For quiet a long time now there has been no treatment for metastatic colon cancer patients beyond second line except Regorafenib and TAS 103 which have shown some effectiveness but not long lasting and in recent times Immunotherapy in colon cancer has opened a new field of treatment where patients with MSI-H do well and survive for longer time.And in few patients there is a complete response. 9810619717. Initialyy pemrolizumab was approved but now nivolumab is approved as well.But the irony is that only 2 out of 17 patients were MSI-H at our centre.
Objective: To analyze the sonographic features of different histopathological subtypes of borderline ovarian tumors (BOTs) confirmed by pathology, and to study the ultrasound performances of various types in borderline ovarian tumors.
Study Design: Retrospective analysis was performed on the pathological results and ultrasound projection findings of 129 patients diagnosed as BOTs by ultrasound department of our hospital from January 2012 to November 2019. All patients were confirmed by surgical pathology and scanned consecutively by the investigators using transabdominal or transvaginal ultrasound examination.
Results: Serous borderline tumors (SBOTs) were observed, and the prevalence rate (53%) was significantly higher than that of other subtypes, and the probability of bilateral lesions was higher (40%). The sonogram often showed ultrasound features of papillary neoplasm in the lesion and good internal echo (p<0.05). Mucinous borderline ovarian tumors (MBOTs) were mostly unilateral lesions (86%). The prevalence was second only to SBOTs. Histomorphological examinations were divided into gastrointestinal-type and endocervical-type. Among them, the gastrointestinal type of MBOTs were mostly unilateral, and their incidence was higher than that of endocervical-type of MBOTs. Compared with other pathological subtypes, the gastrointestinal type is more likely to show the sonographic characteristics of huge space occupying in the pelvic and abdominal cavity (mean diameter >10 cm), polycystic, multiple septums, and poor internal echo (p<0.05). The ultrasonographic features of the endocervical-type of MBOTs were similar to those of SBOTs. Compared with gastrointestinal type, the sonographic images showed smaller lesion diameter, less septal or cyst, and more papillary excrescences in the tumor (p<0.05). The borderline clear cell tumor is the intermediate transition between the clear cell adenofibroma and the clear cell carcinoma. The clinical manifestations are diverse and lack specificity. The histology of sonography was mainly solid, and the multiple microcapsules were honeycomb-like. It can also be shown as cystic. Among the 169 patients with BOTs, 20 cases of SBOTs, 17 cases of MBOTs, and 10 cases of other rare subtypes were complicated with other diseases or multiple subtypes. This study did not find significant ultrasonic characteristics were used for distinguish them from other subtypes.
Conclusion: BOTs is a common disease in women during the reproductive period. It is characterized by the development of malignant tumors. Its clinical and pathological subtypes are complex and diverse. It leads many doctors to use the terms “large pelvic mass” and “solid ovarian mass” for diagnosis because of their lack of experience and understanding.
Keywords: adenocarcinoma, mucinous; adenocarcinoma, serous; borderline ovarian tumors; diagnostic imaging; ovarian neoplasms; papillary neoplasms; prognosis; transvaginal ultrasound, ultrasonography
BACKGROUND: Sequential Epstein-Barr virus (EBV)–positive B cell lymphoma to the initial diagnosis of angioimmunoblastic T cell lymphoma (AITL) is very rare, the exact mechanism and standard therapy of which is still being explored. CASE: A 50-year-old man was admitted to our hospital in January 2014 with a three-week history of enlargement of multiple lymph nodes. His initial pathological evaluation indicated AILT. The reactivation of EBV was observed during the immunosuppression therapy for AITL, accompanied by onset of subcutaneous nodules proven to be EBV-positive diffuse large B cell lymphoma (DLBCL) based on the pathological findings of rebiopsy. The patient was successfully treated with chidamide, a histone deacetylase (HDAC) inhibitor, and rituximab.
Conclusion: The sufficient surveillance for serum EBV and repeat biopsy is necessary for patients with AITL, and this treatment modality may become an active option.
Keywords: angioimmunoblastic T cell lymphoma, Epstein-Barr virus, HDAC inhibitor, non-Hodgkin lymphoma, peripheral T cell lymphoma
Objective: Tongue squamous cell carcinoma (TSCC) is a prominent type of oral cancer. Despite the numerous research studies on SCC and microRNAs (miRs), the relation between TSCC and miR-135b-5p is poorly discussed. This experiment aims to find out the possible effect of miR-135b-5p on TSCC with the network of its downstream genes.
Study Design: TSCC tissues and adjacent normal tissues were harvested. Then, expression of miR-135b-5p and AT-rich interactive domain‑containing protein 1A gene (ARID1A) and the phosphatidyl inositol 3-kinase/protein kinase B (PI3K/AKT) pathway was analyzed. After the transfection of miR-135b-5p inhibitor and its negative control into TSCC cells, functional assays were employed to measure cell proliferation, apoptosis, and cycle. Next, the target relation between miR-135b-5p and ARID1A was confirmed. In addition, the fact that miR-135b-5p promoted TSCC development via mediating ARID1A was demonstrated by functional rescue experiment.
