. These data demonstrate that genomic alterations change the morphology of cancer cells, as in the case of WGD, but possibly also that certain aberrations preferentially occur in distinct cell types, reflected by the tumor histology. Whatever is the cause or consequence in this equation, these associations lay out a route towards genomically defined histopathology subtypes, which will enhance and refine conventional assessment. Further, a broad range of transcriptomic correlations was observed reflecting both immune cell infiltration and cell proliferation that leads to higher tumor densities. These examples illustrated the remarkable property that machine learning does not only establish novel molecular associations from pre-computed histopathological feature sets but also allows the localisation of these traits within a larger image. While this exemplifies the power of a large scale data analysis to detect and localise recurrent patterns, it is probably not superior to spatially annotated training data. Yet such data can, by definition, only be generated for associations which are known beforehand. This appears straightforward, albeit laborious, for existing histopathology classifications, but more challenging for molecular readouts. Yet novel spatial transcriptomic44,45 and sequencing technologies46 bring within reach spatially matched molecular and histopathological data, which would serve as a gold standard in combining imaging and molecular patterns. Across cancer types, computational histopathological features showed a good level of prognostic relevance, substantially improving prognostic accuracy over conventional grading and histopathological subtyping in the majority of cancers. It is this very remarkable that such predictive It is made available under a CC-BY-NC 4.0 International license. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. bioRxiv preprint first posted online Oct. 25, 2019; doi: http://dx.doi.org/10.1101/813543. The copyright holder for this preprint signals can be learned in a fully automated fashion. Still, at least at the current resolution, the improvement over a full molecular and clinical workup was relatively small. This might be a consequence of the far-ranging relations between histopathology and molecular phenotypes described here, implying that histopathology is a reflection of the underlying molecular alterations rather than an independent trait. Yet it probably also highlights the challenges of unambiguously quantifying histopathological signals in – and combining signals from – individual areas, which requires very large training datasets for each tumour entity. From a methodological point of view, the prediction of molecular traits can clearly be improved. In this analysis, we adopted – for the reason of simplicity and to avoid overfitting – a transfer learning approach in which an existing deep convolutional neural network, developed for classification of everyday objects, was fine tuned to predict cancer and normal tissue types. The implicit imaging feature representation was then used to predict molecular traits and outcomes. Instead of employing this two-step procedure, which risks missing patterns irrelevant for the initial classification task, one might directly employ either training on the molecular trait of interest, or ideally multi-objective learning. Further improvement may also be related to the choice of the CNN architecture. Everyday images have no defined scale due to a variable z-dimension; therefore, the algorithms need to be able to detect the same object at different sizes. This clearly is not the case for histopathology slides, in which one pixel corresponds to a defined physical size at a given magnification. Therefore, possibly less complex CNN architectures may be sufficient for quantitative histopathology analyses, and also show better generalisation. Here, in our proof-of-concept analysis, we observed a considerable dependence of the feature representation on known and possibly unknown properties of our training data, including the image compression algorithm and its parameters. Some of these issues could be overcome by amending and retraining the network to isolate the effect of confounding factors and additional data augmentation. Still, given the flexibility of deep learning algorithms and the associated risk of overfitting, one should generally be cautious about the generalisation properties and critically assess whether a new image is appropriately represented. Looking forward, our analyses revealed the enormous potential of using computer vision alongside molecular profiling. While the eye of a trained human may still constitute the gold standard for recognising clinically relevant histopathological patterns, computers have the capacity to augment this process by sifting through millions of images to retrieve similar patterns and establish associations with known and novel traits. As our analysis showed this helps to detect histopathology patterns associated with a range of genomic alterations, transcriptional signatures and prognosis – and highlight areas indicative of these traits on each given slide. It is therefore not too difficult to foresee how this may be utilised in a computationally augmented histopathology workflow enabling more precise and faster diagnosis and prognosis. Further, the ability to quantify a rich set of histopathology patterns lays out a path to define integrated histopathology and molecular cancer subtypes, as recently demonstrated for colorectal cancers47 .

Lastly, our analyses provide It is made available under a CC-BY-NC 4.0 International license. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

bioRxiv preprint first posted online Oct. 25, 2019; doi: http://dx.doi.org/10.1101/813543.

The copyright holder for this preprint proof-of-concept for these principles and we expect them to be greatly refined in the future based on larger training corpora and further algorithmic refinements.

https://www.biorxiv.org/content/biorxiv/early/2019/10/25/813543.full.pdf

 

July 27, 2016
world map illustration
Illustration by Tricia Seibold and iStock/liuzishan

During his 2016 State of the Union address, President Barack Obama called on Vice President Joe Biden – who had months earlier lost his son Beau to brain cancer – to head a “moonshot” to significantly accelerate research into the disease. The president said he wanted to harness the spirit of American innovation that took us from zero to landing a man on the moon in a decade to similarly find new ways to prevent, diagnose and treat cancer.

One of those intrigued by that call to action was Stanford’s Jan Liphardt, an associate professor of bioengineering who specializes in biophysics, the tumor microenvironment and data analysis. Stanford Engineering talked to Liphardt about how he came to be involved with the moonshot and his approach to using data and the voice of patients to better understand cancer and how it can be treated, and how sharing information can better inform the course of cancer research.

How did you get involved in the National Cancer Moonshot?

In March, after the president’s charge, the vice president challenged scientists, doctors, industry and patients to give their best ideas to the moonshot. The White House also reached out to a few outsiders, myself included. The White House instructions were unusual: “Do something big and different. There is no money and you have 87 days. Go.”

I like a challenge, and this was a chance to serve, even in the face of administrative hurdles. So I looked for advice, teammates and support. Russ Altman, a colleague at Stanford, suggested it was time to give patients a way to volunteer their own health data in order to help find cures. I collaborated with Peter Kuhn, a professor of medicine and engineering at the University of Southern California, who’s known for carefully listening to cancer patients, advocates and their supporters. In short order we had links with advocates like AnneMarie Ciccarella, Sonja Durham, Lori Marx-Rubiner, Jack Whelan and Jack Park. That’s how we got to CancerBase.org.

What’s the idea the team came up with?

We thought for about a week: What would matter to the patients that Stanford and other research institutions serve? What would scale? Well, we’re not going to run a clinical trial, go near protected health information, invent a new drug or write a research proposal. There’s no time for that. Whatever it was, it had to be useful, scalable, legal and different. That pointed to data, the web, patients and decisions.

One thing jumped out: Right now, there’s significant friction in medical data sharing. People all over the world can already effortlessly share other kinds of information – pictures, movies, ideas, stories, tweets. Increasingly, they are using the same tools to share personal medical information. It’s remarkable what cancer patients already share: diagnoses, genomes, pathology images. But that information is not yet widely used to understand where they are with their diseases.

Ideally, everyone, including scientists and doctors, would have as much information as possible at their fingertips. Many patients think when they give data for research, magically scientists all over the world can dig into this information, find patterns and help. The practical reality is that it’s nearly impossible for any one scientist to access the amounts of data they would like.

So that’s the simple idea: A global map and give patients the tools they need to share their data – if they want to. They can donate information for the greater good. In return, we make a simple promise: When you post data, we’ll anonymize them and make them available to anyone on Earth in one second. We plan to display this information like real-time traffic data. HIPAA doesn’t apply to this direct data-sharing. The patients can give us whatever information they want, and they can tell us what they want us to do with it. We’re a conduit. Their data belong to them, not to us.

How does it work?

Today we ask just five basic questions. Over time we will add more. You join, give some information, and we’ll put you on a global map. Right now, some of the things we don’t know about cancer are incredibly simple: Where is everyone on Earth with cancer? How old are they? What is their diagnosis? Did their cancers metastasize? Global, instantaneous data sharing is the story.

In a second phase, we are going to see if we can plot all the information just like Waze does for traffic. Our role is to synthesize the information and plot it in ways that ordinary people can understand. Think of it this way – patients want to be able to chart their treatment path. Who went straight, who went left? People just getting on the highway are curious about what people did who came before them, and what happened to those people. Did they arrive at the destination easily and promptly? We’re a real-time diagnosis and therapy mapping service for cancer.

You say that giving patients a way to share their health data is important to help finding cures. Why?

