Pub Date : 2019-10-07DOI: 10.1200/jgo.2019.5.suppl.29
Hyun-jeung Choi, Inseon Lee, M. Lee, K. Jung, Keunsook K Lee, YoungJoon Moon, Kwang Joong Kim
29 Background: Hematological malignancies are forms of cancer that originates in blood-forming tissue, such as bone marrow, or in the cells of the immune system. Detection of genetic alteration in hematological malignancies are increasingly important because of diverse variants associated with classification and diagnosis of subtypes, and prognostic and therapeutic-response prediction. Next-generation sequencing (NGS) is a powerful technology to simultaneously analyze multiple genes to identify clinically well-described variants, as well as rare variants related to hematological malignancies for clinical diagnostics. Methods: We developed the targeted NGS panel (HEMEaccuTest) and automatic analysis software (NGeneAnalySys) for estimating pathogenicity of genetic variants related to hematological malignancies. HEMEaccuTest covers entire coding region of 108 genes that have putatively known for associations with the diseases according to the WHO, NCCN and ELN guidelines. The diagnostic utility of HEMEaccuTest and NGeneAnalySys were validated using reference materials and clinical specimens. Results: The results showed that pathogenic variants were effectively detected with an average coverage depth of 600X and a minimum coverage depth of 100X. It demonstrated an excellent limit of detection, with 100% sensitivity for SNVs at 2% VAF and for indel at 4% VAF. In addition, the analytical sensitivity, specificity and precision of the panel were higher compared to conventional methods such as Sanger sequencing, FISH, and real-time PCR. Noticeably, the approximately 300-bp-size insertions of FLT3-ITD was efficiently detected by a simulating algorithm. Conclusions: This analytical validation study demonstrated that HEMEaccuTest and NGeneAnalySys can be an excellent and useful tool for disease definition and therapeutic strategy in hematological malignancies. NGeneAnalySys provides the evidence-based categorization and clinical interpretation supported by Tier classification (Therapeutic, Prognostic, Diagnostic) of professional guidelines (ACMG/AMP, AMP/ASCO/CAP. etc).
{"title":"Validation and utilization of NGS-based HEMEaccuTest panel and analysis software for hematological malignancies.","authors":"Hyun-jeung Choi, Inseon Lee, M. Lee, K. Jung, Keunsook K Lee, YoungJoon Moon, Kwang Joong Kim","doi":"10.1200/jgo.2019.5.suppl.29","DOIUrl":"https://doi.org/10.1200/jgo.2019.5.suppl.29","url":null,"abstract":"29 Background: Hematological malignancies are forms of cancer that originates in blood-forming tissue, such as bone marrow, or in the cells of the immune system. Detection of genetic alteration in hematological malignancies are increasingly important because of diverse variants associated with classification and diagnosis of subtypes, and prognostic and therapeutic-response prediction. Next-generation sequencing (NGS) is a powerful technology to simultaneously analyze multiple genes to identify clinically well-described variants, as well as rare variants related to hematological malignancies for clinical diagnostics. Methods: We developed the targeted NGS panel (HEMEaccuTest) and automatic analysis software (NGeneAnalySys) for estimating pathogenicity of genetic variants related to hematological malignancies. HEMEaccuTest covers entire coding region of 108 genes that have putatively known for associations with the diseases according to the WHO, NCCN and ELN guidelines. The diagnostic utility of HEMEaccuTest and NGeneAnalySys were validated using reference materials and clinical specimens. Results: The results showed that pathogenic variants were effectively detected with an average coverage depth of 600X and a minimum coverage depth of 100X. It demonstrated an excellent limit of detection, with 100% sensitivity for SNVs at 2% VAF and for indel at 4% VAF. In addition, the analytical sensitivity, specificity and precision of the panel were higher compared to conventional methods such as Sanger sequencing, FISH, and real-time PCR. Noticeably, the approximately 300-bp-size insertions of FLT3-ITD was efficiently detected by a simulating algorithm. Conclusions: This analytical validation study demonstrated that HEMEaccuTest and NGeneAnalySys can be an excellent and useful tool for disease definition and therapeutic strategy in hematological malignancies. NGeneAnalySys provides the evidence-based categorization and clinical interpretation supported by Tier classification (Therapeutic, Prognostic, Diagnostic) of professional guidelines (ACMG/AMP, AMP/ASCO/CAP. etc).","PeriodicalId":15862,"journal":{"name":"Journal of global oncology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43721837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-10-07DOI: 10.1200/jgo.2019.5.suppl.41
C. Su, Juan Zhou, X. Chu, Jinrong Zhao
41 Background: Lung cancer is the most common cause of mortality in both men and women, accounting for one-quarter of all cancer deaths. Most lung cancer-associated deaths result from metastasis, especially brain metastasis. Metastasis associated mutations are important biomarkers for metastasis prediction and outcome improvement. The current study aimed to reveal the molecular mechanisms and the genetic alterations involved in metastasis from lung tumors to the brain. Methods: We carried out whole exome sequencing (WES) of the primary tumors and the corresponding brain metastases from 15 patients with metastatic non-small-cell lung carcinoma. Results: We identified novel lung cancer metastases associated genes (CHEK2P2, BAGE2, AHNAK2) and epigenetic factors (miR-4436A, miR-6077). Lung-brain metastasis samples have more similar Ti/Tv(transition/transversion) profile with brain cancer. Focal adhesion, PI3K-Akt signaling pathway, MAPK signaling pathway are some of the most important tumor onset and metastasis pathways. Alternative splicing, Methylation and EGF-like domain are important metabolic abnormal for the lung-metastasis cancers. Conclusions: We conducted a pairwise lung-brain metastasis based WES and identified some novel metastasis related mutations which provided potential biomarkers for prognosis and targeted therapeutics.