Results: miR-135b-5p was upregulated in TSCC tissues and cells, while ARID1A was suppressed (p< 0.05). Silenced miR-135b-5p discouraged TSCC cell proliferation, improved apoptosis, induced cell cycle arrest, and increased ARID1A expression while inactivating the PI3K/AKT axis (p<0.05). Furthermore, knockdown of ARID1A reversed the impacts on TSCC cell proliferation and apoptosis exerted by silencing miR-135b-5p.
Conclusion: This research supported that silenced miR-135b-5p impeded TSCC proliferation and apoptosis by promoting ARID1A and inactivating the PI3K/AKT axis, which may provide some indications for TSCC alleviation.
Keywords: apoptosis; ARID1A; ARID1A protein, human; carcinoma, squamous cell; cell line, tumor; cell proliferation; drug resistance, neoplasm; microRNA-135b-5p; microRNAs; PI3K/AKT pathway; neoplasm metastasis; neoplastic stem cells; proliferation; protein binding; tongue; tongue squamous cell carcinoma
Objective: The prognostic indictors of age-related poor outcomes in patients with acute myeloid leukemia (AML) are still controversial. The aim of this work was to provide comprehensive insights into the effect of different hemocytes and to investigate the association between age and clinical features in adult patients with AML.
Study Design: A retrospective study was performed to determine the role of age in the therapeutic outcomes of AML. A total of 166 newly diagnosed adult patients’ data from January 2015 to November 2019 in Zhongshan Hospital of Xiamen University were collected and analyzed.
Results: Older patients presented a poorer prognosis (p=0.001) with shorter overall survival, which is served as age-related outcomes. Binary logistic regression demonstrated that cytogenetic risk (OR=4.508, 95% CI 2.733–7.435), leukocyte (OR=7.410, 95% CI 1.139–5.910), and bone marrow blast cells (OR=3.261, 95% CI 1.075–5.615) were independent indictors for age-related prognosis. In addition, Kaplan-Meier curve also revealed that the above factors were associated with overall survival (all p values <0.001).
Conclusion: Cytogenetic risk, leukocyte, and bone marrow blast cells are dominant factors which account for the age-related poor outcomes and shorter overall survival in AML.
Keywords: acute myeloid leukemia, adult, cytogenetic risk, hemocyte, leukemia, overall survival
Objective: The association between telomerase reverse transcriptase (TERT) promoter mutation and outcome of melanoma is unclear and controversial. We aim to conduct a meta-analysis and investigate whether the TERT promoter mutation is a prognostic factor of melanoma.
Study Design: Appropriate studies were searched in 3 databases: PubMed, Web of Science, and Embase. Pooled hazard ratios (HRs) were counted through random effects model.
Results: Heterogeneity was moderate in overall survival (OS) (I2=43.7%, p=0.059) and low in disease-free survival (DFS) (I2=0.0%, p=0.587). Sensitivity analysis indicated that the removal of any of the study did not affect the final results. Evidence for publication bias was not found (Begg’s test, p=0.281; Egger’s test, p=0.078). The pooled OS HRs from combined effects analysis was determined (HR 1.07; 95% CI 0.83–1.39, p=0.585), together with the pooled HRs of DFS (HR 1.65; 95% CI 1.02–2.66, p=0.042). TERT promoter mutation predicted a good outcome in meta-static melanoma patients (HR 0.66; 95% CI 0.46–0.96, p=0.042). The pooled HRs of combined mutation in TERT promoter and BRAF (HR 6.27; 95% CI 2.7–14.58, p=0.000) predicted a bad outcome in melanoma patients.
Conclusion: TERT promoter mutation significantly predicted poor DFS outcome but, on the contrary, predicted a good outcome in metastatic melanoma patients. The combined TERT promoter and BRAF mutation was a significant independent factor of OS in melanoma patients.
Keywords: melanoma; meta-analysis; mutation; prognosis; promoter regions, genetic; skin neoplasms; telomerase; TERT promoter mutation; TERT protein, human
Objective: To analyze the sonographic features of different histopathological subtypes of borderline ovarian tumors (BOTs) confirmed by pathology, and to study the ultrasound performances of various types in borderline ovarian tumors.
Study Design: Retrospective analysis was performed on the pathological results and ultrasound projection findings of 129 patients diagnosed as BOTs by ultrasound department of our hospital from January 2012 to November 2019. All patients were confirmed by surgical pathology and scanned consecutively by the investigators using transabdominal or transvaginal ultrasound examination.
Results: Serous borderline tumors (SBOTs) were observed, and the prevalence rate (53%) was significantly higher than that of other subtypes, and the probability of bilateral lesions was higher (40%). The sonogram often showed ultrasound features of papillary neoplasm in the lesion and good internal echo (p<0.05). Mucinous borderline ovarian tumors (MBOTs) were mostly unilateral lesions (86%). The prevalence was second only to SBOTs. Histomorphological examinations were divided into gastrointestinal-type and endocervical-type. Among them, the gastrointestinal type of MBOTs were mostly unilateral, and their incidence was higher than that of endocervical-type of MBOTs. Compared with other pathological subtypes, the gastrointestinal type is more likely to show the sonographic characteristics of huge space occupying in the pelvic and abdominal cavity (mean diameter >10 cm), polycystic, multiple septums, and poor internal echo (p<0.05). The ultrasonographic features of the endocervical-type of MBOTs were similar to those of SBOTs. Compared with gastrointestinal type, the sonographic images showed smaller lesion diameter, less septal or cyst, and more papillary excrescences in the tumor (p<0.05). The borderline clear cell tumor is the intermediate transition between the clear cell adenofibroma and the clear cell carcinoma. The clinical manifestations are diverse and lack specificity. The histology of sonography was mainly solid, and the multiple microcapsules were honeycomb-like. It can also be shown as cystic. Among the 169 patients with BOTs, 20 cases of SBOTs, 17 cases of MBOTs, and 10 cases of other rare subtypes were complicated with other diseases or multiple subtypes. This study did not find significant ultrasonic characteristics were used for distinguish them from other subtypes.