Let me give you a specific example. At Stanford, I’m part of a team of cancer biologists and clinicians funded by the Stanford Cancer Institute to think about the next generation of screening for breast cancer in the U.S. Every year, the U.S. uses mammography to screen more than 40 million women for breast cancer. In this project, it quickly became clear that there is currently no central, easy-to-access repository of mammograms for research use.

That’s a major lost opportunity – our nation spends billions on screening, but we don’t store, share and analyze this information in a scalable and simple manner. In the traditional approach, our team would spend several hundred thousand dollars, and about three years, to assemble perhaps 1,000 mammograms. We would then use this tiny dataset to try to find something interesting, but since the dataset is so small, we would be blind to rare features of breast cancer and its predictors. It clearly makes a lot more sense to compare and explore 100 million images.

This sounds completely impossible until you realize that Instagram users upload 58 million images every day. Once you start to think about supposedly intractable research problems from a web or social networking perspective, new possibilities open. Imagine, for example, if there were a simple way for every single woman on Earth to upload and share her de-identified mammogram? Or more generally, imagine a world in which patients have the tools to globally share de-identified health data, if they want to. That’s exactly the idea behind CancerBase – let’s just give people those tools and see what happens.

How much data and how many people are needed to make this viable?

We think we are going to need several tens-of-thousands of members. There are approximately 50 million people on Earth with a cancer diagnosed in the last five years, and 200 million more people have an immediate family member with cancer. Almost 2 billion people are active on Twitter and Facebook – a quarter of the world’s population. If just a few percent of those people sign up, we could do something no one on Earth has done before.

Are there hopes to create a “developer community,” people who find ways to use your data that you didn’t even think about or have the time to work on?

Definitely. As much as we think we can predict what these data are useful for, we don’t really know. By making the anonymized data available to everyone within one second, they might start to do things that we never dreamed of. The more eyes look at these data, the better off everyone will be. The dream is to have cancer-relevant medical data flow unimpeded around the world in seconds, so that everyone, wherever they are, can see and use this information.

SOURCE

https://engineering.stanford.edu/news/how-data-can-help-us-understand-cancer-and-its-treatment

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3D Imaging of Cancer Cells

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

3D Imaging of Cancer Cells Could Lead to Improved Ability of Pathologists and Radiologists to Plan Cancer Treatments and Monitor Cell Interactions

Dark Daily Apr 8th 2016        Jon Stone

https://www.linkedin.com/pulse/3d-imaging-cancer-cells-could-lead-improved-ability-plan-joseph-colao

 

3D Imaging of Cancer Cells Could Lead to Improved Ability of Pathologists and Radiologists to Plan Cancer Treatments and Monitor Cell Interactions.

New technology from researchers at the University of Texas Southwestern Medical Center enables the ability to study cancer cells in their native microenvironments.

Imaging research is one step closer to giving clinicians a way to do high-resolution scans of malignant cells in order to diagnose cancer and help identify useful therapies. If this technology were to prove successful in clinical studies, it might change how anatomic pathologists and radiologists diagnose and treat cancer.

Researchers at the University of Texas Southwestern Medical Center developed a way to create near-isotropic, high-resolution scans of cells within their microenvironments. The process involves utilizing a combination of two-photonBessel beams and specialized filtering.

New Imaging Approach Could be Useful to Both Pathologists and Radiologists

In a recent press release, senior author Reto Fiolka, PhD, said “there is clear evidence that the environment strongly affects cellular behavior—thus, the value of cell culture experiments on glass must at least be questioned. Our microscope is one tool that may bring us a deeper understanding of the molecular mechanisms that drive cancer cell behavior, since it enables high-resolution imaging in more realistic tumor.”

In a study in Developmental Cell, Erik S. Welf, PhD, et al, described the new microenvironmental selective plane illumination microscopy (meSPIM). When developing the technology, the team outlined three goals:

1. The microscope design must not prohibitively constrain microenvironmental properties.

2. Spatial and temporal resolution must match the cellular features of interest.

3. Spatial resolution must be isotropic to avoid spatial bias in quantitative measurements.

This new technology offers pathologists and medical laboratory scientists a new look at cancer cells and other diseases. The study notes that meSPIM eliminates the influence of stiff barriers, such as glass slide covers, while also allowing a level of control over both mechanical and chemical influences that was previously impossible.

Early meSPIM Research Reveals New Cell Behaviors

Early use of meSPIM in observing melanoma cells is already offering new insights into the relationship between the cell behavior of cellular- and subcellular-scale mechanisms and the microenvironment in which these cells exist. The study notes, “The ability to image fine cellular details in controllable microenvironments revealed morphodynamic features not commonly observed in the narrow range of mechanical environments usually studied in vitro.”

One such difference is the appearance of blebbing. Created by melanoma cells and lines, these small protrusions are thought to aid in cell mobility and survival. Using meSPIM, observers could follow the blebbing process in real-time. Formation of blebs on slides and within an extracellular matrix (ECM) showed significant differences in both formation and manipulation of the surrounding microenvironment.

The team is also using meSPIM to take a look at membrane-associated biosensor and cytosolic biosensor signals in 3D. They hope that investigation of proteins such as phosphatidylinositol 3-kinase (PI3K) and protein kinase C will help to further clarify the roles these signals play in reorientation of fibroblasts.

meSPIM combined with computer vision enables imaging, visualization, and quantification of how cells alter collagen fibers over large distances within an image volume measuring 100 mm on each side. (Photo Copyright: Welf and Driscoll et al.)

The research team believes this opens new possibilities for studying diseases at a subcellular level, saying, “Cell biology is necessarily restricted to studying what we can measure. Accordingly, while the last hundred years have yielded incredible insight into cellular processes, unfortunately most of these studies have involved cells plated onto flat, stiff surfaces that are drastically different from the in vivo microenvironment …

“Here, we introduce an imaging platform that enables detailed subcellular observations without compromising microenvironmental control and thus should open a window for addressing these fundamental questions of cell biology.”

Limitations of meSPIM

One significant issue associated with the use of meSPIM is the need to process the large quantity of data into useful information. Algorithms currently allow for automatic bleb detection. However, manual marking, while time consuming, still provides increased accuracy. Researchers believe the next step in improving the quality of meSPIM scans lie in computer platforms designed to extract and process the scan data.

Until this process is automated, user bias, sample mounting, and data handling will remain risks for introducing errors into the collected data. Yet, even in its early stages, meSPIM offers new options for assessing the state of cancer cells and may eventually provide pathologists and radiologists with additional information when creating treatment plans or assessments.

 

Seeing cancer cells in 3-D (w/ Video)

http://phys.org/news/2016-02-cancer-cells-d-video.html

 

Cancer in 3-D

http://cdn.phys.org/newman/csz/news/800/2016/cancerin3d.png

Extracted surfaces of two cancer cells. (Left) A lung cancer cell colored by actin intensity near the cell surface. Actin is a structural molecule that is integral to cell movement. (Right) A melanoma cell colored by PI3-kinase activity near the cell surface. PI3K is a signaling molecule that is key to many cell processes. Credit: Welf and Driscoll et al.

Cancer cells don’t live on glass slides, yet the vast majority of images related to cancer biology come from the cells being photographed on flat, two-dimensional surfaces—images that are sometimes used to make conclusions about the behaviour of cells that normally reside in a more complex environment. But a new high-resolution microscope, presented February 22 in Developmental Cell, now makes it possible to visualize cancer cells in 3D and record how they are signaling to other parts of their environment, revealing previously unappreciated biology of how cancer cells survive and disperse within living things.

“There is clear evidence that the environment strongly affects cellular behavior—thus, the value of cell culture experiments on glass must at least be questioned,” says senior author Reto Fiolka, an optical scientist at the University of Texas Southwestern Medical Center. “Our is one tool that may bring us a deeper understanding of the molecular mechanisms that drive cancer cell behavior, since it enables high-resolution imaging in more realistic tumor environments.”