{"title":"Genetic mutations associated with lung cancer metastasis to the brain.","authors":"C. Su, Juan Zhou, X. Chu, Jinrong Zhao","doi":"10.1200/jgo.2019.5.suppl.41","DOIUrl":"https://doi.org/10.1200/jgo.2019.5.suppl.41","url":null,"abstract":"41 Background: Lung cancer is the most common cause of mortality in both men and women, accounting for one-quarter of all cancer deaths. Most lung cancer-associated deaths result from metastasis, especially brain metastasis. Metastasis associated mutations are important biomarkers for metastasis prediction and outcome improvement. The current study aimed to reveal the molecular mechanisms and the genetic alterations involved in metastasis from lung tumors to the brain. Methods: We carried out whole exome sequencing (WES) of the primary tumors and the corresponding brain metastases from 15 patients with metastatic non-small-cell lung carcinoma. Results: We identified novel lung cancer metastases associated genes (CHEK2P2, BAGE2, AHNAK2) and epigenetic factors (miR-4436A, miR-6077). Lung-brain metastasis samples have more similar Ti/Tv(transition/transversion) profile with brain cancer. Focal adhesion, PI3K-Akt signaling pathway, MAPK signaling pathway are some of the most important tumor onset and metastasis pathways. Alternative splicing, Methylation and EGF-like domain are important metabolic abnormal for the lung-metastasis cancers. Conclusions: We conducted a pairwise lung-brain metastasis based WES and identified some novel metastasis related mutations which provided potential biomarkers for prognosis and targeted therapeutics.","PeriodicalId":15862,"journal":{"name":"Journal of global oncology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47283507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-10-07DOI: 10.1200/jgo.2019.5.suppl.101
E. Gordon, S. Chawla, F. Hall
101 Background: Targeted gene delivery in vivo has long been considered the “Holy Grail” of gene therapy. Methods: We reviewed long-term data of patients with advanced chemotherapy-resistant malignancies, previously-treated patients with two tumor-targeted retrovectors: (1) encoding cytotoxic dominant negative cyclin G1, DeltaRex-G (formerly Rexin-G), and (2) encoding cytokine GMCSF plus suicide gene HStk, DeltaVax (formerly Reximmune-C). Results: Ninety-nine patients received > 5,000 intravenous infusions of DeltaRex-G; another 16 patients received 288 intravenous infusions of DeltaRex-G + 96 infusions of DeltaVax followed by valacyclovir p.o. No therapy-related bone marrow suppression, organ dysfunction or delayed treatment related adverse events were observed. Survival analysis showed 5.0% 10-year overall survival rate for patients who received DeltaRex-G alone, and 18.8% for DeltaRex-G + DeltaVax. Conclusions: Data analysis indicates that tumor-targeted gene delivery in vivo, represented by cytocidal DeltaRex-G, with or without immuno-stimulatory DeltaVax, has induced prolonged ( > 10 years) sustained remissions in cancer patients presenting with advanced chemotherapy-resistant solid and hematologic malignancies—plausibly due to safety, selectivity, and immune modulation. While the curative potential of precision targeted genetic medicine necessarily remains an academic question; it is clear that these initial long-term, cancer-free ( > 10 year) survivors represent a major milestone in both cancer therapy and immunotherapy. Phase 2-3 clinical trials are planned for these hard-to treat malignancies.