Conclusion: BOTs is a common disease in women during the reproductive period. It is characterized by the development of malignant tumors. Its clinical and pathological subtypes are complex and diverse. It leads many doctors to use the terms “large pelvic mass” and “solid ovarian mass” for diagnosis because of their lack of experience and understanding.
Keywords: adenocarcinoma, mucinous; adenocarcinoma, serous; borderline ovarian tumors; diagnostic imaging; ovarian neoplasms; papillary neoplasms; prognosis; transvaginal ultrasound, ultrasonography
BACKGROUND: Sequential Epstein-Barr virus (EBV)–positive B cell lymphoma to the initial diagnosis of angioimmunoblastic T cell lymphoma (AITL) is very rare, the exact mechanism and standard therapy of which is still being explored. CASE: A 50-year-old man was admitted to our hospital in January 2014 with a three-week history of enlargement of multiple lymph nodes. His initial pathological evaluation indicated AILT. The reactivation of EBV was observed during the immunosuppression therapy for AITL, accompanied by onset of subcutaneous nodules proven to be EBV-positive diffuse large B cell lymphoma (DLBCL) based on the pathological findings of rebiopsy. The patient was successfully treated with chidamide, a histone deacetylase (HDAC) inhibitor, and rituximab.
Conclusion: The sufficient surveillance for serum EBV and repeat biopsy is necessary for patients with AITL, and this treatment modality may become an active option.
Keywords: angioimmunoblastic T cell lymphoma, Epstein-Barr virus, HDAC inhibitor, non-Hodgkin lymphoma, peripheral T cell lymphoma
Objective: Tongue squamous cell carcinoma (TSCC) is a prominent type of oral cancer. Despite the numerous research studies on SCC and microRNAs (miRs), the relation between TSCC and miR-135b-5p is poorly discussed. This experiment aims to find out the possible effect of miR-135b-5p on TSCC with the network of its downstream genes.
Study Design: TSCC tissues and adjacent normal tissues were harvested. Then, expression of miR-135b-5p and AT-rich interactive domain‑containing protein 1A gene (ARID1A) and the phosphatidyl inositol 3-kinase/protein kinase B (PI3K/AKT) pathway was analyzed. After the transfection of miR-135b-5p inhibitor and its negative control into TSCC cells, functional assays were employed to measure cell proliferation, apoptosis, and cycle. Next, the target relation between miR-135b-5p and ARID1A was confirmed. In addition, the fact that miR-135b-5p promoted TSCC development via mediating ARID1A was demonstrated by functional rescue experiment.
Results: miR-135b-5p was upregulated in TSCC tissues and cells, while ARID1A was suppressed (p< 0.05). Silenced miR-135b-5p discouraged TSCC cell proliferation, improved apoptosis, induced cell cycle arrest, and increased ARID1A expression while inactivating the PI3K/AKT axis (p<0.05). Furthermore, knockdown of ARID1A reversed the impacts on TSCC cell proliferation and apoptosis exerted by silencing miR-135b-5p.
Conclusion: This research supported that silenced miR-135b-5p impeded TSCC proliferation and apoptosis by promoting ARID1A and inactivating the PI3K/AKT axis, which may provide some indications for TSCC alleviation.
Keywords: apoptosis; ARID1A; ARID1A protein, human; carcinoma, squamous cell; cell line, tumor; cell proliferation; drug resistance, neoplasm; microRNA-135b-5p; microRNAs; PI3K/AKT pathway; neoplasm metastasis; neoplastic stem cells; proliferation; protein binding; tongue; tongue squamous cell carcinoma
Objective: The prognostic indictors of age-related poor outcomes in patients with acute myeloid leukemia (AML) are still controversial. The aim of this work was to provide comprehensive insights into the effect of different hemocytes and to investigate the association between age and clinical features in adult patients with AML.
Study Design: A retrospective study was performed to determine the role of age in the therapeutic outcomes of AML. A total of 166 newly diagnosed adult patients’ data from January 2015 to November 2019 in Zhongshan Hospital of Xiamen University were collected and analyzed.
Results: Older patients presented a poorer prognosis (p=0.001) with shorter overall survival, which is served as age-related outcomes. Binary logistic regression demonstrated that cytogenetic risk (OR=4.508, 95% CI 2.733–7.435), leukocyte (OR=7.410, 95% CI 1.139–5.910), and bone marrow blast cells (OR=3.261, 95% CI 1.075–5.615) were independent indictors for age-related prognosis. In addition, Kaplan-Meier curve also revealed that the above factors were associated with overall survival (all p values <0.001).