Read more at: http://phys.org/news/2016-02-cancer-cells-d-video.html#jCp

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Laser Therapy Opens Blood-Brain Barrier

Curator: Larry H. Bernstein, MD, FCAP

 

Laser Surgery Opens Blood-Brain Barrier to Chemotherapy

http://www.photonics.com/Article.aspx?AID=58445

ST. LOUIS, March 11, 2016 — A laser probe has been used to open the brain’s protective cover, enabling delivery of chemotherapy drugs to patients with glioblastoma — the most common and aggressive form of brain cancer.

In a pilot study conducted by the Washington University School of Medicine in St. Louis, Mo., 14 patients with glioblastoma underwent minimally invasive laser surgery to treat a recurrence of their tumors. Heat from the laser was already known to kill brain tumor cells but, unexpectedly, the researchers found that the technology penetrated the blood-brain barrier.

“The laser treatment kept the blood-brain barrier open for four to six weeks, providing us with a therapeutic window of opportunity to deliver chemotherapy drugs to the patients,” said neurosurgery professor Eric Leuthardt, MD, who also treats patients at Barnes-Jewish Hospital. “This is crucial because most chemotherapy drugs can’t get past the protective barrier, greatly limiting treatment options for patients with brain tumors.

The team is still closely following the patients, though early results indicate they are doing better on average, in terms of survival and clinical outcomes, than what the researchers would expect with other treatment methods.

Glioblastomas are one of the most difficult cancers to treat. Most patients diagnosed with this type of brain tumor survive just 15 months, according to the American Cancer Society.

The research is part of a larger phase II clinical trial that will involve 40 patients. Twenty patients were enrolled in the pilot study, 14 of whom were found to be suitable candidates for the minimally invasive laser surgery, a technology that Leuthardt helped pioneer.

The laser technology was approved by the FDA in 2009 as a surgical tool to treat brain tumors. The Washington team’s research marks the first time the laser has been shown to disrupt the blood-brain barrier, which shields the brain from harmful toxins but inadvertently blocks potentially helpful drugs, such as chemotherapy.

As part of the trial, doxorubicin, a widely used chemotherapy, was delivered intravenously to 13 patients in the weeks following the laser surgery. Preliminary data indicate that 12 patients showed no evidence of tumor progression during the short, 10-week time frame of the study. One patient experienced tumor growth before chemotherapy was delivered; the tumor in another patient progressed after chemotherapy was administered, the researcher reported.

The laser surgery was well-tolerated by the patients in the trial; most went home one to two days afterward, and none experienced severe complications. The surgery was performed while a patient lies in an MRI scanner, providing the neurosurgical team with a real-time look at the tumor. Using an incision of only 3 mm, a neurosurgeon robotically inserted the laser to heat up and kill brain tumor cells at a temperature of about 150 °F.

“The laser kills tumor cells, which we anticipated,” said Leuthardt. “But, surprisingly, while reviewing MRI scans of our patients, we noticed changes near the former tumor site that looked consistent with the breakdown of the blood-brain barrier.”

Leuthardt confirmed and further studied these imaging findings with study co-author Dr. Joshua Shimony, a professor of radiology at Washington University.

The researchers, including co-corresponding author Dr. David Tran, a neuro-oncologist now at the University of Florida, performed follow-up testing, which showed that the degree of permeability through the blood-brain barrier peaked one to two weeks after surgery but that the barrier remained open for up to six weeks.

Other successful attempts to breach the barrier have left it open for only a short time — about 24 hours — not long enough for chemotherapy to be consistently delivered, or have resulted in only modest benefits, the researchers said. The laser technology leaves the barrier open for weeks — long enough for patients to receive multiple treatments with chemotherapy. Further, the laser only opens the barrier near the tumor, leaving the protective cover in place in other areas of the brain. This has the potential to limit the harmful effects of chemotherapy drugs in other areas of the brain, the researchers said.

The findings also suggest that other approaches, such as cancer immunotherapy — which harnesses cells of the immune system to seek out and destroy cancer — could also be useful for patients with glioblastomas.

The researchers are planning another clinical trial that combines the laser technology with chemotherapy and immunotherapy, as well as trials to test targeted cancer drugs that normally can’t breach the blood-brain barrier.

The research was published in Plos One (doi: 10.1371/journal.pone.0148613).

 

Hyperthermic Laser Ablation of Recurrent Glioblastoma Leads to Temporary Disruption of the Peritumoral Blood Brain Barrier

Poor central nervous system penetration of cytotoxic drugs due to the blood brain barrier (BBB) is a major limiting factor in the treatment of brain tumors. Most recurrent glioblastomas (GBM) occur within the peritumoral region. In this study, we describe a hyperthemic method to induce temporary disruption of the peritumoral BBB that can potentially be used to enhance drug delivery.

 Methods

Twenty patients with probable recurrent GBM were enrolled in this study. Fourteen patients were evaluable. MRI-guided laser interstitial thermal therapy was applied to achieve both tumor cytoreduction and disruption of the peritumoral BBB. To determine the degree and timing of peritumoral BBB disruption, dynamic contrast-enhancement brain MRI was used to calculate the vascular transfer constant (Ktrans) in the peritumoral region as direct measures of BBB permeability before and after laser ablation. Serum levels of brain-specific enolase, also known as neuron-specific enolase, were also measured and used as an independent quantification of BBB disruption.

Results

In all 14 evaluable patients, Ktrans levels peaked immediately post laser ablation, followed by a gradual decline over the following 4 weeks. Serum BSE concentrations increased shortly after laser ablation and peaked in 1–3 weeks before decreasing to baseline by 6 weeks.

Conclusions   

The data from our pilot research support that disruption of the peritumoral BBB was induced by hyperthemia with the peak of high permeability occurring within 1–2 weeks after laser ablation and resolving by 4–6 weeks. This provides a therapeutic window of opportunity during which delivery of BBB-impermeant therapeutic agents may be enhanced.

Trial Registration  

ClinicalTrials.gov NCT01851733

Citation: Leuthardt EC, Duan C, Kim MJ, Campian JL, Kim AH, Miller-Thomas MM, et al. (2016) Hyperthermic Laser Ablation of Recurrent Glioblastoma Leads to Temporary Disruption of the Peritumoral Blood Brain Barrier. PLoS ONE 11(2): e0148613.  http://dx.doi.org:/10.1371/journal.pone.0148613

Glioblastoma (GBM) is the most common and lethal malignant brain tumor in adults [1]. Despite advanced treatment, median survival is less than 15 months, and fewer than 5% of patients survive past 5 years [2, 3]. Effective treatment options for recurrent GBM remain very limited and much of research and development efforts in recent years have focused on this area of greatly unmet needs. Up to 90% of recurrent tumors develop within the 2–3 cm margin of the primary site and are thought to arise from microscopic glioma cells that infiltrate the peritumoral brain region prior to resection of the primary tumor [4, 5]. Therefore elimination of infiltrative GBM cells in this region likely will improve long-term disease control.

Inadequate CNS delivery of therapeutic drugs due to the blood brain barrier (BBB) has been a major limiting factor in the treatment of brain tumors. The presence of contrast enhancement on standard brain MRI qualitatively reflects a disrupted state of the BBB. For this reason, drug access to the viable contrast enhanced tumor rim is likely significantly higher than to the peritumoral region, which usually does not have contrast enhancement [6, 7]. Evidence supporting this hypothesis came from studies in which drug levels of cytotoxic agents were sampled in tumors and the surrounding brain tissue at the time of surgery or autopsy. Drug concentrations were at the highest in the enhancing portion of tumors, and then rapidly decreased up to 40 fold lower by 2–3 cm distance from the viable tumor edge [810]. Overall, these observations suggest that the BBB and its integrity negatively correlate with delivery and potentially therapeutic effects of BBB impermeant drugs.

To circumvent the BBB problem in local drug delivery, recent approaches have focused on bypassing it. A previously described method is the use of Gliadel, a polymer wafer impregnated with the chemotherapeutic agent carmustine (BCNU) and placed intra-operatively in the resection cavity to bypass the BBB. This approach resulted in a statistically significant but modest survival advantage in both newly diagnosed and recurrent GBM [1113]. The modest benefit of Gliadel could be due to the short duration of drug delivery as nearly 80% of BCNU is released from the wafer over a period of only 5 days [14]. This observation further supports the notion that the BBB is critical to chemotherapy effect. However, Gliadel is not widely utilized as it requires an open craniotomy and can impair wound healing. Another approach of bypassing the BBB is the convection-enhanced delivery system in which a catheter is surgically inserted into the tumor to deliver chemotherapy [15]. This procedure requires prolonged hospitalization to maintain the external catheter to prevent serious complications and as a result has not been used extensively.