{"title":"Survival data following phase 1/2 studies using precision tumor-targeted gene delivery to advanced chemotherapy-resistant malignancies.","authors":"E. Gordon, S. Chawla, F. Hall","doi":"10.1200/jgo.2019.5.suppl.101","DOIUrl":"https://doi.org/10.1200/jgo.2019.5.suppl.101","url":null,"abstract":"101 Background: Targeted gene delivery in vivo has long been considered the “Holy Grail” of gene therapy. Methods: We reviewed long-term data of patients with advanced chemotherapy-resistant malignancies, previously-treated patients with two tumor-targeted retrovectors: (1) encoding cytotoxic dominant negative cyclin G1, DeltaRex-G (formerly Rexin-G), and (2) encoding cytokine GMCSF plus suicide gene HStk, DeltaVax (formerly Reximmune-C). Results: Ninety-nine patients received > 5,000 intravenous infusions of DeltaRex-G; another 16 patients received 288 intravenous infusions of DeltaRex-G + 96 infusions of DeltaVax followed by valacyclovir p.o. No therapy-related bone marrow suppression, organ dysfunction or delayed treatment related adverse events were observed. Survival analysis showed 5.0% 10-year overall survival rate for patients who received DeltaRex-G alone, and 18.8% for DeltaRex-G + DeltaVax. Conclusions: Data analysis indicates that tumor-targeted gene delivery in vivo, represented by cytocidal DeltaRex-G, with or without immuno-stimulatory DeltaVax, has induced prolonged ( > 10 years) sustained remissions in cancer patients presenting with advanced chemotherapy-resistant solid and hematologic malignancies—plausibly due to safety, selectivity, and immune modulation. While the curative potential of precision targeted genetic medicine necessarily remains an academic question; it is clear that these initial long-term, cancer-free ( > 10 year) survivors represent a major milestone in both cancer therapy and immunotherapy. Phase 2-3 clinical trials are planned for these hard-to treat malignancies.","PeriodicalId":15862,"journal":{"name":"Journal of global oncology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42232150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-10-07DOI: 10.1200/jgo.2019.5.suppl.57
Hiroaki Ito, Tomokazu Miyazaki, N. Uragami, N. Yokoyama, H. Inoue
57 Background: Cancer is an important disease that accounts for many of the causes of death worldwide, and early diagnosis is important for improving treatment results. In medical care, blood test is a simple and excellent test method, but there is still no cancer blood diagnosis method with high accuracy that can be performed in general hospitals. We are trying to detect cancer patients by analyzing serum using Raman spectroscopy. Methods: Among the outpatients who underwent upper gastrointestinal endoscopy or colonoscopy, 236 subjects who agreed to participate in the study were included. Raman scattering spectra were measured by irradiating a 1064 nm wavelength laser for 15 seconds with serum collected from the subject before endoscopic examination. The average value measured a total of three times was taken as the measured value, and the three measured values were averaged to obtain the value of each examinee. In the obtained Raman scattering spectra, the scattering spectral intensities of the wavelength originating in the specific molecules were analyzed. Results: We were able to obtain clear Raman scattering spectra of all serum samples. When comparing the Raman scattering spectral intensities of the wavelength originating in specific molecules, a large number of serum measurement values were gathered at the center, and the measurement values of the cancer patients' serum were over low or high. By setting the appropriate cutoff line, cancer patients (gastric cancer or colon cancer) and non-cancerous persons could be relatively clearly distinguished (sensitivity, 100%; Specificity, 75%). Conclusions: Our micro Raman system is able to acquire Raman scattering spectra of serum samples. Furthermore, it has been suggested that cancer diagnosis using serum could be possible by comparing the scattering spectral intensities caused by specific molecules. Clinical trial information: UMIN000034306.
{"title":"Analysis of serum by Raman spectroscopy finds changes in blood metabolites of cancer patients in 45 seconds.","authors":"Hiroaki Ito, Tomokazu Miyazaki, N. Uragami, N. Yokoyama, H. Inoue","doi":"10.1200/jgo.2019.5.suppl.57","DOIUrl":"https://doi.org/10.1200/jgo.2019.5.suppl.57","url":null,"abstract":"57 Background: Cancer is an important disease that accounts for many of the causes of death worldwide, and early diagnosis is important for improving treatment results. In medical care, blood test is a simple and excellent test method, but there is still no cancer blood diagnosis method with high accuracy that can be performed in general hospitals. We are trying to detect cancer patients by analyzing serum using Raman spectroscopy. Methods: Among the outpatients who underwent upper gastrointestinal endoscopy or colonoscopy, 236 subjects who agreed to participate in the study were included. Raman scattering spectra were measured by irradiating a 1064 nm wavelength laser for 15 seconds with serum collected from the subject before endoscopic examination. The average value measured a total of three times was taken as the measured value, and the three measured values were averaged to obtain the value of each examinee. In the obtained Raman scattering spectra, the scattering spectral intensities of the wavelength originating in the specific molecules were analyzed. Results: We were able to obtain clear Raman scattering spectra of all serum samples. When comparing the Raman scattering spectral intensities of the wavelength originating in specific molecules, a large number of serum measurement values were gathered at the center, and the measurement values of the cancer patients' serum were over low or high. By setting the appropriate cutoff line, cancer patients (gastric cancer or colon cancer) and non-cancerous persons could be relatively clearly distinguished (sensitivity, 100%; Specificity, 75%). Conclusions: Our micro Raman system is able to acquire Raman scattering spectra of serum samples. Furthermore, it has been suggested that cancer diagnosis using serum could be possible by comparing the scattering spectral intensities caused by specific molecules. Clinical trial information: UMIN000034306.","PeriodicalId":15862,"journal":{"name":"Journal of global oncology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46455959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-10-07DOI: 10.1200/jgo.2019.5.suppl.33