Conclusion: Cytogenetic risk, leukocyte, and bone marrow blast cells are dominant factors which account for the age-related poor outcomes and shorter overall survival in AML.
Keywords: acute myeloid leukemia, adult, cytogenetic risk, hemocyte, leukemia, overall survival
Objective: The association between telomerase reverse transcriptase (TERT) promoter mutation and outcome of melanoma is unclear and controversial. We aim to conduct a meta-analysis and investigate whether the TERT promoter mutation is a prognostic factor of melanoma.
Study Design: Appropriate studies were searched in 3 databases: PubMed, Web of Science, and Embase. Pooled hazard ratios (HRs) were counted through random effects model.
Results: Heterogeneity was moderate in overall survival (OS) (I2=43.7%, p=0.059) and low in disease-free survival (DFS) (I2=0.0%, p=0.587). Sensitivity analysis indicated that the removal of any of the study did not affect the final results. Evidence for publication bias was not found (Begg’s test, p=0.281; Egger’s test, p=0.078). The pooled OS HRs from combined effects analysis was determined (HR 1.07; 95% CI 0.83–1.39, p=0.585), together with the pooled HRs of DFS (HR 1.65; 95% CI 1.02–2.66, p=0.042). TERT promoter mutation predicted a good outcome in meta-static melanoma patients (HR 0.66; 95% CI 0.46–0.96, p=0.042). The pooled HRs of combined mutation in TERT promoter and BRAF (HR 6.27; 95% CI 2.7–14.58, p=0.000) predicted a bad outcome in melanoma patients.
Conclusion: TERT promoter mutation significantly predicted poor DFS outcome but, on the contrary, predicted a good outcome in metastatic melanoma patients. The combined TERT promoter and BRAF mutation was a significant independent factor of OS in melanoma patients.
Keywords: melanoma; meta-analysis; mutation; prognosis; promoter regions, genetic; skin neoplasms; telomerase; TERT promoter mutation; TERT protein, human
Acute myeloid leukemia (AML) is a hematopoietic malignancy with a dismal outcome in the majority of cases. A detailed understanding of the genetic alterations and gene expression changes that contribute to its pathogenesis is important to improve prognostication, disease monitoring, and therapy. In this context, leukemia-associated misexpression of microRNAs (miRNAs) has been studied, but no coherent picture has emerged yet, thus warranting further investigations.
Neuroblastomas are rare extracranial tumors of the pediatric population arising from cells of the embryological sympathetic nervous system. These malignancies most commonly occur in the abdomen, but other sites include the chest, neck, and pelvis with a predisposition for lymphatic and hematogenous
spread. Metastasis to the bone is a poor prognostic indicator, requiring surgical excision and other extensive medical management.
Overexpression of YAP 1 contributes to progressive features and poor prognosi...Enrique Moreno Gonzalez
Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.
Differences in microRNA expression during tumor development in the transition...Enrique Moreno Gonzalez
The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate.
Low expression of N-myc downstream-regulated gene 2 in oesophageal squamous c...Enrique Moreno Gonzalez
It is currently unclear whether a correlation exists between N-myc downstream-regulated gene 2 (NDRG2) expression and oesophageal squamous cell carcinoma (ESCC). The aim of this study was to examine the underlying clinical significance of NDRG2 expression in ESCC patients and to investigate the effects of NDRG2 up-regulation on ESCC cell growth in vitro and in vivo.
Clinical and experimental studies regarding the expression and diagnostic val...Enrique Moreno Gonzalez
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a multifunctional Ig-like cell adhesion molecule that has a wide range of biological functions. According to previous reports, serum CEACAM1 is dysregulated in different malignant tumours and associated with tumour progression. However, the serum CEACAM1 expression in nonsmall-cell lung carcinomas (NSCLC) is unclear. The different expression ratio of CEACAM1-S and CEACAM1-L isoform has seldom been investigated in NSCLC. This research is intended to study the serum CEACAM1 and the ratio of CEACAM1-S/L isoforms in NSCLC.
Clinical Genomics for Personalized Cancer Medicine: Recent Advances, Challeng...Yoon Sup Choi
I reviewed recent advances, challenges, and opportunities to implement clinical cancer genomics. Case studies of advanced systems, such as Foundation Medicine, MI-ONCOSEQ are introduced for benchmark. A few fundamental limitations to establish personalized oncology are also discussed.
History of DICER1 mutation
DICER1 function
Mutated DICER1 – tumorigenic mechanism
Constellation of lesions associated with DICER1
DICER1 IHC
When to test?