The role of hyperthermia in inducing BBB disruption has been previously described in animal models of CNS hyperthermia. In a rodent model of glioma, the global heating of the mouse’s head to 42°C for 30 minutes in a warm water bath significantly increased the brain concentration of a thermosensitive liposome encapsulated with adriamycin chemotherapy [16]. To effect more locoregional hyperthermia, retrograde infusion of a saline solution at 43°C into the left external carotid artery in the Wistar rat reversibly increased BBB permeability to Evans-blue albumin in the left cerebral hemisphere [17]. In another approach, neodymium-doped yttrium aluminum garnet (Nd:YAG) laser-induced thermotherapy to the left forebrain of Fischer rats resulted in loco-regional BBB disruption as evidenced by passage of Evans blue dye, serum proteins (e.g. fibrinogen & IgM), and the chemotherapeutic drug paclitaxel for up to several days after thermotherapy [18]. The effect of hyperthermia on the BBB of human brain has not been examined.

Here we describe an approach to induce sustained, local disruption of the peritumoral BBB using MRI-guided laser interstitial thermal therapy, or LITT. The biologic effects and correlation with MRI findings of LITT have been studied in both animal and human models since the development of LITT over twenty years ago. A well-described zonal distribution of histopathological changes with corresponding characteristic MR imaging findings centered on the light-guide track replace the lesion targeted for thermal therapy. The central treatment zone shows development of coagulative necrosis with complete loss of normal neurons or supporting structures immediately following therapy, corresponding to hyperintense T1-weighted signal intensity relative to normal brain [1922]. The peripheral zone of the post-treatment lesion is characterized by avid enhancement with intravenous gadolinium contrast agents, which peaks several days following thermal therapy and persists for many weeks after the procedure. Gadolinium contrast enhancement in the brain following LITT is due to leakage of gadolinium contrast into the extravascular space across a disrupted BBB [2023]. The perilesional zone of hyperintense signal intensity of FLAIR-weighted images develops within 1–3 days of thermal treatment and persists for 15–45 days [22].

We demonstrate that in addition to cytoreductive ablation of the main recurrent tumor, hyperthermic exposure of the peritumoral region resulted in localized, lasting disruption of the BBB as quantified by dynamic contrast-enhanced MRI (DCE-MRI) and serum levels of brain-specific enolase (BSE), thus providing a therapeutic window of opportunity for enhanced delivery of therapeutic agents.

Table 1. Patient Baseline Demographics and Characteristics.
TMZ/RT: Stupp protocol of 60 Gy radiotherapy plus concurrent 75mg/m2 daily temozolomide. Doxorubicin treatment: Timing of 20mg/m2 IV weekly doxobubicin treatment after LITT. Early = Starting within 1 week after LITT; Late = Starting at 6 weeks after LITT.  http://dx.doi.org:/10.1371/journal.pone.0148613.t001
……
Quantitative measurement of LITT-induced peritumoral BBB disruption by DCE-MRI

Brain MRI obtained within 48 hours following LITT showed the targeted tumor replaced by a post-treatment lesion corresponding to the volume of treated tissue on intraoperative thermometry maps. The post-treatment lesion lost the original rim of tumor-associated contrast enhancement and instead demonstrated central hyperintense T1-weighted signal compared to the pre-treated tumor and normal brain and a faint, newly developed discontinuous rim of peripheral contrast enhancement extending beyond the original tumor-associated enhancing rim (Fig 2A). These findings are consistent with a loss of viable tumor tissue caused by LITT, thus achieving an effective cytoreduction similar to open surgical resection. Of note, the rim of new peripheral contrast enhancement persisted for at least the next 28 days (Fig 2B–2E). Perilesional edema qualitatively evaluated on FLAIR-weighted images increased from pretreatment imaging at week 2 and persisted at week 4 following LITT (Fig 2F–2I). Perilesional edema decreased on subsequent MRI examinations. These findings qualitatively indicate that peritumoral BBB is disrupted by LITT and that the disruption peaks within approximately 2 weeks after the procedure.

……

Fig 3 demonstrates the Ktrans time curves for our cohort of patients. In all subjects the Ktrans in the ROIs within the enhancing ring around the ablated tumor is highly elevated in the first few days after the procedure and then progressively decreases at approximately the 4-week time point. The bottom right subplot in Fig 3 is an average of the Ktrans time courses from all the subjects with adjacent curves indicating the plus and minus one standard error of the mean curves. This figure demonstrates the peak Ktrans value immediately after the LITT procedure with persistent elevation out to about 4 weeks. Radiographically, persistent contrast enhancement and FLAIR hyperintensity were observed well past 6 weeks and in many cases more than 10 weeks later. Several patients had recurrent tumor by radiographic criteria (increasing size of the edema and enhancing area around the tumor site) and these patients also demonstrated a corresponding increase in the Ktrans value. These recurrences occurred after the 10-week mark and thus were not included in Fig 3. Importantly no difference in the pattern of Ktrans tracing was consistently observed between the 10 patients receiving late doxorubicin treatment and the 4 patients receiving early doxorubicin treatment. In summary, these results indicate that the peritumoral BBB disruption as measured by Ktrans peaked immediately after LITT and persisted above baseline for an additional 4 weeks.

……

To optimize the ELISA assay for BSE, we collected sera from 3 patients with a newly diagnosed low-grade (WHO grade 2) glioma before and after their planned craniotomy and surgical resection, and determined serum concentrations of BSE. WHO grade 2 gliomas were chosen for the optimization because as they are generally non-contrast enhanced tumors on brain MRI, tumor-associated BBB is relatively intact and consequently, serum concentrations of brain-specific factors are predicted to be low pre-operatively and to then rise post-operatively due to the BBB compromise from the surgery. Serum BSE concentrations were low prior to surgery and then, as predicted, consistently increased after open craniotomy and tumor resection, thus indicating that this method had adequate sensitivity in detecting changes in serum levels of BSE due to disruption of the BBB (Fig 4).

Fig 4. Optimization of the BSE ELISA assay for measuring BBB disruption.

Serum concentrations of BSE before and after open craniotomy for surgical debulking in 3 subjects (A, B, and C) with a low-grade glioma, WHO grade II. *p<0.05.  http://dx.doi.org:/10.1371/journal.pone.0148613.g004

……

Fig 5. BBB disruption induced by LITT as measured by serum biomarkers
Serum concentrations of BSE for each of the 14 evaluable subjects in the study (A-N) and as the mean + SEM (O) as a function of time in days from the LITT procedure. In 7/14 subjects, serum BSE levels slightly decreased immediately after LITT, then in 13/14 subjects, serum BSE levels rose shortly after LITT, peaked between 1–3 weeks after LITT, and then decreased by the 6-week time point. In Patient #12, serum BSE concentration increased at week 10 coincident with an increased Ktrans at the same time point, consistent with a recurrent tumor as demonstrated on diagnostic MR imaging. Patient #15’s serum BSE concentration began to rise by week 4, consistent with early multifocal recurrent disease as demonstrated on diagnostic MR imaging.  http://dx.doi.org:/10.1371/journal.pone.0148613.g005
…….

LITT is a minimally invasive neurosurgical technique that achieves effective tumor cytoreduction of brain tumors using a laser to deliver hyperthermic ablation. Here we have demonstrated that an unexpected, potentially useful effect of LITT is its ability to also disrupt the BBB in the peritumoral region that extends outwards 1–2 cm from the viable tumor rim. Importantly, the disruption persists in all 14 evaluable, treated patients for up to 4 weeks after LITT as measured quantitatively by DCE-MRI and up to 6 weeks as measured by serum levels of the brain-specific factor BSE. These observations indicate that after LITT there is a window during which enhanced local delivery of therapeutic agents into the desired location (i.e. peritumoral region) can potentially be achieved.