Siwei Wang, Yi-qun Zhou, Jue Fan, R. Yin
33 Background: Immuno-checkpoint inhibition therapies has been revolutionizing cancer treatment. Yet only a fraction of patients show durable responses , whereas the majority of treated patients show relatively low clinical response. This difference is likely to be caused by the heterogeneity of both cancer cells and cells involved in the tumor microenvironment (TME). However, the extent of this heterogeneity, how it is shaped by other factors in the tumor and vice versa, remains poorly understood. Methods: To explore the heterogeneity of lung adenocarcinoma, we obtained tumor tissuesand peripheral blood froma cohort of 30 treatment-naive patients. For each sample, single-cell RNA sequencingand whole exome sequencing(WES) wereperformed. A graph-based unsupervised clusteringmethod was usedand cell types were assignedto clusters based on marker gene expression. The sub-types of both cancer cells and TME cells along with their gene expression patterns were comparedbetween different cancer stages and mutation status. Results: we presented a landscape of cancer and TME transcriptome in human lung adenocarcinoma at single-cell resolution. We found the expression of cancer cells exhibits distinct characteristics with different TNM stages. For instance, the tumor cells of a patient classified as T1aN2M0 highly express genes enriched in the cell migration pathway. By comparing TME cells among patients with different mutation status, we identified changes in various T cell subtypes and tumor-infiltrating myeloid cells. Conclusions: This study provided a detailed cell atlas of lung adenocarcinoma and identified gene expression patterns that are unique to specific TNM stages. Moreover, single-cell analyses offer valuable knowledgeof immune changes for each patient subgroup, providing ausefultool for the rational design of immunetherapies.
{"title":"A transcriptomic landscape of cancer and TME in early-stage lungadenocarcinomaby single-cell sequencing.","authors":"Siwei Wang, Yi-qun Zhou, Jue Fan, R. Yin","doi":"10.1200/jgo.2019.5.suppl.33","DOIUrl":"https://doi.org/10.1200/jgo.2019.5.suppl.33","url":null,"abstract":"33 Background: Immuno-checkpoint inhibition therapies has been revolutionizing cancer treatment. Yet only a fraction of patients show durable responses , whereas the majority of treated patients show relatively low clinical response. This difference is likely to be caused by the heterogeneity of both cancer cells and cells involved in the tumor microenvironment (TME). However, the extent of this heterogeneity, how it is shaped by other factors in the tumor and vice versa, remains poorly understood. Methods: To explore the heterogeneity of lung adenocarcinoma, we obtained tumor tissuesand peripheral blood froma cohort of 30 treatment-naive patients. For each sample, single-cell RNA sequencingand whole exome sequencing(WES) wereperformed. A graph-based unsupervised clusteringmethod was usedand cell types were assignedto clusters based on marker gene expression. The sub-types of both cancer cells and TME cells along with their gene expression patterns were comparedbetween different cancer stages and mutation status. Results: we presented a landscape of cancer and TME transcriptome in human lung adenocarcinoma at single-cell resolution. We found the expression of cancer cells exhibits distinct characteristics with different TNM stages. For instance, the tumor cells of a patient classified as T1aN2M0 highly express genes enriched in the cell migration pathway. By comparing TME cells among patients with different mutation status, we identified changes in various T cell subtypes and tumor-infiltrating myeloid cells. Conclusions: This study provided a detailed cell atlas of lung adenocarcinoma and identified gene expression patterns that are unique to specific TNM stages. Moreover, single-cell analyses offer valuable knowledgeof immune changes for each patient subgroup, providing ausefultool for the rational design of immunetherapies.","PeriodicalId":15862,"journal":{"name":"Journal of global oncology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41534235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-10-07DOI: 10.1200/jgo.2019.5.suppl.69
Z. Dayao, B. Tawfik, J. Abernathy, C. Wiggins, A. Gundelach, R. Lauer
69 Background: The Institute of Medicine endorses delivery of survivorship care plans (SCPs) to the growing number of cancer survivors in order to improve the coordination of care between oncologists and primary care providers (PCPs). In response, the Commission on Cancer (COC) has increased the SCP delivery requirement to >50% of eligible patients, a goal that is difficult to meet given limited resources. Here we outline the initiatives taken to achieve this goal at the University of New Mexico Comprehensive Cancer Center (UNMCCC). Methods: Prior to 2017, SCPs were not routinely delivered. Beginning 2017, providers were tasked to complete and deliver printed SCPs , resulting in a 17% rate of SCP completion. However, there was general lack of provider support and enthusiasm as the process was time consuming with no method for identifying eligible patients and tracking SCP delivery. In 2018, designated staff was assigned to partially complete the SCPs to assist providers, resulting in an increase in SCP delivery rate to 41%. However, the same barriers existed. SCP softwares, although available, were expensive. A cost effective process therefore was needed. A committee was then formed to create a system-wide process utilizing the existing electronic health record (EHR) MOSAIQ. ASCO based SCPs were created. Once providers identify eligible patients, an SCP electronic order was initiated. Designated staff then partially completes the SCPs based on review of medical records. The EHR extracts data items including demographics, PCP information, cancer type and stage. The EHR is programmed to flag SCPs ready for delivery which the provider then edits and approves. This system tracks multiple time points including referral, completion and delivery of SCPs. This new process was implemented in April 2019. Quarterly reviews are set to assess metrics. Results: Utilizing existing EHR (MOSAIQ), a new SCP delivery process was created that allows tracking of assembly, completion and timing of delivery. Conclusions: To overcome existing barriers to SCP completion and delivery, a new cost effective process was created utilizing existing staff and EHR resources. Institutional support is key to the success of this initiative.
