Conference Schedule

Day1: June 11, 2018

Keynote Forum

Biography

Metellus Philippe is a Professor of Neurosurgery at the Clairval Hospital Center in Marseille, France. He is specialized in brain tumors and is the actual Leader of the glioma and the brain metastases program in France. Besides his clinical activity, he is running translational and basic science research program in the INSERM UMR 911 unit. His clinical and research activities are focused on Gliomas and Brain Metastases. A surgical research program on gliomas located in eloquent areas including awake craniotomies with electroencephalographic recordings has been developed with his neurological team in 2011. Also, a translational research program on gliomas and brain metastases biology is conducted with the Oncological Transfer Laboratory at the Aix-Marseille University. These programs involve a multi-disciplinary brain tumor consortium including Neurologists, Neuro-Oncologists, Medical-Oncologists, Radiation-Oncologists, Neuro-Radiologists, Pathologists and the translational oncology university platform. Since 2011, he organizes the Annual Brain Metastases Research and Emerging Therapies Conference in Marseille.
 

Abstract

The brain can be a sanctuary for metastatic cancer disease as many anti-cancer drugs are unable to cross an intact bloodbrain barrier allowing tumors to grow even when extracranial disease is effectively treated with chemotherapy or targeted therapies. Surgery plays an indispensable role in the treatment of brain metastases (BM), and the benefit of surgery has been documented in numerous studies. However, standard surgical treatment of cerebral metastases is often insufficient in achieving local tumor control, becoming obvious in the high local recurrence rate of surgically resected cerebral metastases without subsequent radiation therapy, which was estimated to be about 50% in some studies warranting an adjuvant treatment of the surgical cavity. Recently, two randomized clinical trials provided convincing evidence that adjuvant stereotactic radiosurgery (SRS) in patients with limited number of BM was associated with an increased local control. However, the still relative high rate of local recurrence, especially in large BM questioned the technique of irradiation and the actual need to better assess the quality of surgical resection. Indeed, one of the challenges of postoperative SRS is the target delineation. Another issue is our capability to accurately assess the extent of resection. We will discuss here, the potential interest of different SRS strategies as well as new surgical techniques such as fluorescence-guided resection in these patients. Also, surgical resection of brain metastases is more often included in a global diagnostic strategy aims to identify specific molecular profiles that could help defining a more tailored systemic treatment. Evaluation of available and future surgical approaches is thus of great importance. The goal of this work is to reappraise new approaches and strategies in the surgery of cerebral metastases at the molecular biology era.
 

Biography

David I Smith received his PhD in Biochemistry from the University of Wisconsin in Madison in 1978. His first academic position was at Wayne State University School of Medicine and in 1996 he moved to the Mayo Clinic as a Professor in the Department of Laboratory Medicine and Pathology. He is also the Chairman of the Technology Assessment Group for the Mayo Clinic Center for Individualized Medicine. His laboratory utilizes next generation sequencing to study the different ways that human papillomavirus can cancer in different tissues. His group also studies the common fragile sites which are regions of profound instability found in all individuals.
 

Abstract

Advances in DNA sequencing have improved dramatically over the past 10 years. In 2000 the first draft of the human genome was developed using Sanger sequencing technology. This technology required individual DNA molecules to be cloned into E. coli, and then the resulting amplified fragments were sequenced in microliter sized reactions. The cost for the generation of the first draft sequence of the human genome cost almost three billion dollars. The advent of next generation sequencing based upon massively parallel sequencing utilized PCR-based methodologies to amplify DNA fragments and dramatically decreased reaction volumes into the picoliter range. While the first next generation sequencer was capable of 20 million base pairs of sequence per run subsequent sequence technologies were capable of much greater sequence outputs. The Illumina DNA sequencers have now increased sequence output from one billion base pairs to over 6 trillion base pairs of sequence per run. In my presentation I will describe the different next generation sequencing platforms and discuss their strengths and weaknesses. I will further describe the different types of sequencing that can be performed on these platforms and how this will totally transform clinical oncology in just the next few years. These technologies enable true personalized cancer treatment and this will completely change how we can prevent cancers, detect them earlier and also treat each individual patient with cancer.

Biography

Young Rok Do has his expertise in evaluation and passion in improving the outcome of CML treatment. His open and contextual evaluation model based on clinical trial creates new pathways for improving CML. He has built this achievement after years of experience in research, evaluation, teaching and administration both in hospital and education institutions.
 