Therapeutic options
Tumor markers (TMs) refer to a class of substances that are directly produced by tumor cells or other cells of the body in response to tumors during its development and proliferation stages. Tumor markers essentially are proteins, hormones,
enzymes (isozymes), polyamines, and oncogene products, which presents in the blood, body fluids, cells or tissues of patients. They can quantitatively and qualitatively reveal the presence of tumors, which provides strong experimental
basis to estimate what the type of tumor is, what stage of the tumor has been developed to, the therapeutic effect and prognosis. www.antibody-creativebiolabs.com
This presentation is part of MIU CE Pharmacy Program and is designed primarily for pharmacists with the following learning objectives:
1- Explain the mechanisms of action behind immune response to cancer and the application of immunotherapy in cancer treatment
2- Distinguish new and emerging immunotherapy classes and individual agents efficacy, safety to therapy in cancer treatment
3-Strategies to counsel and assist patients to overcome barriers to therapy, including Treatment side effects to improve adherence to therapy
Acute myeloid leukemia (AML) is a hematopoietic malignancy with a dismal outcome in the majority of cases. A detailed understanding of the genetic alterations and gene expression changes that contribute to its pathogenesis is important to improve prognostication, disease monitoring, and therapy. In this context, leukemia-associated misexpression of microRNAs (miRNAs) has been studied, but no coherent picture has emerged yet, thus warranting further investigations.
Neuroblastomas are rare extracranial tumors of the pediatric population arising from cells of the embryological sympathetic nervous system. These malignancies most commonly occur in the abdomen, but other sites include the chest, neck, and pelvis with a predisposition for lymphatic and hematogenous
spread. Metastasis to the bone is a poor prognostic indicator, requiring surgical excision and other extensive medical management.
Overexpression of YAP 1 contributes to progressive features and poor prognosi...Enrique Moreno Gonzalez
Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.
Differences in microRNA expression during tumor development in the transition...Enrique Moreno Gonzalez
The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate.
Low expression of N-myc downstream-regulated gene 2 in oesophageal squamous c...Enrique Moreno Gonzalez
It is currently unclear whether a correlation exists between N-myc downstream-regulated gene 2 (NDRG2) expression and oesophageal squamous cell carcinoma (ESCC). The aim of this study was to examine the underlying clinical significance of NDRG2 expression in ESCC patients and to investigate the effects of NDRG2 up-regulation on ESCC cell growth in vitro and in vivo.
Clinical and experimental studies regarding the expression and diagnostic val...Enrique Moreno Gonzalez
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a multifunctional Ig-like cell adhesion molecule that has a wide range of biological functions. According to previous reports, serum CEACAM1 is dysregulated in different malignant tumours and associated with tumour progression. However, the serum CEACAM1 expression in nonsmall-cell lung carcinomas (NSCLC) is unclear. The different expression ratio of CEACAM1-S and CEACAM1-L isoform has seldom been investigated in NSCLC. This research is intended to study the serum CEACAM1 and the ratio of CEACAM1-S/L isoforms in NSCLC.
Clinical Genomics for Personalized Cancer Medicine: Recent Advances, Challeng...Yoon Sup Choi
I reviewed recent advances, challenges, and opportunities to implement clinical cancer genomics. Case studies of advanced systems, such as Foundation Medicine, MI-ONCOSEQ are introduced for benchmark. A few fundamental limitations to establish personalized oncology are also discussed.
History of DICER1 mutation
DICER1 function
Mutated DICER1 – tumorigenic mechanism
Constellation of lesions associated with DICER1
DICER1 IHC
When to test?
Therapeutic options
Tumor markers (TMs) refer to a class of substances that are directly produced by tumor cells or other cells of the body in response to tumors during its development and proliferation stages. Tumor markers essentially are proteins, hormones,
enzymes (isozymes), polyamines, and oncogene products, which presents in the blood, body fluids, cells or tissues of patients. They can quantitatively and qualitatively reveal the presence of tumors, which provides strong experimental
basis to estimate what the type of tumor is, what stage of the tumor has been developed to, the therapeutic effect and prognosis. www.antibody-creativebiolabs.com
This presentation is part of MIU CE Pharmacy Program and is designed primarily for pharmacists with the following learning objectives:
1- Explain the mechanisms of action behind immune response to cancer and the application of immunotherapy in cancer treatment
2- Distinguish new and emerging immunotherapy classes and individual agents efficacy, safety to therapy in cancer treatment
3-Strategies to counsel and assist patients to overcome barriers to therapy, including Treatment side effects to improve adherence to therapy
Prognosis of Invasive Micropapillary Carcinoma of the Breast Analyzed by Usin...daranisaha
Invasive micropapillary carcinoma (IMPC) is a rare type of breast cancer with high frequency of regional lymph node metastasis. However, the prognosis of IMPC has remained controversial for decades. We aimed to compare the differences of prognosis between IMPC and Invasive ductal carcinoma(IDC) of the breast by utilizing Surveillance, Epidemiology, and End Results (SEER) database.
Prognosis of Invasive Micropapillary Carcinoma of the Breast Analyzed by Usin...eshaasini
Invasive micropapillary carcinoma (IMPC) is a rare type of breast cancer with high frequency of regional lymph node metastasis. However, the prognosis of IMPC has remained controversial for decades. We aimed to compare the differences of prognosis between IMPC and Invasive ductal carcinoma(IDC) of the breast by utilizing Surveillance, Epidemiology, and End Results (SEER) database
Prognosis of Invasive Micropapillary Carcinoma of the Breast Analyzed by Usin...semualkaira
Invasive micropapillary carcinoma (IMPC) is a rare type of breast cancer with high frequency of regional lymph node metastasis. However, the prognosis of IMPC has remained controversial for decades. We aimed to compare the differences of prognosis between IMPC and Invasive ductal carcinoma(IDC) of the breast by utilizing Surveillance, Epidemiology, and End Results (SEER) database.