{"title":"Building a survivorship care plan delivery process: Experience in an academic center.","authors":"Z. Dayao, B. Tawfik, J. Abernathy, C. Wiggins, A. Gundelach, R. Lauer","doi":"10.1200/jgo.2019.5.suppl.69","DOIUrl":"https://doi.org/10.1200/jgo.2019.5.suppl.69","url":null,"abstract":"69 Background: The Institute of Medicine endorses delivery of survivorship care plans (SCPs) to the growing number of cancer survivors in order to improve the coordination of care between oncologists and primary care providers (PCPs). In response, the Commission on Cancer (COC) has increased the SCP delivery requirement to >50% of eligible patients, a goal that is difficult to meet given limited resources. Here we outline the initiatives taken to achieve this goal at the University of New Mexico Comprehensive Cancer Center (UNMCCC). Methods: Prior to 2017, SCPs were not routinely delivered. Beginning 2017, providers were tasked to complete and deliver printed SCPs , resulting in a 17% rate of SCP completion. However, there was general lack of provider support and enthusiasm as the process was time consuming with no method for identifying eligible patients and tracking SCP delivery. In 2018, designated staff was assigned to partially complete the SCPs to assist providers, resulting in an increase in SCP delivery rate to 41%. However, the same barriers existed. SCP softwares, although available, were expensive. A cost effective process therefore was needed. A committee was then formed to create a system-wide process utilizing the existing electronic health record (EHR) MOSAIQ. ASCO based SCPs were created. Once providers identify eligible patients, an SCP electronic order was initiated. Designated staff then partially completes the SCPs based on review of medical records. The EHR extracts data items including demographics, PCP information, cancer type and stage. The EHR is programmed to flag SCPs ready for delivery which the provider then edits and approves. This system tracks multiple time points including referral, completion and delivery of SCPs. This new process was implemented in April 2019. Quarterly reviews are set to assess metrics. Results: Utilizing existing EHR (MOSAIQ), a new SCP delivery process was created that allows tracking of assembly, completion and timing of delivery. Conclusions: To overcome existing barriers to SCP completion and delivery, a new cost effective process was created utilizing existing staff and EHR resources. Institutional support is key to the success of this initiative.","PeriodicalId":15862,"journal":{"name":"Journal of global oncology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42803165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-10-07DOI: 10.1200/jgo.2019.5.suppl.84
Dingxin Liu, D. Li, Wu Jiang, Z. Pan, Xiaoshi Zhang, P. Ding
84 Background: Although PD-1 blockade has significantly improved the survival of metastatic colorectal cancer with DNA Mismatch Repair-Deficient/Microsatellite Instability-High (MSI-H), the data on neoadjuvant setting is limited. Methods: In this retrospective study, we enrolled eight patients with advanced MSI-H colorectal cancer from three hospitals. four patients are locally advanced and four are metastatic. All the patients received at least two doses of PD-1 antibody with or without chemotherapy as neoadjuvant therapy. The aim of the present study was to evaluate the short‐term efficacy and toxicities of this strategy. Results: Neoadjuvant PD-1 Blockade is well tolerated with a few immune-related side-effect profiles. All the enrolled patients had a major response in imaging and/or pathological evaluation. Five of the seven resected patients were evaluated as pathological complete response. One patient without surgery has a cCR tumor response. For the patients with radical surgery, there is no surgery-related complication observed. Conclusions: Neoadjuvant PD-1 blockade induced tumor regression with a major clinical and pathological response in advanced dMMR/MSI-H colorectal cancer. Further studies are required to evaluate the long-term effect of this strategy.