Abstract

Background: Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved in Korea for CML-CP in patients newly diagnosed or with insufficient response to other TKIs. This study called RERISE study (NCT01511289) was conducted to evaluate the efficacy and safety of radotinib as first-line therapy for CML-CP. In RERISE phase 3 studies, radotinib demonstrated significantly higher and faster rates of major molecular response (MMR) than imatinib in patients with newly diagnosed CML-CP. By 12 and 24 months follow up, MMR (BCRABL1IS ≤ 0.1%) and MR4.5 (BCR-ABL1IS ≤ 0.0032%) in radotinib 300 mg twice daily (BID) were higher than imatinib group. Also, early molecular response (EMR) at 3- or 6- months could predict better outcomes in both radotinib or imatinib groups. To confirm the long-term benefits and risks of radotinib 300mg bid and imatinib 400mg qd, we update the results from RERISE phase 3 study based on a minimum follow-up of 36 months. Methods: This multinational, open-label study assigned patients (1:1:1) to one of two bid radotinib doses, or imatinib qd. The primary endpoint was MMR by 12 months. 241 patients were randomized 1:1:1 to radotinib 300 mg bid (n=79), radotinib 400 mg bid (n=81), or imatinib 400 mg qd (n=81). Methods have been previously reported (Blood 2015 126:476). We evaluated MMR and MR4.5, overall survival (OS), and progression-free survival (PFS) by 36 months. Also, we analyzed the clinical impacts of early and deeper molecular response in radotinib 300mg bid and imatinib 400 mg qd groups. Results: By 36 months, MMR was significantly higher in patients receiving radotinib 300 mg bid compared with imatinib 400mg qd. The MR4.5 rate by 36 months was also higher for radotinib compared to imatinib (43% vs. 28%; P=0.0538). More patients treated with radotinib achieved additional MMR and MR4.5 since 12 months and time to MR4.5 was faster in radotinib than imatinib (median 924 vs. 1,095 days; P=0.2534). Of 59 patients 
who had MMR by 36 months, 18 patients achieved MMR, and of 34 patients who had MR4.5 by 36 months, 22 patients achieved MR4.5 since 12 months. Estimated OS and PFS rate at 36 months were not significantly different in two groups (99% vs. 98%; P=0.6204, 99% vs. 96%; P=0.3070). Treatment failure was lower in radotinib group compared with imatinib group (Table). The safety profiles were consistent with those previously reported and most of adverse events (AEs) have developed within 12 months. Since 12 months, newly developed AEs such as rash, nausea/vomiting, pruritis, musculoskeletal pain, fatigue, hyperbilirubinemia, and ALT elevation, etc. have shown minimal increase by 36 months FU. Conclusions: With a minimum 36 months follow-up, radotinib continued to demonstrate significantly higher rates of MMR and MR4.5 than imatinib in newly diagnosed CML-CP. Also, these responses with radotinib were earlier and deeper compared with imatinib. These results still demonstrate that radotinib can be one of the standards of care in newly diagnosed CML-CP and support the higher possibility of treatment-free remission (TFR) on frontline therapy with radotinib. 

Biography

Karol Sikora is Founder and Chief Medical Officer of Proton Partners International. He was also Founder and CMO of Cancer Partners UK, now Genesis Care, which built Britain’s largest network of independent cancer treatment centers. He was Professor and Chairman of the Department of Cancer Medicine at Imperial College School of Medicine and is still honorary Consultant Oncologist at Hammersmith Hospital, London. He is Dean of Medicine at Britain’s first independent Medical School at the University of Buckingham. He is a Fellow of Corpus Christi College, Cambridge where he obtained a double first and trained at The Middlesex and St Bartholomew’s Hospitals, researching with Nobel Prize winner, Dr. Sydney Brenner. He was Chief of the WHO Cancer Programme for three years and has published over 300 papers and written or edited 20 books.
 

Abstract

Over 50% of cancer patients are now cured using combinations of surgery, radiotherapy and drugs. Smart modern diagnostics have accelerated the time from first symptom to treatment so detecting cancer at an earlier stage. And we are at the threshold of a revolution in personalized medicine based on genomics. This is a very exciting time for oncology. As always, the key to the delivery of excellence in cancer care is putting the patients right at the center of the pathway. That is why the Rutherford Cancer Centers are designed to deliver all modalities of care other than surgery in a relaxed and pleasant environment. Radiotherapy is used in half our patients to eradicate primary tumours. Proton therapy (PT) allows the more precise delivery of radiotherapy and so reduces long term damage to normal tissues surrounding a cancer. But it is expensive, costing two to ten times more per treatment, depending on the system type. Meaningful, large scale, randomized trials with protons versus photons are unlikely for all clinical indications. Instead, the pre-treatment comparison of proton beam therapy (PT) versus state of the art intensity modulated radiotherapy (IMRT) in individual patients using preset metrics of plan quality will be used for deciding whether PT has significant advantages. This assessment can be made objectively by treatment planning software systems. Payers, government and insurers, will use set criteria to assess the value of PT in an individual using a comparative equation incorporating tumor control, early and late toxicity and overall lifetime costs of care. Such analyses will determine the level of the therapeutic 
plateau in the relationship of cost to gain in clinical outcome. The range of published estimates for the optimal use of protons in radical radiotherapy ranges from 1% (UK, NHS) to 20% in the US. Recent policy studies from several European countries indicate a 10-15% PT use in patients if they are to be optimally treated with radical radiotherapy. That would require 10-20 PT facilities for Britain. We are building five centers in the UK, one in Abu Dhabi and one here in Dublin. Without this initiative, the quality of radiotherapy UK would seriously fall behind all our neighboring countries.

Tracks

  • Organ Specific Cancer | Molecular Diagnosis and Diagnostics | Cancer Therapy
Location: Beech Suite
Speaker

Juan Pablo Marquez Manriquez

Sonora Cancer Research Center (CICS USA), USA

Chair

Speaker

Julie Smith Gagen

University of Nevada, USA

Co Chair

Biography

Martin Orlando Rosas Delgado has received his Medical degree from the University of Sonora campus Hermosillo. Currently he is a 3rd year CancerVac Fellow, and he is ready to start Internal Medicine and eventually Medical Oncology. During the past three years as CancerVac fellow he initially took one year of Clinical Oncology work on CICS Sonora, one year of clinically relevant work and now he is charge of the Ovarian Refractory Clinic in order to try to rescue to all the patients out of treatment with very interesting results. He performs all the clinical histories, clinical exploration, and analysis of the PET and CT scans in order to make correlations in coordination with other members of the group of his clinical and image observation with pathological and clinical laboratory and immunology parameters. He is currently performing his own project as part of his academic formation CancerVac fellow with potential positive clinical results in refractory ovary cancer patients. He is also actively involved in the training of the first year CancerVac fellows and he deliver several courses such as Medical Biochemistry, Oncology Radiology, Medical Immunology I and II, Principles of Internal Medicine and the application and importance of the clinically relevant research. 