Prognosis of Invasive Micropapillary Carcinoma of the Breast Analyzed by Usin...semualkaira
Invasive micropapillary carcinoma (IMPC) is a rare type of breast cancer with high frequency of regional lymph node metastasis. However, the prognosis of IMPC has remained controversial for decades. We aimed to compare the differences of prognosis between IMPC and Invasive ductal carcinoma(IDC) of the breast by utilizing Surveillance, Epidemiology, and End Results (SEER) database.
Prognosis of Invasive Micropapillary Carcinoma of the Breast Analyzed by Usin...semualkaira
Invasive micropapillary carcinoma (IMPC) is a rare type of breast cancer with high frequency of regional lymph node metastasis. However, the prognosis of IMPC has remained controversial for decades. We aimed to compare the differences of prognosis between IMPC and Invasive ductal carcinoma(IDC) of the breast by utilizing Surveillance, Epidemiology, and End Results (SEER) database
dkNET Webinar: Leveraging Computational Strategies to Identify Type 1 Diabete...dkNET
dkNET New Investigator Pilot Program in Bioinformatics Awardee Webinar Series
Presenter: Wenting Wu, PhD. Research Assistant Professor, Center for Diabetes and Metabolic Diseases, Department of Medical and Molecular Genetics, Associate Director of Data and Analytics Core for Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine
Abstract
Type 1 diabetes (T1D) is an immune-mediated disease that results in insulin insufficiency and affects 0.3% of the population, including both children and adults. To support clinical trial efforts, there is an urgent need to develop reliable biomarkers capable of predicting T1D risk and guiding therapeutic interventions. Recently, whole blood bulk RNA sequencing has been used to guide T1D clinical trial design and assess response to disease modifying interventions. While the use of bulk RNA sequencing is cost-effective, these datasets provide limited information about cell specific gene expression changes. Here, we aimed to apply computational strategies to deconvolute cell type composition using cell specific gene expression references. Single-cell RNA sequencing (scRNA-seq) was conducted to profile peripheral blood mononuclear cells obtained from youth within recent T1D onset and age- and sex-matched controls and identified 31 distinct cell clusters. Using this pre-defined reference dataset, we ran computational algorithms CIBERSORTx and other deconvolution methods simultaneously to deconvolute cell proportions using public clinical trial data. We focused our initial analysis on data from the TN-20 Rituximab trial, which tested the anti-CD20 monoclonal antibody rituximab vs placebo in recent onset T1D. This talk will introduce recent advances of scRNA-seq techniques and computational deconvolution methods and demonstrate that how we apply different deconvolution approaches for secondary analysis of existing clinical trial data, in the purpose of linking cell specific immune signatures associated with drug responder status.
Upcoming webinars schedule: https://dknet.org/about/webinar
Zeine Seminar 2010, Cancer Associated Fibroblasts and Microvascular Prolifera...Rana ZEINE, MD, PhD, MBA
World Cancer Congress 2010
Presence of Cancer-Associated Fibroblasts correlates with Microvascular Proliferation which is a Poor Prognostic Factor in Neuroblastoma Tumors
5-YEAR SURVIVAL OF UPPER THIRD ESOPHAGEAL CANCER PATIENTS WAS SIGNIFICANTLY SUPERIOR IN COMPARISON WITH MIDDLE AND LOWER THIRD ESOPHAGEAL CANCER PATIENTS AFTER RADICAL SURGERY AND STRONGLY DEPENDED ON PHASE TRANSITION EARLY-INVASIVE CANCER, LYMPH NODE METASTASES, CELL RATIO FACTORS AND ADJUVANT CHEMOIMMUNORADIOTHERAPY
Similar to Immunotherapy in metastatic colon cancer (20)
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
The Gram stain is a fundamental technique in microbiology used to classify bacteria based on their cell wall structure. It provides a quick and simple method to distinguish between Gram-positive and Gram-negative bacteria, which have different susceptibilities to antibiotics
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
Adv. biopharm. APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMSAkankshaAshtankar
MIP 201T & MPH 202T
ADVANCED BIOPHARMACEUTICS & PHARMACOKINETICS : UNIT 5
APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMS By - AKANKSHA ASHTANKAR
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
2. Fluorinated Pyrimidines, A New Class ofTumour-
Inhibitory Compounds
Nature-1957
Rat hepatomas use uracil more efficiently than non-
malignant tissue
3. T-STAGE N-STAGE M-STAGE
Tumor cell
extension
and invasion
CD3+ T cells CD8+ T cells Density Location (CT, IM)Immunoscore
Host immune
response
Mucinous CCS1
CCS2Medullary
Adeno. NOS
Serrated
Signet ring cell
Enterocyte
Goblet-like
Transit-amplifying-S
Inflammatory
Stem-like
CIN
MSI
CIMP CCS3Transit-amplifying-R
BRAF
APC
KRAS
TP53
Morphology Cell of origin Molecular pathway Mutation status Gene expression
Tumor cell
characteristics
Ways to classify
CTNNB1
Micropapillary
Cribriform comedo
-type
Galon et al. J Pathol. 2014
Colorectal cancer classifications
4. Memory T cells, in particular, TEM correlate with the absence
of early-metastatic invasion, and improved clinical outcome
in colorectal carcinoma.