{"title":"PD-1 blockade in neoadjuvant setting of DNA mismatch repair-deficient/microsatellite instability-high colorectal cancer.","authors":"Dingxin Liu, D. Li, Wu Jiang, Z. Pan, Xiaoshi Zhang, P. Ding","doi":"10.1200/jgo.2019.5.suppl.84","DOIUrl":"https://doi.org/10.1200/jgo.2019.5.suppl.84","url":null,"abstract":"84 Background: Although PD-1 blockade has significantly improved the survival of metastatic colorectal cancer with DNA Mismatch Repair-Deficient/Microsatellite Instability-High (MSI-H), the data on neoadjuvant setting is limited. Methods: In this retrospective study, we enrolled eight patients with advanced MSI-H colorectal cancer from three hospitals. four patients are locally advanced and four are metastatic. All the patients received at least two doses of PD-1 antibody with or without chemotherapy as neoadjuvant therapy. The aim of the present study was to evaluate the short‐term efficacy and toxicities of this strategy. Results: Neoadjuvant PD-1 Blockade is well tolerated with a few immune-related side-effect profiles. All the enrolled patients had a major response in imaging and/or pathological evaluation. Five of the seven resected patients were evaluated as pathological complete response. One patient without surgery has a cCR tumor response. For the patients with radical surgery, there is no surgery-related complication observed. Conclusions: Neoadjuvant PD-1 blockade induced tumor regression with a major clinical and pathological response in advanced dMMR/MSI-H colorectal cancer. Further studies are required to evaluate the long-term effect of this strategy.","PeriodicalId":15862,"journal":{"name":"Journal of global oncology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42912677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-10-07DOI: 10.1200/jgo.2019.5.suppl.112
C. Speers, S. L. Chang, B. Chandler, A. Pesch, A. Michmerhuizen, K. Wilder-Romans, S. Nyati, L. Pierce
112 Background: Unmet clinical needs in breast cancer (BC) management include the identification of patients at high risk to fail locally despite standard local therapy and an understanding of the biology of these recurrences. We previously reported a radiation response signature and here extend those studies to identify a signature predictive of timing of recurrence after RT. Methods: 2 independent patient cohorts were used for training (119 pts) and validation (112 pts). All patients received RT after BCS and systemic therapy as appropriate. Spearman’s rank correlation to correlate gene expression to recurrence time was used for feature selection. Significant genes were used to train a linear model which was locked before validation. Cox regression was used for both UVA and MVA. Results: Spearman’s correlation identified 485 genes whose expression was significantly associated with recurrence time (+/-3 yrs). Feature reduction refined the list to 41 genes retained within the signature. In training, the correlation of score to recurrence time was 0.85, p-value < 1.3x10-31; AUC of 0.91. External validation in an independent BC validation set accurately identified patients with early vs. late recurrences (correlation= 0.75, p-value = 0.001, AUC = 0.92, sens.=0.75, spec.= 1.0, PPV = 1.0, NPV = 0.8). Unique associations of breast cancer intrinsic subtype to timing of local recurrence were found. In UVA and MVA the signature remained the most significant factor associated with recurrence. GSEA analysis of the 41 genes retained within the signature identified proliferation and EGFR concepts associated with early recurrences and luminal and ER-signaling pathways associated with late recurrences. Knockdown of genes associated with the early and late recurrences demonstrated novel effects on proliferation and clonogenic survival, respectively. Conclusions: We report a BC gene expression signatures that may be useful in identifying patients unlikely to respond to adjuvant RT and may be used to predict timing of recurrences, with implications for potential treatment intensification and duration of follow-up for women with breast cancer treated with RT.