Abstract

Martin Orlando Rosas Delgado has received his Medical degree from the University of Sonora campus Hermosillo. Currently he is a 3rd year CancerVac Fellow, and he is ready to start Internal Medicine and eventually Medical Oncology. During the past three years as CancerVac fellow he initially took one year of Clinical Oncology work on CICS Sonora, one year of clinically relevant work and now he is charge of the Ovarian Refractory Clinic in order to try to rescue to all the patients out of treatment with very interesting results. He performs all the clinical histories, clinical exploration, and analysis of the PET and CT scans in order to make correlations in coordination with other members of the group of his clinical and image observation with pathological and clinical laboratory and immunology parameters. He is currently performing his own project as part of his academic formation CancerVac fellow with potential positive clinical results in refractory ovary cancer patients. He is also actively involved in the training of the first year CancerVac fellows and he deliver several courses such as Medical Biochemistry, Oncology Radiology, Medical Immunology I and II, Principles of Internal Medicine and the application and importance of the clinically relevant research. 

Biography

Juan Pablo Marquez Manriquez is a Medical Oncologist with training in Mexico, California and Seattle, Washington. His passion for Immunology and Oncology emerged from the very early stages of his life, as he prepared in pre-medicine by studying Pharmaceutical Chemist Biologist and later Medicine. He is currently developing projects for the prevention of gastrointestinal cancer in the CICS, USA, Seattle campus. He is currently specializing in the prevention of recurrence of tumors of high clinical impact such as ovary, triple negative breast, inflammatory breast, colorectal and multiple myeloma. Since 2002, he has presented scientific papers at multiple international congresses, led by AACR, ASCO, AAI, SITC and ESMO. He worked as a Medical Doctor at the Tumor Vaccine Group of the University of Washington. He is a Director General of the Cancer Research Center in Sonora (CICS) both at the Ciudad Obregón Sonora campus and at the Seattle Washington campus (CICS USA), although his base is in Seattle. In coordination with CICS and various institutions at the international level, CICS is developing through the investigations of his and CICS scientific medical team preventive vaccines to prevent cancer and its recurrences. They are also generating the combination of therapies that will allow for longer remissions and fewer recurrences for different types of tumors. 

Abstract

Background: Refractory tumors are a challenge. Tumor adaptive immune infiltration in several tumors, even when refractory, is not uncommon. It is clear that the future of oncology treatments is the combination of therapies to revert chemoresistance. We treat in pilot study 25 patients with refractory tumors using 22 peptides from biological and relevant proteins in combination with oxaliplatin and doxorubicin as immunogenic chemotherapy. After the end of the treatment, we observed an effective clinical response in 100% of the cases. Methods: After approval by the local ethics committee, we treated patients such as high grade serous ovarian cancer (n=8), soft sarcomas (n=5), pancreatic cancer (n=2) and triple negative breast cancer (n=10). Blood was drawn before, during and after treatment to monitor the adaptive immune response by granzyme B and interferon-gamma ELISPOT. Also, we collected serum for ELISA. DTH was performed before and after treatment in leg and primary tumor area. 22 peptides were administrated subcutaneously (SC) every week for 4 weeks in the axillary and inguinal lymph nodes. Afterwards, the peptides were administrated subcutaneously in the areas with tumor activity according with CT and/or PET scan. Doxorubicin and oxaliplatin were administered at low dose (immunogenic chemotherapy) four times for every two weeks. Results: The treatment was well tolerated in 100% of the patients with minimal local dermatological reactions in the peptide administration site. 100% of the subjects entered remission according with the CT scan. Importantly, the clinical remission correlated with the infiltration of CD8 cells in the DTH site. Also, all the patients had a statistically significant CD8 immune response against all the peptides. This was 
especially remarkable for fascin (p=0.0001), Ape-1 (p=0.0001), Bcl-2 (p=0.001) and VCP (p=0.005) peptides. Conclusions: Combination therapy with multipeptide antigen specific active immunotherapy with immunogenic chemotherapy is feasible and demonstrated remarkable clinical results, as remission were reached even in refractory patients. We observed multiple lymphadenopathies in the CT scans that correlate with the clinical and the granzyme immune response.

Biography

Julie Smith Gagen MPH, PhD is an Associate Professor at the University of Nevada, Reno in the School of Community Health Sciences which offers MPH and PhD programs. As an epidemiologist, she uses epidemiology to inform health policy to promote equity in utilization and access to healthcare. Her current area of focus is on the real-world use of diagnostics and treatments for patients with cancer of unknown primary. Another area of focus is on prevention treatments that can slow the progression of nonalcoholic steatohepatitis and liver cancer. She has published in many peer-reviewed high impact journals including but limited to Statistical Methods in Medical Research, Journal of Epidemiology and Community Health, Psycho-Oncology, Journal of Cancer Research and Clinical Oncology, and Cancer Causes and Control.

Abstract

Purpose: Cancer of unknown primary (CUP) patients has metastatic cancer with no identifiable primary tumor after a battery of guideline-recommended diagnostic tests. Currently, no guideline recommending organization recommends molecular profiling to identify the primary tumor. We characterized the effectiveness of molecular profiling diagnostic testing on receipt of site-specific treatments and overall survival among a population-based sample of CUP patients diagnosed between 2005 and 2015.  Methods: Patients with cancer of unknown primary were identified in the Surveillance Epidemiology and End Results (SEER)-Medicare database (n=10,575).  SEER is the cancer registry used to calculate US population-based incidence rates of cancer. Medicare database contains all billed medical procedures received before and after a cancer diagnosis. The effectiveness of the diagnostic procedures regarding overall survival was examined in patients who received the initial battery of guideline-recommended diagnostic tests and survived at least three months (to allow time to receive the molecular diagnostic testing) using Cox proportional hazards regression and mediation analysis for treatment effects. Results: Only 35.3% of CUP patients received timely guideline recommended initial diagnostic procedures. Receipt of all guideline-recommended initial diagnostic procedures was associated with a 15% reduced risk all-cause death, 36.9% of this reduction in death would remain if everyone received treatment. Receipt of molecular profiling was all associated with a nearly a 50% lower risk of death relative to comparable patients not receiving this molecular profiling, as indicated by the statistic, a hazard ratio (95% confidence interval) of 0.67(0.56,0.80). Conclusions:  This research expands on small clinical studies demonstrating the benefit of molecular diagnostic tests to a population-based cohort of patients who received molecular testing despite a lack of clinical guideline support. This research provides evidence to guideline producing organizations of the utility of molecular provides in a large and diverse population
based cohort; namely more effective treatment and longer survival.