Pagès F, et al. N Engl J Med. 2005
Pagès F & Galon J. N Engl J Med. 2006
*
5. Quantification of immune cell densities (6640 IHC) revealed the major
positive role of cytotoxic and memory T cells for patient’s survival
A Novel Paradigm for Cancer
Galon J et al. Science 2006
ImmunoscoreImmune contexture
The foundation a new concept
Cohort 1:
patients
n= 415
Validation cohorts: n= 188 patients
6. COX multivariate analysis (OS) in all stages I, II, III patients
Parameter HR P value
• T-stage
• N-stage
• Differentiation
• Immunoscore
1.2 0.25
1.4 0.15
1.1 0.84
1.9 0.00001
Novel Paradigm
Galon J et al. Science 2006
Galon J et al. Cancer Res. 2007
“Contexture: the act of assembling parts into a whole; an arrangement of interconnected parts”
“Immune Contexture” : nature, immune functional orientation, density, and
location within distinct tumor regions, of a natural in situ immune reaction
Invasive margin (IM)
tumor
tumor
immune
immune
Center of the tumor (CT)
7. Prolonged survival in patients with high Immunoscore (Im)
based on the evaluation of CD45RO-CT/IM and CD8-CT/IM
Mlecnik et al. J Clin Oncol 2011
Survival (months)
P<0.0001
Disease-FreeSurvival(%)
0
20
40
60
80
100
0 20 40 60 80 100 120 140 160 180
Im4
Im3
Im2
Im1
Im0
AJCC/UICC-Stage I-III
Disease-FreeSurvival(%)
Im4
Im3
Im2
Im1
Im0
0
20
40
60
80
100
0 20 40 60 80 100 120 140 160 180
Survival (months)
P<0.0001
AJCC/ UICC-Stage I-IV
8. Tumor progression, invasion and recurrence are dependent on the immune contexture
and Immunoscore
Pre-existing immunity is determining the fate and survival of the patient
Galon J et al. Science 2006. Mlecnik B et al. JCO 2011
Cox Multivariate analysis including Immunoscore
9. Immune
Functional
orientation
IFNG GZMA
IL12 GZMB
TBX21 GZMH
IRF1 PRF
STAT1 GLNY
MADCAM1
ICAM1
VCAM1
ITGAE
Quantification (cells/mm2)
Adaptive immunity, cytotoxic, memory T cells
Tumor center, Margin, Tertiary lymphoid ilets
Immune contexture
Immunologic
Constant of
Rejection
(other diseases)
CX3CL1
CXCL9
CXCL10
CCL5
CCL2
Location
Immunoscore
The overlap between the immune contexture, the
immunologic constant of rejection and the Immunoscore
CXCL13
IL21, IL15
Galon J et al.
Immunity 2013
-> ImmunoSign
10. immune signatures
NON-Immune signatures
Prognostic Predictive
The overlap between prognostic, predictive and mechanistic
Mechanistic
IMMUNE signatures
Prognostic
Mechanistic
Predictive
ICR
Immune
contexture
Galon J et al. Immunity 2013
Immunoscore
Th1
Cytotoxicity
Chemokines
Cytokines
Adhesion
11. • Evolution of the tumor microenvironment with tumor progression?
• Immune escape mechanisms in human tumors?
Understanding the evolution of the immune response
with tumor progression using systems biology
-> Spatio-temporal dynamics
of the immune response with tumor progression
Bindea G et al. Immunity, 2013
Tis
T1 T2 T3 T4
∆ ∆ ∆ ∆
T-Stage
16. Patients with MSI-H have multiple Frameshift mutations
(Fsmut)
MSS MSI-H
cohort 1
cohort 2
0
ExomeSeq Multiplex FSmut validation
Mlecnik et al. Immunity 2016
17.
18. Most of over-expressed genes in MSI-H patients correspond to
immune-related genes
Gene functions and gene distribution analysis using ClueGO software
Mlecnik et al. Immunity 2016
19. Patients with MSI-H have increased intratumoral T-cell
proliferationTriple immunofluorescence quantification in situ
Increased CD3+Ki67+ cells in the center, invasive margin and tertiary lymphoid structures in patinets with MSI-H
Mlecnik et al. Immunity 2016
20. Most MSI and a subgroup of MSS patients have high intratumoral adaptive immune gene expression
Functional effector anti-frameshift mutation CTLs kill tumor cells in MSI patients
Genetic evidence of immunoediting in human CRC, in particular for MSI patients
Immunoscore gives an indicator of tumor recurrence and survival beyond MSI staging
Mlecnik et al. Immunity 2016
21. Patient 1 (weak)
CD3
Tumor
Patient 2 (moderate) Patient 3 (strong)
How to explain “Hot” and “Cold” immune infiltrated tumors ?