{"title":"A signature predictive of early versus late recurrence after radiation (RT) for breast cancer that may inform the biology of early, aggressive recurrences.","authors":"C. Speers, S. L. Chang, B. Chandler, A. Pesch, A. Michmerhuizen, K. Wilder-Romans, S. Nyati, L. Pierce","doi":"10.1200/jgo.2019.5.suppl.112","DOIUrl":"https://doi.org/10.1200/jgo.2019.5.suppl.112","url":null,"abstract":"112 Background: Unmet clinical needs in breast cancer (BC) management include the identification of patients at high risk to fail locally despite standard local therapy and an understanding of the biology of these recurrences. We previously reported a radiation response signature and here extend those studies to identify a signature predictive of timing of recurrence after RT. Methods: 2 independent patient cohorts were used for training (119 pts) and validation (112 pts). All patients received RT after BCS and systemic therapy as appropriate. Spearman’s rank correlation to correlate gene expression to recurrence time was used for feature selection. Significant genes were used to train a linear model which was locked before validation. Cox regression was used for both UVA and MVA. Results: Spearman’s correlation identified 485 genes whose expression was significantly associated with recurrence time (+/-3 yrs). Feature reduction refined the list to 41 genes retained within the signature. In training, the correlation of score to recurrence time was 0.85, p-value < 1.3x10-31; AUC of 0.91. External validation in an independent BC validation set accurately identified patients with early vs. late recurrences (correlation= 0.75, p-value = 0.001, AUC = 0.92, sens.=0.75, spec.= 1.0, PPV = 1.0, NPV = 0.8). Unique associations of breast cancer intrinsic subtype to timing of local recurrence were found. In UVA and MVA the signature remained the most significant factor associated with recurrence. GSEA analysis of the 41 genes retained within the signature identified proliferation and EGFR concepts associated with early recurrences and luminal and ER-signaling pathways associated with late recurrences. Knockdown of genes associated with the early and late recurrences demonstrated novel effects on proliferation and clonogenic survival, respectively. Conclusions: We report a BC gene expression signatures that may be useful in identifying patients unlikely to respond to adjuvant RT and may be used to predict timing of recurrences, with implications for potential treatment intensification and duration of follow-up for women with breast cancer treated with RT.","PeriodicalId":15862,"journal":{"name":"Journal of global oncology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43002114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-10-07DOI: 10.1200/jgo.2019.5.suppl.86
Hui Min Vivian Teo, Siu Wei. Goh, Intan Permata Sari, W. Chew, H. Lim, R. Dasgupta, Ankur Sharma
86 Background: Natural killer (NK) cells play promising roles in cancer surveillance and possess multiple unique characteristics for allogenic cell transfer (ACT) in the cancer immunotherapy. However, most studies were applicable to ex vivo expanded NK cells from the peripheral blood, which requires massive amount of cell numbers for the initial isolation and expansion. Moreover, recent studies have demonstrated a phenotypic heterogeneity between peripheral and tissue resident NK cells. Methods: In this study, we aim to establish the ex vivo expansion of tumor infiltrating NK cells directly from diagnostic breast core biopsies followed by functional validation through in vitro assays. Results: A total of 20 breast TILs models, including T and NK cells, were successfully established through genetically modified K562 feeder cells co-culture approach. These models represented all the major sub-types (hormone positive and negative) of breast cancers. Next, we extensively evaluated the tumor-reactivity of the selected NK models via effector:target cytotoxicity assays. Interestingly, non-invasive breast tumor line has exhibited a strong preferential kill by NK cells whereas the invasive line counterpart was able to escape NK cell-mediated cytotoxicity. Conclusions: The resource generated in this study has revealed tumor infiltrating NK cells as a potential tool for cell-based therapy in solid tumors. Furthermore, this study provides a platform to investigate the immune-resistance mechanism involved between tumor and NK cells, thus, paving the way to the discovery of novel cancer immunotherapy targets.
{"title":"Generation of personalized tumor Biopsy-Derived Natural Killer (BDNK) cells.","authors":"Hui Min Vivian Teo, Siu Wei. Goh, Intan Permata Sari, W. Chew, H. Lim, R. Dasgupta, Ankur Sharma","doi":"10.1200/jgo.2019.5.suppl.86","DOIUrl":"https://doi.org/10.1200/jgo.2019.5.suppl.86","url":null,"abstract":"86 Background: Natural killer (NK) cells play promising roles in cancer surveillance and possess multiple unique characteristics for allogenic cell transfer (ACT) in the cancer immunotherapy. However, most studies were applicable to ex vivo expanded NK cells from the peripheral blood, which requires massive amount of cell numbers for the initial isolation and expansion. Moreover, recent studies have demonstrated a phenotypic heterogeneity between peripheral and tissue resident NK cells. Methods: In this study, we aim to establish the ex vivo expansion of tumor infiltrating NK cells directly from diagnostic breast core biopsies followed by functional validation through in vitro assays. Results: A total of 20 breast TILs models, including T and NK cells, were successfully established through genetically modified K562 feeder cells co-culture approach. These models represented all the major sub-types (hormone positive and