Biography

Gray Kueberuwa PhD is a Doctor of Oncology working in the Clinical and Experimental Immunology Group within the Department of Cancer Sciences at the University of Manchester, UK. His research interests include chimeric antigen receptor (CAR) T-cell therapy of cancer, tumor infiltrating lymphocyte (TIL) therapy of cancer and the production of immune regulatory agents from within therapeutic cells. 

Abstract

Background: Brain tumours are the most common solid malignancy of childhood, accounting for >20% of all paediatric cancers. Collectively, they remain the leading cause of cancerrelated death and long-term morbidity in children. Infant lesions fare poorly since intensifying potentially effective conventional therapy causes overwhelming toxicity without conferring significant survival advantage. Tumour infiltrating lymphocyte (TIL) therapy consists of extracting immune cells from surgically removed tumours and growing them in the lab. This not only allows immune cells to be switched back on, but increases their total number. In this study we are investigating whether applying tumor-infiltrating leukocytes (TIL) therapy to paediatric brain tumours is feasible. Objectives: We seek to assess, if there are significant T-cell infiltrates in high grade paediatric brain tumours. Whether these cells can be efficiently expanded ex vivo and the antitumor reactivity of expanded TILs against autologous tumor ex vivo. Methods: We report initial evidence that there is a significant presence of TILs in 4 high grade paediatric brain tumour patients with cell type and phenotype analyzed by time of flight cytometry (cyTOF) upon dissociation after resection and after three weeks expansion in interleukin-2 (IL-2). Results: Initial samples have displayed up to 1300-fold expansion of TILs upon three weeks of culture and cyTOF analysis has shown that expanded cells have an increased capacity to secrete effector cytokines compared to peripheral blood lymphocytes cultured in the same conditions. Crucially, multiplex analysis of supernatant following co-culture of with autologous tumour and tumour lines shows that expanded cells possess anti-cancer activity. Conclusions: These promising results suggest that TIL therapy for paediatric brain tumours may be feasible. Analysis of an increased number of samples will be required to substantiate this, along with optimization of methodology to produce clinically relevant numbers of cells.

Biography

Lital Keinan Boker, MD, PhD, MPH, has her expertise in cancer epidemiology, particularly breast cancer. She is involved in etiological research, as well as early detection and log-term outcomes of cancer survivors. In addition to that, she is also involved in the research of long-term physical health outcomes in Holocaust survivors, and now starts studying also the second generation of Holocaust survivors. Her research work is done within her capacity as both the Deputy Director of the Israel Center for Disease Control in the Israel Ministry of Health, and her position as an Associate Professor in the School of Public Health in the University of Haifa. 

Abstract

Statement of the Problem: Male breast cancer (MBC) accounts for 1% of all breast cancer. Adult obesity and tallness are risk factors for MBC, but the role of adolescent fatness is largely unknown. We aimed to assess the association between body mass index (BMI) in adolescence and the incidence of MBC in a large cohort of 16-19 year-old Israeli males. Methodology & Theoretical Orientation: 1,382,093 Jewish Israeli males aged 16-19 who underwent anthropometric measurements, a general intelligence test (GIT) and other examinations during 1967-2011, were followed up to 31.12.2012 for MBC incidence. Cox proportional hazards models assessed the association between adolescent BMI (as WHO BMI categories and as age-specific CDC percentiles) and time to MBC diagnosis, adjusting for sociodemographic covariates. Findings: Of 100 MBC (Male Breast Cancer) cases diagnosed during 29,386,233 person-years of follow-up, 97 were included in multivariable analyses. Compared to ‘healthy’ BMI (18.524.9kg/m2) and adjusted for year of birth, country of origin and GIT score, higher adolescent BMI was associated with higher MBC risk: hazard ratio (HR) =2.01 (95% confidence interval (CI) 1.14-3.55, p=0.015) in overweight (25.0≤BMI<30.0kg/m2) adolescents; and HR=4.97 (95%CI 2.14-11.53, p=0.0002) in obese (BMI≥30.0kg/m2) adolescents. When CDC age-specific BMI percentiles were assessed results were similar and statistically significant for obesity. Additionally, low (vs. high) GIT score (HR=4.76, 95%CI 1.96-12.50, p=0.001) and European (vs. west-Asian) origin (HR=1.99, 95%CI 1.19-3.34, p=0.009) were independent predictors of MBC.
Conclusion & Significance: Measured adolescent overweight and obesity are associated with increased risk of MBC, suggesting a modifiable risk factor potentially allowing for early intervention. The novel association with cognitive function should be further explored

Biography

Esam Ahmed Z Omar has graduated from University of London, Eastman Dental Institute, United Kingdom after a residency program at UCL Hospitals and Eastman Dental Institute, London, UK, with Master’s degree and Fellowship of Royal College of Surgeons in Ireland FFDRCSI in 2005. He is a fellow of International Association of Oral and Maxillofacial Surgery and Senior Fellow of Head and Neck Optical Diagnostic Society, London. UK. 