In all of the patients in this series, the peaks of serum concentrations of BSE showed wider variations and were delayed from several days to 1–2 weeks following the peak of BBB disruption as measured by Ktrans. The wider variations and delay of BSE concentrations lead to relatively low correlation coefficients between the two parameters and could be explained by: 1) the higher data point resolution for the serum values versus DCE-MRI values (weekly versus biweekly, respectively); 2) interval physiologic breakdown of thermally ablated tissue coupled with subsequent diffusion and equilibration between the intracranial and peripheral compartments; and 3) high inter-tumor heterogeneity among patients resulting in a wide variation in the rates at which ablated tissues of different compositions are broken down and released into the circulation. Whether these differences may be in part due to tumor-related factors such as IDH1/2 mutations and MGMT promoter methylation is unclear due to the small number of subjects. More importantly, both methods showed that the peritumoral BBB disruption induced by LITT was temporary, decreasing soon after peaking and being resolved by 4–6 weeks in most patients. In addition, although no significant difference in all the BBB measurement parameters was observed between the early and late doxorubicin treatment arms, the number of evaluable subjects was too small to allow generalization at this time.

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President Carter’s Status

Author: Larry H. Bernstein, MD, FCAP

 

 

Most Experts Not Surprised by Carter’s Status 

But early response does not mean ‘cure’

http://www.medpagetoday.com/HematologyOncology/SkinCancer/55076

 

http://clf1.medpagetoday.com/media/images/55xxx/55076.jpg

by Charles Bankhead
Staff Writer, MedPage Today

 

Former President Jimmy Carter’s announcement that he is free of metastatic melanoma surprised many people but, not most melanoma specialists contacted by MedPage Today.

With the evolution of modern radiation therapy techniques and targeted drugs, more patients with metastatic melanoma achieve complete and partial remissions, including remission of small brain metastases like the ones identified during the evaluation and initial treatment of Carter. However, the experts — none of whom have direct knowledge of Carter’s treatment or medical records — cautioned that early remission offers no assurance that the former president is out of the woods.

“If I had a patient of my own with four small brain mets undergoing [stereotactic radiation therapy], I would tell them that I fully expected the radiation to take care of those four lesions,” said Vernon K. Sondak, MD, of Moffitt Cancer Center in Tampa. “The fact that President Carter reports that it has done just that is not a surprise to me at all.

“I would also tell my patient that the focused radiation only treats the known cancer in the brain, and that if other small areas of cancer are present, they will likely eventually grow large enough to need radiation or other treatment as well, and that periodic brain scans will be required to monitor for this possibility.”

Carter also is being treated with the immune checkpoint inhibitor pembrolizumab (Keytruda), which is known to stimulate immune cells that then migrate to tumor sites to eradicate the lesions, noted Anna Pavlick, DO, of NYU Langone Medical Center in New York City.

“Melanoma is no longer a death sentence, and we are really changing what happens to patients,” said Pavlick. “It really is amazing.”

Carter’s melanoma story began to emerge in early August when he had surgery to remove what was described as “a small mass” from his liver. Following the surgery, Carter announced that his doctors had discovered four small melanoma lesions in his brain, confirming a suspicion the specialists had shared with him at the time of the surgery.

Carter subsequently underwent focused radiation therapy to eradicate the brain lesions and initiated a 12-week course of treatment with pembrolizumab. The radiation therapy-targeted therapy combination was a logical option for Carter, given observations that the PD-L1 inhibitor has synergy with radiation, noted Stergios Moschos, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center at Chapel Hill.

“I have seen this in other patients with metastatic melanoma,” said Gary K. Schwartz, MD, of Columbia University Medical Center in New York City. “It is remarkable but absolutely possible within the realm of immunotherapy today.”

Although Carter’s announcement is undeniably good news, the optimism should be tempered by a long-term perspective, suggested Nagla Abdel Karim, MD, PhD, of the University of Cincinnati Medical Center.

“We do have similar stories; however, we would be careful to call it a ‘complete remission’ and ‘disease control’ and not a ‘cure,’ so far,” said Karim. “We would resume therapy and follow-up any autoimmune side effects. Most important is the quality of life, which he seems to enjoy, and we are very happy with that.”

Darrell S. Rigel, MD, also of NYU Langone Medical Center, represented the lone dissenter among specialists who responded to MedPage Today‘s request for comments.

“I’m happy for him, but it’s very unusual, especially in older men, who usually have a worse prognosis,” said Rigel. “He is on a new drug that may have a little more promise, but there is no definitive cure at this point.”

 

 

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Brain Cancer Vaccine in Development and other considerations

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

GEN News Highlights   Mar 3, 2016

Advanced Immunotherapeutic Method Shows Promise against Brain Cancer

http://www.genengnews.com/gen-news-highlights/advanced-immunotherapeutic-method-shows-promise-against-brain-cancer/81252433/

 

http://www.genengnews.com/Media/images/GENHighlight/Mar3_2016_LeuvenLab_CellDeathMouseBrain6232214015.jpg

The researchers induced a specific type of cell death in brain cancer cells from mice. The dying cancer cells were then incubated together with dendritic cells, which play a vital role in the immune system. The researchers discovered that this type of cancer cell killing releases “danger signals” that fully activate the dendritic cells. “We re-injected the activated dendritic cells into the mice as a therapeutic vaccine,” Professor Patrizia Agostinis explains. “That vaccine alerted the immune system to the presence of dangerous cancer cells in the body. As a result, the immune system could recognize them and start attacking the brain tumor.” [©KU Leuven Laboratory of Cell Death Research & Therapy, Dr. Abhishek D. Garg]

 

Scientists from KU Leuven in Belgium say they have shown that next-generation cell-based immunotherapy may offer new hope in the fight against brain cancer.

Cell-based immunotherapy involves the injection of a therapeutic anticancer vaccine that stimulates the patient’s immune system to attack the tumor. Thus far, the results of this type of immunotherapy have been mildly promising. However, Abhishek D. Garg and Professor Patrizia Agostinis from the KU Leuven department of cellular and molecular medicine believe they have found a novel way to produce more effective cell-based anticancer vaccines.

The researchers induced a specific type of cell death in brain cancer cells from mice. The dying cancer cells were then incubated together with dendritic cells, which play a vital role in the immune system. The investigators discovered that this type of cancer cell killing releases “danger signals” that fully activate the dendritic cells.

“We re-injected the activated dendritic cells into the mice as a therapeutic vaccine,” explains Prof. Agostinis. “That vaccine alerted the immune system to the presence of dangerous cancer cells in the body. As a result, the immune system could recognize them and start attacking the brain tumor.”

Combined with chemotherapy, this novel cell-based immunotherapy drastically increased the survival rates of mice afflicted with brain tumors. Almost 50% of the mice were completely cured. None of the mice treated with chemotherapy alone became long-term survivors.

“The major goal of any anticancer treatment is to kill all cancer cells and prevent any remaining malignant cells from growing or spreading again,” says Professor Agostinis. “This goal, however, is rarely achieved with current chemotherapies, and many patients relapse. That’s why the co-stimulation of the immune system is so important for cancer treatments. Scientists have to look for ways to kill cancer cells in a manner that stimulates the immune system. With an eye on clinical studies, our findings offer a feasible way to improve the production of vaccines against brain tumors.”

The team published its study (“Dendritic Cell Vaccines Based on Immunogenic Cell Death Elicit Danger Signals and T Cell–Driven Rejection of High-Grade Glioma”) in Science Translational Medicine.