negative) of breast cancers. Next, we extensively evaluated the tumor-reactivity of the selected NK models via effector:target cytotoxicity assays. Interestingly, non-invasive breast tumor line has exhibited a strong preferential kill by NK cells whereas the invasive line counterpart was able to escape NK cell-mediated cytotoxicity. Conclusions: The resource generated in this study has revealed tumor infiltrating NK cells as a potential tool for cell-based therapy in solid tumors. Furthermore, this study provides a platform to investigate the immune-resistance mechanism involved between tumor and NK cells, thus, paving the way to the discovery of novel cancer immunotherapy targets.","PeriodicalId":15862,"journal":{"name":"Journal of global oncology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46048082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-10-07DOI: 10.1200/jgo.2019.5.suppl.62
Qin Xu, Yi-Bin Lin, Xian Lin, Jing Liu, Li Li, Peng Zheng, Bin Liu, H. Shi
62 Background: To better understand the mechanism contributing to cervical carcinogenesis, we perform a comprehensive analysis of genomic alterations in cervical cancer (CC). Methods: We conducted whole-exome sequencing of 43 CCs and established strict integrated workflow of genomic analysis. Correlation analysis was performed to measure the relationships between gene mutations and clinical characteristics of CC patients. Results: Genomic analysis revealed 28 genes frequently mutated in CC including BRD4 (4/43), AXL (4/43), MED12 (4/43), which are undetermined genomic features in CC, and identified recurrent genetic mutations in PIK3CA (16/43), KMT2D (11/43), KMT2C (6/43), FBXW7 (5/43), FAT1 (5/43), ERBB2 (4/43), EP300 (3/43) and NFE2L2 (3/43). Intriguingly, CC patients harbored high frequent mutations in BRCA2 (7/43), but not in BRCA1. The relationship between BRCA2 mutations and clinical factors is yet to be determined. The identified mutations predominately resulted in the dysregulation of the PI3K/AKT/mTOR pathway. Interestingly, we found that AXL mutations were positively correlated with FIGO stage ( P = 0.028), regional lymph node metastasis ( P = 0.011) and distant metastasis ( P = 0.022). KMT2C mutations were positively correlated with FIGO stage ( P = 0.004) and distant metastasis ( P = 0.009). SF3B1 mutations were positively correlated with regional lymph node metastasis ( P = 0.027) and distant metastasis ( P< 0.001). NFE2L2, ERBB2, RAC1, MED12, MET, BAP1, PTPRD and HNF1Amutations were positively correlated with distant metastasis ( P = 0.045, P = 0.004, P = 0.022, P = 0.001, P< 0.001, P< 0.001, P = 0.014, P< 0.001, respectively). POLD1 mutations were positively associated with regional lymph node metastasis ( P = 0.029). However, NOTCH1 mutations were negatively associated with regional lymph node metastasis ( P = 0.047). STK11 mutations were negatively associated with FIGO stage ( P = 0.013). Conclusions: Our results highlight the application of deep sequencing for understanding the molecular mechanisms and uncovering potential diagnostic and therapeutic targets of CC.
{"title":"Clinical factors associated with comprehensive genomic variation profiling of cervical cancer.","authors":"Qin Xu, Yi-Bin Lin, Xian Lin, Jing Liu, Li Li, Peng Zheng, Bin Liu, H. Shi","doi":"10.1200/jgo.2019.5.suppl.62","DOIUrl":"https://doi.org/10.1200/jgo.2019.5.suppl.62","url":null,"abstract":"62 Background: To better understand the mechanism contributing to cervical carcinogenesis, we perform a comprehensive analysis of genomic alterations in cervical cancer (CC). Methods: We conducted whole-exome sequencing of 43 CCs and established strict integrated workflow of genomic analysis. Correlation analysis was performed to measure the relationships between gene mutations and clinical characteristics of CC patients. Results: Genomic analysis revealed 28 genes frequently mutated in CC including BRD4 (4/43), AXL (4/43), MED12 (4/43), which are undetermined genomic features in CC, and identified recurrent genetic mutations in PIK3CA (16/43), KMT2D (11/43), KMT2C (6/43), FBXW7 (5/43), FAT1 (5/43), ERBB2 (4/43), EP300 (3/43) and NFE2L2 (3/43). Intriguingly, CC patients harbored high frequent mutations in BRCA2 (7/43), but not in BRCA1. The relationship between BRCA2 mutations and clinical factors is yet to be determined. The identified mutations predominately resulted in the dysregulation of the PI3K/AKT/mTOR pathway. Interestingly, we found that AXL mutations were positively correlated with FIGO stage ( P = 0.028), regional lymph node metastasis ( P = 0.011) and distant metastasis ( P = 0.022). KMT2C mutations were positively correlated with FIGO stage ( P = 0.004) and distant metastasis ( P = 0.009). SF3B1 mutations were positively correlated with regional lymph node metastasis ( P = 0.027) and distant metastasis ( P< 0.001). NFE2L2, ERBB2, RAC1, MED12, MET, BAP1, PTPRD and HNF1Amutations were positively correlated with distant metastasis ( P = 0.045, P = 0.004, P = 0.022, P = 0.001, P< 0.001, P< 0.001, P = 0.014, P< 0.001, respectively). POLD1 mutations were positively associated with regional lymph node metastasis ( P = 0.029). However, NOTCH1 mutations were negatively associated with regional lymph node metastasis ( P = 0.047). STK11 mutations were negatively associated with FIGO stage ( P = 0.013). Conclusions: Our results highlight the application of deep sequencing for understanding the molecular mechanisms and uncovering potential diagnostic and therapeutic targets of CC.","PeriodicalId":15862,"journal":{"name":"Journal of global oncology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44581691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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