Abstract

Background: Oral squamous cell carcinoma (OSCC) has a remarkably high incidence worldwide, and a fairly serious prognosis, encouraging further research in to advanced technologies for non-invasive methods of making early diagnoses, ideally in primary care settings. Objectives: Our purpose was to examine the accuracy of TNMs classification system in assessment of OSCC. Data sources: MEDLINE, EMBASE, and CINAHL were searched to identify prognostic factors of OSCC and other information published between 1985 and 10 August 2014; the searches of MEDLINE and EMBASE were updated to November 2015. The search was restricted to peer-reviewed articles published in English. Review Methods: In this review article, the factors of prognosis of OSCC which not included in TNMs staging system have been reviewed, their effect on the prognosis of the patients and survival rate have been discussed. Results: This study identified 196 studies of prognostic factors, 
evaluation and assessment of OSCC. Site of the tumour 38 studies, tumour’s thickness 52 studies, biological behaviour 26 studies, OSCC histological variant and effect in prognosis 38 studies, pattern of invasive front 19 studies, stromal lymphocytic infiltrations 23 studies. All previous factors are important in prognosis of OSCC and are not included routinely in oral cancer patient’s evaluation and assessment. Conclusion: The outcome of OSCC is greatly influenced by the stage of the disease. The TNMs staging system is not including many factors which are strongly contribute to prognosis of oral cancer and period of survival rate.
 

Day2: June 12, 2018

Keynote Forum

Biography

Alejandro Camacho Hernandez is a Hematologist Oncologist with training in Mexico, Mayo Clinic Rochester Minnesota, Massachusetts General Hospital and Arizona Cancer Center, USA. He became clinically speaking in expert in solid and hematological tumors microenvironment by manipulating with a cocktail of repurposing drugs the pro-tumors cells of the immune system such as Foxp3 positive cells, Th2, Th17, myeloid suppressor cells, etc. He is currently developing in Ciudad Obregon, several clinical pilot protocols to prevent multiple myeloma relapse and he already presented his preliminary data at ESMO 2015 in Vienna. He identified 14 biologically and clinically relevant proteins from multiple myeloma patients and now he designed 36 peptides containing CD8 and Th1 epitopes and according with his preliminarily data is very promising in combination with repurposing drugs of the tumor microenvironment. He works at the alliance in ImmunoOncology from Seattle and Sonora. He is also studying the potential role in prospective studies of patients with different types of tumors of the role of the platelets, coagulation factors and acute phase proteins in order to try at least five different drugs to combine with the standard of care treatment and look for clinical benefits either in PFS or OS 

Abstract

Background: The tumor microenvironment has been studied for many years and there are a few clinical studies and usually using one drug. We study four potential drugs able to modulate the microenvironment clinically by applying the treatment between intravenous (IV) and subcutaneous (SC) close to the primary tumor and their metastasis. We used bortezomib, gemcitabine, zoledronic acid and cyclophosphamide one week IV and oneweek SC. We were able to demonstrate that this quadruple combination was able to modulate several pro-tumoral mechanisms such as cytokines, platelets and pro-tumor immune cells and ultimate the tumor stroma with clinical significance of the modulation of tumor microenvironment. Methods: Refractory patients with diverse neoplasias and Karnofsky > at 80% n=18 were treated with this combination after the local IRB ethics committee approval. We started treating IV with the four drugs and after one week we treated with subcutaneous injections in the primary tumor site and metastasis (2 ml per injection in each site). We selected the SC injection sites in base at the most recent CT scan. ELISA such as IL-6, IL-12, TNF-alpha and IL-10 measured cytokines. Results: The treatment was well tolerated with minor adverse events such as nausea, flu-like symptoms, mild pain in the SC injections and diarrhea. The combination was able to reduce primary tumor, hepatic and lung metastasis in 11/18 patients. Additionally, IL-6 was down regulated in the 11 patients with response (p=0.01) and IL-12 was increased (p=0.005). Discussion: Refractory patients are a challenge as unfortunately even the patients are in that clinical condition some of them are 
still well preserved to try therapies that potentially may impact the tumor and improve the chances to have less palliative care especially in patients with good clinical conditions. The quadruple combination so far decreased bad prognosis cytokines such as IL-6 and increase cytokines such as IL-12 that improve the polarization of dendritic cells to activate the cells to Th1 cells to have a better tumor microenvironment. Treat systemically is a feasible approach that we will prepare for a phase I/II clinical trial.
 

Biography

Douglas E Gladstone is an Associate Professor in the Department of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. He is a Clinical Director of the Outpatient Bone Marrow Transplant Unit. In 2017, he led an educational program discussing how to lower donor specific antibodies to permissible levels for allogeneic bone marrow transplantation at the Annual American Society of Hematology conference 

Abstract

Allogeneic hematopoietic stem cell recipients may have performed antibodies directed against foreign HLA antigens. The use of partially HLA-mismatched allogeneic hematopoietic stem cell donors allows for the possibility of the presence of circulating HLA donor-specific antibodies (DSAs) in the recipient. The presence of DSAs at the time of stem cell infusion increases the risk of primary graft failure. Recently developed technology using solid phase immunoassays (SPIs) with fluorochromeconjugated beads has greatly improved the ability to detect and classify DSAs. When used in combination with the classic lymphocytotoxic complement-dependent and flow cytometric cross match tests, SPIs help provide DSA strength assessment. Both CD34+ cells and T-cells are required for donor engraftment; however, the expression of HLA antibodies varies between these cells: all HLA loci are expressed on CD34+ cells (HLA-A highest, HLA- DQ lowest); HLA-A and B expression is higher on CD34+ cells than on T cells; HLA-C expression is lower on CD34+ than on T cells. Parous females frequently harbor DSAs. DSAs tend to be of higher intensity when directed against haploidentical first-degree relatives. DSA assessment requires frequent monitoring as their relative strength can change over time. Importantly, patients who harbor flow cytometric cross match detectable DSA who are treated with a combination of plasma exchange with intravenous immune immunoglobulin, tacrolimus and mycophenolate mofetil can often lower DSA levels to well below flow cross match detection. Although the criteria that constitutes a prohibitive DSA is unknown, desensitization can result in engraftment rates as experienced in fully HLA-matched allogeneic blood or marrow transplantation recipients.
 