 

Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell–driven rejection of high-grade glioma

 

SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma

 

Cortical GABAergic excitation contributes to epileptic activities around human glioma

 

Spherical Nucleic Acid Nanoparticle Conjugates as an RNAi-Based Therapy for Glioblastoma

Glioblastoma multiforme (GBM) is a neurologically debilitating disease that culminates in death 14 to 16 months after diagnosis. An incomplete understanding of how cataloged genetic aberrations promote therapy resistance, combined with ineffective drug delivery to the central nervous system, has rendered GBM incurable. Functional genomics efforts have implicated several oncogenes in GBM pathogenesis but have rarely led to the implementation of targeted therapies. This is partly because many “undruggable” oncogenes cannot be targeted by small molecules or antibodies. We preclinically evaluate an RNA interference (RNAi)–based nanomedicine platform, based on spherical nucleic acid (SNA) nanoparticle conjugates, to neutralize oncogene expression in GBM. SNAs consist of gold nanoparticles covalently functionalized with densely packed, highly oriented small interfering RNA duplexes. In the absence of auxiliary transfection strategies or chemical modifications, SNAs efficiently entered primary and transformed glial cells in vitro. In vivo, the SNAs penetrated the blood-brain barrier and blood-tumor barrier to disseminate throughout xenogeneic glioma explants. SNAs targeting the oncoprotein Bcl2Like12 (Bcl2L12)—an effector caspase and p53 inhibitor overexpressed in GBM relative to normal brain and low-grade astrocytomas—were effective in knocking down endogenous Bcl2L12 mRNA and protein levels, and sensitized glioma cells toward therapy-induced apoptosis by enhancing effector caspase and p53 activity. Further, systemically delivered SNAs reduced Bcl2L12 expression in intracerebral GBM, increased intratumoral apoptosis, and reduced tumor burden and progression in xenografted mice, without adverse side effects. Thus, silencing antiapoptotic signaling using SNAs represents a new approach for systemic RNAi therapy for GBM and possibly other lethal malignancies.

 

Rapid, Label-Free Detection of Brain Tumors with Stimulated Raman Scattering Microscopy

Surgery is an essential component in the treatment of brain tumors. However, delineating tumor from normal brain remains a major challenge. We describe the use of stimulated Raman scattering (SRS) microscopy for differentiating healthy human and mouse brain tissue from tumor-infiltrated brain based on histoarchitectural and biochemical differences. Unlike traditional histopathology, SRS is a label-free technique that can be rapidly performed in situ. SRS microscopy was able to differentiate tumor from nonneoplastic tissue in an infiltrative human glioblastoma xenograft mouse model based on their different Raman spectra. We further demonstrated a correlation between SRS and hematoxylin and eosin microscopy for detection of glioma infiltration (κ = 0.98). Finally, we applied SRS microscopy in vivo in mice during surgery to reveal tumor margins that were undetectable under standard operative conditions. By providing rapid intraoperative assessment of brain tissue, SRS microscopy may ultimately improve the safety and accuracy of surgeries where tumor boundaries are visually indistinct.

 

Neural Stem Cell–Mediated Enzyme/Prodrug Therapy for Glioma: Preclinical Studies

 

Magnetic Resonance Metabolic Imaging of Glioma

 

Exploiting the Immunogenic Potential of Cancer Cells for Improved Dendritic Cell Vaccines

Cancer immunotherapy is currently the hottest topic in the oncology field, owing predominantly to the discovery of immune checkpoint blockers. These promising antibodies and their attractive combinatorial features have initiated the revival of other effective immunotherapies, such as dendritic cell (DC) vaccinations. Although DC-based immunotherapy can induce objective clinical and immunological responses in several tumor types, the immunogenic potential of this monotherapy is still considered suboptimal. Hence, focus should be directed on potentiating its immunogenicity by making step-by-step protocol innovations to obtain next-generation Th1-driving DC vaccines. We review some of the latest developments in the DC vaccination field, with a special emphasis on strategies that are applied to obtain a highly immunogenic tumor cell cargo to load and to activate the DCs. To this end, we discuss the effects of three immunogenic treatment modalities (ultraviolet light, oxidizing treatments, and heat shock) and five potent inducers of immunogenic cell death [radiotherapy, shikonin, high-hydrostatic pressure, oncolytic viruses, and (hypericin-based) photodynamic therapy] on DC biology and their application in DC-based immunotherapy in preclinical as well as clinical settings.

Cancer immunotherapy has gained considerable momentum over the past 5 years, owing predominantly to the discovery of immune checkpoint inhibitors. These inhibitors are designed to release the brakes of the immune system that under physiological conditions prevent auto-immunity by negatively regulating cytotoxic T lymphocyte (CTL) function. Following the FDA approval of the anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibody (mAb) ipilimumab (Yervoy) in 2011 for the treatment of metastatic melanoma patients (1), two mAbs targeting programed death (PD)-1 receptor signaling (nivolumab and pembrolizumab) have very recently joined the list of FDA-approved checkpoint blockers (respectively, for the treatment of metastatic squamous non-small cell lung cancer and relapsed/refractory melanoma patients) (2, 3).

However, the primary goal of cancer immunotherapy is to activate the immune system in cancer patients. This requires the induction of tumor-specific T-cell-mediated antitumor immunity. Checkpoint blockers are only able to abrogate the brakes of a functioning antitumoral immune response, implying that only patients who have pre-existing tumor-specific T cells will benefit most from checkpoint blockade. This is evidenced by the observation that ipilimumab may be more effective in patients who have pre-existing, albeit ineffective, antitumor immune responses (4). Hence, combining immune checkpoint blockade with immunotherapeutic strategies that prime tumor-specific T cell responses might be an attractive and even synergistic approach. This relatively new paradigm has lead to the revival of existing, and to date disappointing (as monotherapies), active immunotherapeutic treatment modalities. One promising strategy to induce priming of tumor-specific T cells is dendritic cell (DC)-based immunotherapy.

Dendritic cells are positioned at the crucial interface between the innate and adaptive immune system as powerful antigen-presenting cells capable of inducing antigen-specific T cell responses (5). Therefore, they are the most frequently used cellular adjuvant in clinical trials. Since the publication of the first DC vaccination trial in melanoma patients in 1995, the promise of DC immunotherapy is underlined by numerous clinical trials, frequently showing survival benefit in comparison to non-DC control groups (68). Despite the fact that most DC vaccination trials differ in several vaccine parameters (i.e., site and frequency of injection, nature of the DCs, choice of antigen), DC vaccination as a monotherapy is considered safe and rarely associates with immune-related toxicity. This is in sharp contrast with the use of mAbs or cytokine therapies. Ipilumumab has, for instance, been shown to induce immune-related serious adverse events in up to one-third of treated melanoma patients (1). The FDA approval of Sipuleucel-T (Provenge), an autologous DC-enriched vaccine for hormone-resistant metastatic prostate cancer, in 2010 is really considered as a milestone in the vaccination community (9). After 15 years of extensive clinical research, Sipileucel-T became the first cellular immunotherapy ever that received FDA approval, providing compelling evidence for the substantial socio-economic impact of DC-based immunotherapy. DC vaccinations have most often been applied in patients with melanoma, prostate cancer, high-grade glioma, and renal cell cancer. Although promising objective responses and tumor-specific T cell responses have been observed in all these cancer-types (providing proof-of-principle for DC-based immunotherapy), the clinical success of this treatment is still considered suboptimal (6). This poor clinical efficacy can in part be attributed to the severe tumor-induced immune suppression and the selection of patients with advanced disease status and poor survival prognostics (6, 1012).

There is a consensus in the field that step-by-step optimization and standardization of the production process of DC vaccines, to obtain a Th1-driven immune response, might enhance their clinical efficacy (13). In this review, we address some recent DC vaccine adaptations that impact DC biology. Combining these novel insights might bring us closer to an ideal DC vaccine product that can trigger potent CTL- and Th1-driven antitumor immunity.

One factor requiring more attention in this production process is the immunogenicity of the dying or dead cancer cells used to load the DCs. It has been shown in multiple preclinical cancer models that the methodology used to prepare the tumor cell cargo can influence the in vivo immunogenic potential of loaded DC vaccines (1419). Different treatment modalities have been described to enhance the immunogenicity of cancer cells in the context of DC vaccines. These treatments can potentiate antitumor immunity by inducing immune responses against tumor neo-antigens and/or by selectively increasing the exposure/release of particular damage-associated molecular patterns (DAMPs) that can trigger the innate immune system (14, 1719). The emergence of the concept of immunogenic cell death (ICD) might even further improve the immunogenic potential of DC vaccines. Cancer cells undergoing ICD have been shown to exhibit excellent immunostimulatory capacity owing to the spatiotemporally defined emission of a series of critical DAMPs acting as potent danger signals (20, 21). Thus far, three DAMPs have been attributed a crucial role in the immunogenic potential of nearly all ICD inducers: the surface-exposed “eat me” signal calreticulin (ecto-CRT), the “find me” signal ATP and passively released high-mobility group box 1 (HMGB1) (21). Moreover, ICD-experiencing cancer cells have been shown in various mouse models to act as very potent Th1-driving anticancer vaccines, already in the absence of any adjuvants (21, 22). The ability to reject tumors in syngeneic mice after vaccination with cancer cells (of the same type) undergoing ICD is a crucial hallmark of ICD, in addition to the molecular DAMP signature (21).