Biography

Lital Keinan Boker, MD, PhD, MPH, has her expertise in cancer epidemiology, particularly breast cancer. She is involved in etiological research, as well as early detection and log-term outcomes of cancer survivors. In addition to that, she is also involved in the research of long-term physical health outcomes in Holocaust survivors, and now starts studying also the second generation of Holocaust survivors. Her research work is done within her capacity as both the Deputy Director of the Israel Center for Disease Control in the Israel Ministry of Health, and her position as an Associate Professor in the School of Public Health in the University of Haifa. 

Abstract

Statement of the Problem: The effects of the Holocaust on the survivors have been studied extensively with respect to behavioral and mental aspects, but not somatic morbidity. Previous studies in non-Jewish populations showed that severe hunger during pregnancy in World War II (WWII) or the Chinese great famine resulted in low birth weight of the neonates and in higher susceptibility to metabolic morbidity in the offspring’s adult life. Jewish Holocaust survivors (HS) were exposed to extreme circumstances on WWII. Therefore we reviewed the literature regarding the potential implications of these exposures on the health of the survivors and their offspring. Methodology & Theoretical Orientation: We review the available literature, including studies conducted by the authors, regarding long-term somatic outcomes in both HS and offspring of HS (OHS). Findings: HS were at a higher risk compared to populationbased controls for conditions such as chronic pain, fibromyalgia, functional gastrointestinal complaints, osteoporosis and cancer. Unpublished data also disclosed higher prevalence of dyslipidemia, hypertension and diabetes. The unique group of HS that were born during WWII (1940-1945) and thus were exposed to the Holocaust both directly (first generation) and indirectly through maternal exposure (second generation) showed higher prevalence of components of the metabolic syndrome as well as cardiovascular diseases and cancer. The few available studies on OHS born after WWII disclosed higher prevalence of dyslipidemia and hypertension. Epigenetic studies suggest a mechanism for these transgenerational effects. Conclusion & Significance: HS and OHS may be at a higher risk for certain chronic conditions, mostly metabolic diseases. Health caretakers of these high-risk groups should be aware of the current body of evidence and offer HS and especially OHS opportunities for primary prevention and early detection of 
chronic morbidity. Additionally, there is urgent need to replicate and consolidate these findings, preferably using longitudinal study designs. 

Tracks

  • Clinical Oncology | Cancer Diagnosis and Screening | Cancer Drugs and Vaccines | Cancer Biomarkers | Chemotherapy
Location: Beech Suite
Speaker

David I Smith

Mayo Clinic Centre, USA

Chair

Speaker

Miral Mohammed Mashhour

King Fahad Specialist Hospital, Dammam, Saudi Arabia

Co Chair

Biography

Gloria J Guzman Perez Carrillo is an Assistant Professor of Radiology, Director of the Advanced Neuro-Imaging Initiative, Associate Residency Program Director for Research and Co-Chair of the University of Arizona Health Sciences LGBTQ+ Interest Group. She completed her undergraduate studies at Johns Hopkins University in Baltimore, her Medical degree at the University of Puerto Rico in San Juan, Puerto Rico; Radiology Residency at West Virginia University in Morgantown and; Neuroradiology Fellowship and Neuroradiology Research Fellowship at the Mallinckrodt Institute of Radiology at Washington University in St. Louis. She has also completed Masters in Radiology at the University of Granada in Granada, Spain. She has special research interests in advanced neuroimaging techniques, including functional imaging, diffusion spectrum based imaging, molecular imaging of tumor with F-DOPA in addition to outcomes and translational research of MRI in the field of Neuroradiology Imaging. 

Abstract

Purpose: Brain tumors are typically heterogeneous, and may contain different grades of tumor cells, different types of tumor cells, edema and/or abnormal vascular structures. Anatomical imaging alone can be limited in the evaluation of tumor heterogeneity, especially in those tumors that demonstrate little to no enhancement. While there are physiologic MR tools available in daily clinical practice such as perfusion or diffusion, we wanted to develop a more powerful, sensitive sequence for the characterization of tumor heterogeneity. We propose that tumor heterogeneity imaging (THI) can provide quantitative distributions of different grades of tumor cells and capillary blood perfusion within the tumor in a single clinical imaging scan with more accuracy than previously reported with traditional diffusion techniques. Materials & Methods: 11 adult patients with known or suspected brain gliomas that were non-enhancing or had substantial non-enhancing regions (>50%) underwent simultaneous 3, 4-dihydroxy-6-[18F] fluoro-L- phenylalanine (18FFDOPA) PET/ MRI prior to planned standard-of-care surgical resection and/or stereotactic biopsy. Of these, 7 patients also underwent THI, a new diffusion MRI protocol, microstructure modeling, and inverse computation technique. The THI maps were then compared to the 18FDOPA and coordinate-guided biopsy or surgical resection results. Perfusion maps extracted from THI were calculated. ADC cut-offs for tumor grade based on the THI data were then determined and tumor grade maps created. Results: Grade 4 tumors ADC cutoff was 0.3-0.5×10−3 mm2/s. Grade 3 was 0.5-0.8×10−3 mm2/s. Grade 1 and 2 was 0.81.5×10−3 mm2/s. Table 1 summarizes the subject’s demographic characteristics and well as the correlation between 18F-FDOPA and THI maps. We found that in 7/7 patients (100%) THI maps correlated with tumor grade on pathological evaluation. Interestingly, 18F-FDOPA was negative on subject S7, whereas THI correctly identified not only the tumor, but the tumor grade at the region of stereotactic biopsy sample. 
Conclusion: This preliminary study demonstrated the capability of a new diffusion MRI method, THI, to noninvasively characterize the structural heterogeneity in brain tumors, including various grades of tumor cells and capillary blood perfusion within the tumors, consistent with pathology assessment on biopsy tissues. Although our preliminary data suggest THI is a promising multiparametric imaging technique to accurately measure cellularity and tumor grade, larger studies will be needed before definitive conclusions can be made about the role of this technique. This preliminary study also suggested the unmet need to develop new generation of MRI technique that is capable to provide direct pathophysiological measures for tumor characterization. 