Here, we review the effects of three frequently used immunogenic modalities and four potent ICD inducers on DC biology and their application in DC vaccines in preclinical as well as clinical settings (Tables (Tables11 and and2).2). Moreover, we discuss the rationale for combining different cell death-inducing regimens to enhance the immunogenic potential of DC vaccines and to ensure the clinical relevance of the vaccine product.

A list of prominent enhancers of immunogenicity and ICD inducers applied in DC vaccine setups and their associations with DAMPs and DC biology.
A list of preclinical tumor models and clinical studies for evaluation of the in vivo potency of DC vaccines loaded with immunogenically killed tumor cells.
The Impact of DC Biology on the Efficacy of DC Vaccines

Over the past years, different DC vaccine parameters have been shown to impact the clinical effectiveness of DC vaccinations. In the next section, we will elaborate on some promising adaptations of the DC preparation protocol.

Given the labor-intensive ex vivo culturing protocol of monocyte-derived DCs and inspired by the results of the Provenge study, several groups are currently exploiting the use of blood-isolated naturally circulating DCs (7678). In this context, De Vries et al. evaluated the use of antigen-loaded purified plasmacytoid DCs for intranodal injection in melanoma patients (79). This strategy was feasible and induced only very mild side effects. In addition, the overall survival of vaccinated patients was greatly enhanced as compared to historical control patients. However, it still remains to be determined whether this strategy is more efficacious than monocyte-derived DC vaccine approaches (78). By contrast, experiments in the preclinical GL261 high-grade glioma model recently showed that vaccination with tumor antigen-loaded myeloid DCs resulted in more robust Th1 responses and a stronger survival benefit as compared to mice vaccinated with their plasmacytoid counterparts (80).

In view of their strong potential to stimulate cytotoxic T cell responses, several groups are currently exploring the use of Langerhans cell-like DCs as sources for DC vaccines (8183). These so-called IL-15 DCs can be derived from CD14+monocytes by culturing them with IL-15 (instead of the standard IL-4). Recently, it has been shown that in comparison to IL-4 DCs, these cells have an increased capacity to stimulate antitumor natural killer (NK) cell cytotoxicity in a contact- and IL-15-dependent manner (84). NK cells are increasingly being recognized as crucial contributors to antitumor immunity, especially in DC vaccination setups (85, 86). Three clinical trials are currently evaluating these Langerhans cell-type DCs in melanoma patients (NCT00700167, NCT 01456104, and NCT01189383).

Targeting cancer stem cells is another promising development, particularly in the setting of glioma (87). Glioma stem cells can foster tumor growth, radio- and chemotherapy-resistance, and local immunosuppression in the tumor microenvironment (87, 88). Furthermore, glioma stem cells may express higher levels of tumor-associated antigens and MHC complex molecules as compared to non-stem cells (89, 90). A preclinical study in a rodent orthotopic glioblastoma model has shown that DC vaccines loaded with neuropsheres enriched in cancer stem cells could induce more immunoreactivity and survival benefit as compared to DCs loaded with GL261 cells grown under standard conditions (91). Currently there are four clinical trials ongoing in high-grade glioma patients evaluating this approach (NCT00890032, NCT00846456, NCT01171469, and NCT01567202).

With regard to the DC maturation status of the vaccine product, a phase I/II clinical trial in metastatic melanoma patients has confirmed the superiority of mature antigen-loaded DCs to elicit immunological responses as compared to their immature counterparts (92). This finding was further substantiated in patients diagnosed with prostate cancer and recurrent high-grade glioma (93, 94). Hence, DCs need to express potent costimulatory molecules and lymph node homing receptors in order to generate a strong T cell response. In view of this finding, the route of administration is another vaccine parameter that can influence the homing of the injected DCs to the lymph nodes. In the context of prostate cancer and renal cell carcinoma it has been shown that vaccination routes with access to the draining lymph nodes (intradermal/intranodal/intralymphatic/subcutaneous) resulted in better clinical response rates as compared to intravenous injection (93). In melanoma patients, a direct comparison between intradermal vaccination and intranodal vaccination concluded that, although more DCs reached the lymph nodes after intranodal vaccination, the melanoma-specific T cells induced by intradermal vaccination were more functional (95). Furthermore, the frequency of vaccination can also influence the vaccine’s immunogenicity. Our group has shown in a cohort-comparison trial involving relapsed high-grade glioma patients that shortening the interval between the four inducer DC vaccines improved the progression-free survival curves (58, 96).

Another variable that has been systematically studied is the cytokine cocktail that is applied to mature the DCs. The current gold standard cocktail for DC maturation contains TNF-α, IL-1β, IL-6, and PGE2 (97, 98). Although this cocktail upregulates DC maturation markers and the lymph node homing receptor CCR7, IL-12 production by DCs could not be evoked (97, 98). Nevertheless, IL-12 is a critical Th1-driving cytokine and DC-derived IL-12 has been shown to associate with improved survival in DC vaccinated high-grade glioma and melanoma patients (99, 100). Recently, a novel cytokine cocktail, including TNF-α, IL-1β, poly-I:C, IFN-α, and IFN-γ, was introduced (101, 102). The type 1-polarized DCs obtained with this cocktail produced high levels of IL-12 and could induce strong tumor-antigen-specific CTL responses through enhanced induction of CXCL10 (99). In addition, CD40-ligand (CD40L) stimulation of DCs has been used to mature DCs in clinical trials (100, 103). Binding of CD40 on DCs to CD40L on CD4+ helper T cells licenses DCs and enables them to prime CD8+ effector T cells.

A final major determinant of the vaccine immunogenicity is the choice of antigen to load the DCs. Two main approaches can be applied: loading with selected tumor antigens (tumor-associated antigens or tumor-specific antigens) and loading with whole tumor cell preparations (13). The former strategy enables easier immune monitoring, has a lower risk of inducing auto-immunity, and can provide “off-the-shelf” availability of the antigenic cargo. Whole tumor cell-based DC vaccines, on the other hand, are not HLA-type dependent, have a reduced risk of inducing immune-escape variants, and can elicit immunity against multiple tumor antigens. Meta-analytical data provided by Neller et al. have demonstrated enhanced clinical efficacy in several tumor types of DCs loaded with whole tumor lysate as compared to DCs pulsed with defined tumor antigens (104). This finding was recently also substantiated in high-grade glioma patients, although this study was not set-up to compare survival parameters (105).

Toward a More Immunogenic Tumor Cell Cargo

The majority of clinical trials that apply autologous whole tumor lysate to load DC vaccines report the straightforward use of multiple freeze–thaw cycles to induce primary necrosis of cancer cells (8, 93). Freeze–thaw induced necrosis is, however, considered non-immunogenic and has even been shown to inhibit toll-like receptor (TLR)-induced maturation and function of DCs (16). To this end, many research groups have focused on tackling this roadblock by applying immunogenic modalities to induce cell death.

Immunogenic Treatment Modalities

Tables Tables11 and and22 list some frequently applied treatment methods to enhance the immunogenic potential of the tumor cell cargo that is used to load DC vaccines in an ICD-independent manner (i.e., these treatments do not meet the molecular and/or cellular determinants of ICD). Immunogenic treatment modalities can positively impact DC biology by inducing particular DAMPs in the dying cancer cells (Table (Table1).1). Table Table22 lists the preclinical and clinical studies that investigated their in vivo potential. Figure Figure11 schematically represents the application and the putative modes of action of these immunogenic enhancers in the setting of DC vaccines.

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A schematic representation of immunogenic DC vaccines. Cancer cells show enhanced immunogenicity upon treatment with UV irradiation, oxidizing treaments, and heat shock, characterized by the release of particular danger signals and the (increased) production of tumor (neo-)antigens. Upon loading onto DCs, DCs undergo enhanced phagocytosis and antigen uptake and show phenotypic and partial functional maturation. Upon in vivo immunization, these DC vaccines elicit Th1- and cytotoxic T lymphocyte (CTL)-driven tumor rejection.