Biography

David I Smith received his PhD in Biochemistry from the University of Wisconsin in Madison in 1978. His first academic position was at Wayne State University School of Medicine and in 1996 he moved to the Mayo Clinic as a Professor in the Department of Laboratory Medicine and Pathology. He is also the Chairman of the Technology Assessment Group for the Mayo Clinic Center for Individualized Medicine. His laboratory utilizes next generation sequencing to study the different ways that human papillomavirus can cancer in different tissues. His group also studies the common fragile sites which are regions of profound instability found in all individuals. 

Abstract

Human papillomavirus (HPV) is involved in the development of cervical cancer and a number of other anogenital cancers. It is also increasingly involved in the development of one type of head and neck cancer, namely oropharyngeal squamous cell carcinoma (OPSCC). One key step in the development of many of these cancers is integration of the HPV viral genome somewhere within the human genome, but it is unclear precisely when this occurs, and the precise role that the integration event plays in cancer development. In order to study the different ways that HPV is involved in the development of OPSCC we have been using different genome sequencing technologies to study the physical status of HPV in this cancer. We have used mate-pair next generation sequencing on the Illumina platform and also whole genome sequencing on the BGI Seq500 sequencing platform. This has enabled us to compare these two platforms for their ability to characterize important physical attributes of this cancer including the site of HPV integration, and the resulting dramatic genomic changes of the HPV integration event. We have also been able to determine genome-wide changes in OPSCC separate from the HPV integration event

Biography

Jose Antonio Matute Briceño is currently the Co-director, Chief Pathologist and Investigator from the Binational Sonora Cancer Research Center (CICS) in Seattle/Sonora. One of its main functions is to carry out immuno-advanced cancer reports, molecular pathology and immunological studies such as ELISA, ELISPOT, T cell expansion, and immunogram. In the research area he develops scientific projects with clinic relevance and performed experiments focused on patient’s immune response against cancer. He received specialist training in Pathology at the University of Monterrey, and in 2014 he began training in Immuno-Oncology at the OMA/CICS group, where he developed a diagnostic chart for the immuno-oncopathology evaluation with prognostic and therapeutic implications. He has participated in numerous international conferences of molecular pathology, oncology, USCAP, ASCO, ESMO, where he has made oral and posters presentations. He has been involved in some published scientific articles of the OMA group / CICS and at least five more in preparation. 

Abstract

The delayed-type hypersensitivity (DTH) is a test where we can measure the immune response using active immunotherapy antigen specific (AIAE); these peptides are able to stimulate the immune response against proteins that are present in the tumor cells, with the expectation is that such answers may alter the natural history of the disease. DTH response is one of the few measurements used to determine the effective immunization against the tumor. However, little is known about the ability of DTH to really reflect the development of specific systemic immunity against tumor in patients with cancer.  We have studied the proteins: APE-1, Fascin-1, RCAS-1, SOX-2, EGFR, VCP, Bcl-2 and Survivin, which we have been applied for purposes of active immunotherapy. The immune response has been evaluated through cell proliferation in vitro techniques and indirect ELISA Antigen specific, obtaining favorable results of cellular and humoral response. This study will measure the tissue immunological response by a skin biopsy, this response generated by our peptides after several immunizations and which type of infiltrated lymphocyte (Th1/CD8) are found in the area of the DTH, we also compare the immune contexture (plasma cells, eosinophil’s, neutrophils) of the skin biopsy against the primary tumor. We have performed DTH on patients with tumor progression, relapse prevention and refractories, to see how we can modulate their immune response to peptide immunizations. We have found that cancer patients immunized (AIAE) presented more positive DTH, and more CD8 infiltrate. This could be the result of the modulation of the immune system by poor prognosis protein peptides designed to be recognized by HLA-I and Th1, cells that would be generating a greater area of DTH by lymphocyte infiltration and cells antigen presenting previously stimulated with AIAE. 

Biography

Miral Mohammed Mashhour is a Consultant, Breast and Gynecologic Pathologist. She received fellowship from Toronto, Sunnybrook Hospital, Canada in 2011. She is a Chairman of biobank, she gave many presentations in national and international conferences and she published her articles in many well-known journals. 