Ultraviolet Irradiation ….

Oxidation-Inducing Modalities

In recent years, an increasing number of data were published concerning the ability of oxidative stress to induce oxidation-associate molecular patterns (OAMPs), such as reactive protein carbonyls and peroxidized phospholipids, which can act as DAMPs (28, 29) (Table (Table1).1). Protein carbonylation, a surrogate indicator of irreversible protein oxidation, has for instance been shown to improve cancer cell immunogenicity and to facilitate the formation of immunogenic neo-antigens (30, 31).

One prototypical enhancer of oxidation-based immunogenicity is radiotherapy (21,23). In certain tumor types, such as high-grade glioma and melanoma, clinical trials that apply autologous whole tumor lysate to load DC vaccines report the random use of freeze–thaw cycles (to induce necrosis of cancer cells) or a combination of freeze–thaw cycles and subsequent high-dose γ-irradiation (8, 18) (Table (Table2).2). However, from the available clinical evidence, it is unclear which of both methodologies has superior immunogenic potential. In light of the oxidation-based immunogenicity that is associated with radiotherapy, we recently demonstrated the superiority of DC vaccines loaded with irradiated freeze–thaw lysate (in comparison to freeze–thaw lysate) in terms of survival advantage in a preclinical high-grade glioma model (18) (Table (Table2).2). ….

Heat Shock Treatment

Heat shock is a term that is applied when a cell is subjected to a temperature that is higher than that of the ideal body temperature of the organisms of which the cell is derived. Heat shock can induce apoptosis (41–43°C) or necrosis (>43°C) depending on the temperature that is applied (110). The immunogenicity of heat shock treated cancer cells largely resides within their ability to produce HSPs, such as HSP60, HSP70, and HSP90 (17, 32) (Table (Table1).1). …

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Figure 2

A schematic representation of immunogenic cell death (ICD)-based DC vaccines. ICD causes cancer cells to emit a spatiotemporally defined pattern of danger signals. Upon loading of these ICD-undergoing cancer cells onto DCs, they induce extensive phagocytosis and antigen uptake. Loaded DCs show enhanced phenotypic and functional maturation and immunization with these ICD-based DC vaccines instigates Th1-, Th17-, and cytotoxic T lymphocyte (CTL)-driven antitumor immunity in vivo.
Inducers of Immunogenic Cell Death

Immunogenic cell death is a cell death regimen that is associated with the spatiotemporally defined emission of immunogenic DAMPs that can trigger the immune system (20, 21, 113). ICD has been found to depend on the concomitant induction of reactive oxygen species (ROS) and activation of endoplasmatic reticulum (ER) stress (111). Besides the three DAMPs that are most crucial for ICD (ecto-CRT, ATP, and HMGB1), other DAMPs such as surface-exposed or released HSPs (notably HSP70 and HSP90) have also been shown to contribute to the immunogenic capacity of ICD inducers (20, 21). The binding of these DAMPs to their respective immune receptors (CD91 for HSPs/CRT, P2RX7/P2RY2 for ATP, and TLR2/4 for HMGB1/HSP70) leads to the recruitment and/or activation of innate immune cells and facilitates the uptake of tumor antigens by antigen-presenting cells and their cross-presentation to T cells eventually leading to IL-1β-, IL-17-, and IFN-γ-dependent tumor eradiation (22). This in vivo tumor rejecting capacity induced by dying cancer cells in the absence of any adjuvant, is considered as a prerequisite for an agent to be termed an ICD inducer. …

Although the list of ICD inducers is constantly growing (113), only few of these immunogenic modalities have been tested in order to generate an immunogenic tumor cell cargo to load DC vaccines (Tables (Tables11 and and2).2). Figure Figure22 schematically represents the preparation of ICD-based DC vaccines and their putative modes of action.

Radiotherapy

Ionizing X-ray or γ-ray irradiation exerts its anticancer effect predominantly via its capacity to induce DNA double-strand breaks leading to intrinsic cancer cell apoptosis (114). The idea that radiotherapy could also impact the immune system was derived from the observation that radiotherapy could induce T-cell-mediated delay of tumor growth in a non-irradiated lesion (115). This abscopal (ab-scopus, away from the target) effect of radiotherapy was later explained by the ICD-inducing capacity (116). Together with anthracyclines, γ-irradiation was one of the first treatment modalities identified to induce ICD. …

Shikonin

The phytochemical shikonin, a major component of Chinese herbal medicine, is known to inhibit proteasome activity. It serves multiple biological roles and can be applied as an antibacterial, antiviral, anti-inflammatory, and anticancer treatment. …

High-hydrostatic pressure

High-hydrostatic pressure (HHP) is an established method to sterilize pharmaceuticals, human transplants, and food. HHP between 100 and 250 megapascal (MPa) has been shown to induce apoptosis of murine and human (cancer) cells (121123). While DNA damage does not seem to be induced by HHP <1000 MPa, HHP can inhibit enzymatic functions and the synthesis of cellular proteins (122). Increased ROS production was detected in HHP-treated cancer cell lines and ER stress was evidenced by the rapid phosphorylation of eIF2α (42).  …

Oncolytic Viruses

Oncolytic viruses are self-replicating, tumor selective virus strains that can directly lyse tumor cells. Over the past few years, a new oncolytic paradigm has risen; entailing that, rather than utilizing oncolytic viruses solely for direct tumor eradication, the cell death they induce should be accompanied by the elicitation of antitumor immune responses to maximize their therapeutic efficacy (128). One way in which these oncolytic viruses can fulfill this oncolytic paradigm is by inducing ICD (128).

Thus far, three oncolytic virus strains can meet the molecular requirements of ICD; coxsackievirus B3 (CVB3), oncolytic adenovirus and Newcastle disease virus (NDV) (Table (Table1)1) (113). Infection of tumor cells with these viruses causes the production of viral envelop proteins that induce ER stress by overloading the ER. Hence, all three virus strains can be considered type II ICD inducers (113). …

Photodynamic therapy

Photodynamic therapy (PDT) is an established, minimally invasive anticancer treatment modality. It has a two-step mode of action involving the selective uptake of a photosensitizer by the tumor tissue, followed by its activation by light of a specific wavelength. This activation results in the photochemical production of ROS in the presence of oxygen (129131). One attractive feature of PDT is that the ROS-based oxidative stress originates in the particular subcellular location where the photosensitizer tends to accumulate, ultimately leading to the destruction of the tumor cell (132). …

Combinatorial Regimens

In DC vaccine settings, cancer cells are often not killed by a single treatment strategy but rather by a combination of treatments. In some cases, the underlying rationale lies within the additive or even synergistic value of combining several moderately immunogenic modalities. The combination of radiotherapy and heat shock has, for instance, been shown to induce higher levels of HSP70 in B16 melanoma cells than either therapy alone (16). In addition, a combination therapy consisting of heat shock, γ-irradiation, and UV irradiation has been shown to induce higher levels of ecto-CRT, ecto-HSP90, HMGB1, and ATP in comparison to either therapy alone or doxorubicin, a well-recognized inducer of ICD (57). ….

Triggering antitumor immune responses is an absolute requirement to tackle metastatic and diffusely infiltrating cancer cells that are resistant to standard-of-care therapeutic regimens. ICD-inducing modalities, such as PDT and radiotherapy, have been shown to be able to act as in situ vaccines capable of inducing immune responses that caused regression of distal untreated tumors. Exploiting these ICD inducers and other immunogenic modalities to obtain a highly immunogenic antigenic tumor cell cargo for loading DC vaccines is a highly promising application. In case of the two prominent ICD inducers, Hyp-PDT and HHP, preclinical studies evaluating this relatively new approach are underway and HHP-based DC vaccines are already undergoing clinical testing. In the preclinical testing phase, more attention should be paid to some clinically driven considerations. First, one should consider the requirement of 100% mortality of the tumor cells before in vivo application. A second consideration from clinical practice (especially in multi-center clinical trials) is the fact that most tumor specimens arrive in the lab in a frozen state. This implies that a significant number of cells have already undergone non-immunogenic necrosis before the experimental cell killing strategies are applied. ….

 

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