Abstract

Introduction: Neoadjuvant chemotherapy is well established modality for treatment of large potentially operable and locally advanced breast cancer. Pathological complete response (PCR) following neoadjuvant chemotherapy, which is seen in 3-26% of patients is considered a good but not perfect predictor of survival. Primary breast carcinomas treated with neoadjuvant chemotherapy (NAT) provide an ideal model to evaluate the role of biological markers as predictive and prognostic factors. Ki67 index has been established as a prognostic marker in breast cancer. Aim: This study was designed to investigate the impact of neoadjuvant therapy (NAT) on Ki67 expression and its relationship with chemotherapeutic response in locally advanced breast cancer (LABC). Methodology: Patients with LABC (stage 2B or stage 3) who were entered into the prospective LABC database during 20022008 were included. The neoadjuvant regimen in these patients included anthracycline based chemotherapy (doxorubicin or epirubicin) and in patients with ER/PR negative tumors taxanes (paclitaxel, docetaxel). Ki67 was evaluated in cases with available tissue on preNAT core biopsy and postNAT specimens. Consecutive sections were studied by immunohistochemistry using antibodies directed against ER, PR, HER2/neu and Ki67 (SP6 1:800 Labvision). The percentage of Ki67 positive neoplastic cells (index) was determined using Ventana Image Analysis System. Association between Ki67 pre and postNAT and clinical response and biomarkers was evaluated. Results: 149 patients were enrolled in the LABC database and 77 had tissue available for immunohistochemistry: 76 cases had 
preNAT cores; 63 postNAT resection specimen and overall 62 had both pre and postNAT specimens. High Ki67 index on preNAT biopsy correlated with: Nottingham grade III (p=0.03); ER-ve (p=0.0002); PR-ve (p=0.003). High Ki67 index on preNAT biopsy did not correlate with: Her2/neu+ (p=0.5); nodal status (p=0.19); size (p=0.51) and; predictor of clinical response (p=0.57). High Ki67 index on postNAT specimen correlated with clinical response (p=0.03). Change in Ki67 index between preNAT and postNAT specimens occurred in 61/62 cases (38 decreased, 23 increased). Decreased Ki67 index was associated with ER+ status (p=0.0059) clinical response (p=0.0047) and increased Ki67 index was associated with triple negative (p=0.037) Conclusion: There is a significant association between Ki67 index on preNAT specimen and features of aggressive behavior such as hormone receptor negativity and high tumour grade. This study indicates Ki67 index after neoadjuvant chemotherapy correlates with short term outcome in LABC patients. A recent study found that higher Ki67 values before NAC as well as lower values after NAC might be clinically significant for treating patients. Another study found that higher Ki67 expression after two weeks of endocrine NAT, but not at baseline was statistically significantly associated with lower recurrence-free survival. 

Biography

Ningshu Liu has her research interests in evaluation and passion in improving the health and wellbeing. Her open and contextual evaluation model based on responsive constructivists creates new pathways for improving healthcare. She has built this model after years of experience in research, evaluation, teaching and administration both in hospital and education institutions. The foundation is based on fourth generation evaluation which is a methodology that utilizes the previous generations of evaluation: measurement, description and judgment. It allows for value-pluralism. This approach is responsive to all stakeholders and has a different way of focusing. 

Abstract

Statement of the Problem: Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are two of the most common non-hodgkin lymphoma (NHL) worldwide with a high unmet medical need for relapsed or refractory disease represents from the frontline treatment. Despite the role of PI3K in NHL and solid tumors has been clinically validated, clinical development of PI3K inhibitors has been challenged with the therapeutic window of both pan- and isoform selective PI3K inhibitors. Methodology: Copanlisib is the first pan-PI3K inhibitor with intravenous intermittent dosing regimen developed in clinic. Copanlisib has been extensively studied in various preclinical tumor models in vitro and in vivo, as well as investigated in a series of clinical trials in both NHL and solid tumors. Findings: Investigation of FL and DLBCL patient samples indicates differential and redundant expression of PI3K isoforms. compared to PI3K selective inhibition, copanlisib showed much stronger and broader anti-tumor activity in NHL by overcoming intrinsic resistance caused by multiple PI3K isoform expression and acquired resistance induced by rebound activation of PI3K/AKT and other oncogenic signaling molecules, such as NFB. These findings have been translated into the significant clinical benefits in FL patients with durable objective responses (59%), which led to an accelerated FDA approval for treatment of relapsed or refractory FL. In addition, copanlisib has also demonstrated significant activity in DLBCL patients. Furthermore, recent preclinical study indicates that pulsatile inhibition of PI3K by copanlisib can also enhance anti-tumor immunity by inhibiting immune suppressive Tregs and M2-TAM and stimulating CD8+ T cells and M1 macrophages, and therefore overcome the resistance to immune checkpoint blocks. Conclusion & Significance: Pan-PI3K inhibitor copanlisib with intermittent dosing schedule has been successfully developed 
as an effective and safe therapy for FL. Currently, copanlisib is being investigated in combination with rituximab (CHRONOS-3) or rituximab-chemotherapy (CHRONOS-4) in iNHL, as well as in combination with targeted therapies, such as immune checkpoint inhibitors, in solid tumors. 

Biography

Esam Ahmed Z Omar has graduated from University of London, Eastman Dental Institute, United Kingdom after a residency program at UCL Hospitals and Eastman Dental Institute, London, UK, with master’s degree and Fellowship of Royal College of Surgeons in Ireland FFDRCSI in 2005. He is a fellow of International Association of Oral and Maxillofacial Surgery and Senior Fellow of Head and Neck Optical Diagnostic Society, London. UK. 

Abstract

Background: Oral squamous cell carcinoma (OSCC) has a remarkably high incidence worldwide, and a fairly serious prognosis, encouraging further research into advanced technologies for non-invasive methods of making early diagnoses, ideally in primary care settings. Objective: Our purpose was to examine the validity of using salivary markers changes in OSCC’s patients by advanced nanotechnology and molecular diagnostics for diagnosing OSCC by identifying and evaluating relevant published reports. Methods: MEDLINE, EMBASE, and CINAHL were searched to identify clinical trials and other information published between 1990 and 10 June 2014; the searches of MEDLINE and EMBASE were updated to November 2014. Studies of non-invasive methods of diagnosing OSCC (saliva-based diagnosis and others were included). Data were abstracted and evaluated in duplicate for possible relevance on two occasions at an interval of two months before being included or excluded. Studies met the inclusion criteria and have been assessed by modified version of the quality assessment of diagnostic accuracy studies instrument (QUADAS).
Findings: 163 studies of saliva based oral diagnosis met the inclusion criteria. Forty-two of these studies were assessed by the modified version of the QUADAS instrument. Saliva-based oral cancer diagnosis was found to be promising non-invasive methods for diagnosing OSCC. Conclusions: It is clear that screening for and early detection of cancer and pre-cancerous lesions have the potential to reduce the morbidity and mortality of this disease. Advances in nanotechnology for saliva-based oral diagnosis are a promising pathway for the future development of more effective noninvasive methods for diagnosing OSCC that are easy to perform clinically in primary care settings.