Median OS < 2 years
(death)
4.9 years > 15 years
Im0 Im2 Im4Immunoscore
CD3/CD8
Center/Margin
22. Mechanisms associated with T cells infiltration
Attraction Adhesion
MADCAM1
VCAM1
ICAM1
T cells
IL15
TH1
Cytotoxic
Memory
T cells
CXCL9
CXCL10
CCL2
CCL5
CX3CL1 CXCL13
TFH
B cells
Mlecnik et al. Gastroenterology 2010
Bindea et al. Immunity 2013
Local lymphocyte
proliferation
Mlecnik et al. Science Transl Med 2014
23. Prognostic importance of the in situ immune reaction in
patients with early-stage (Stage I/II) colorectal cancer
Pagès F et al. J. Clin. Oncol. 2009
Stage I cancer
CD45ROCT/IM CD8CT/IM P< .0001
Stage II cancer
Disease-FreeSurvival(%)
100
80
60
40
20
0
0 25 50 75 100 125 150175 200
225
Survival (months)
Im4
Im3
Stage I
patients
Im1-2
Im0
Disease-FreeSurvival(%)
0
20
40
60
80
100
0 25 50 75 100 125 150175 200 225
Survival (months)
Im4
Im3
Stage II
patients
Im1-2
Im0
P< .0001CD45ROCT/IM CD8CT/IM
24. THE IMMUNOSCORE
AS A NEW POSSIBLE
APPROACH IN
THE
CLASSIFICATION OF
CANCERNaples, Italy, Feb 2012 Organizer: P Ascierto, J. Galon, Principal investigator: J. Galon
Immunoscore steering committee: B. Fox, F. Marincola, C. Bifulco, P. Ascierto, J. Galon
Galon J et al. J. Transl. Med. 2012
Galon J et al. J. Pathol. 2014
25. IMMUNOSCORE®
Faisability
IHC automate High-resolution
scanner
whole slide quantification
Digital pathology
-> Conceptual and technological challenge
Immunoscore
Galon J et al. J. Transl. Med. 2012
Galon J et al. J. Pathol. 2014
-> Standardized Operating Procedure
-> Today’s tools for modern pathologists
26.
27. Immunoscore in Colon Cancer:
Pt Population
Characteristics
Training Set
(n = 700)
Internal
Validation Set
(n = 636)
External
Validation Set
(n = 969)
Median age, yrs 68.3 (±12.6) 68.3 (±12.2) 68.2 (± 32.7)
Male, n (%) 346 (49.4) 339 (53.3) 497 (51.3)
T stage, n (%)
T1
T2
T3
T4
37 (5.3)
109 (15.6)
452 (64.6)
102 (14.6)
34 (5.3)
97 (15.3)
427 (67.1)
78 (12.3)
32 (3.3)
153 (15.8)
635 (65.5)
149 (15.4)
N stage, n (%)
N0
N1
N2
508 (73.4)
124 (17.9)
60 (8.7)
482 (76.3)
107 (16.9)
43 (6.8)
608 (64.1)
223 (23.5)
117 (12.3)
Median lymph nodes, n 22.1 (±15.2) 21.8 (±16.9) 16.4 (±11.8)
Proximal colon cancer, n (%)
Distal colon cancer, n (%)
Missing, n (%)
349 (49.9)
349 (49.9)
2 (0.3)
307 (48.3)
327 (51.5)
1 (0.2)
527 (54.9)
431 (44.9)
2 (0.2)
Galon J, et al. ASCO 2016. Abstract 3500.
28. Immunoscore in Colon Cancer:
Characteristics Training Set
Internal
Validation Set
External
Validation Set
Time to end of follow-up
Median survival, mos
5-yr survival rate, %
143.6
(127.3-162.2)
74.9
(71.6-78.2)
180.7
(147.7-197.6)
77.8
(74.5-81.1)
160.1
(124.5-191.4)
68.8
(65.6-72.0)
Recurrence-free survival time
Median survival, mos
5-yr survival rate, %
122.3
(107.6-132.8)
68.3
(64.7-71.9)
140.2
(116.6-150.4)
71.3
(67.6-75.0)
95.1
(80.0-106.9)
58.3
(54.9-61.8)
Galon J, et al. ASCO 2016. Abstract 3500.
29. Immunoscore in Colon Cancer:
Time to Recurrence, Training Set
Outcome
Training Set
High Intermediate Low
Primary objective (high/low):
5-yr time to recurrence, % (95% CI)
67.3
(59.4-76.2)
-- 85.3
(82.1-88.6)
HR (95% CI) 0.41 (0.28-0.61)
P value
C-index
< .0001
0.60
Secondary objective (high/int/low):
5-yr time to recurrence, % (95% CI)
67.3
(59.4-76.2)
81.9
(77.7-86.3)
92.3
(88.2-96.6)
HR (95% CI)
Int vs high: 0.51 (0.34-0.77)
Low vs high: 0.19 (0.10-0.37)
P value
C-index
< .0001
0.64
Galon J, et al. ASCO 2016. Abstract 3500.
30. Immunoscore in Colon Cancer:
Secondary Objectives Efficacy
EndpointsOutcome High Intermediate Low
5-yr time to recurrence, % (95% CI)
69.0
(65.2-72.9)
80.6
(78.3-83.0)
88.9
(86.3-91.6)
HR (95% CI)
P value
Int vs high: 0.58 (0.48-0.71)
Low vs high: 0.29 (0.21-0.38)
< .0001
5-yr DFS, % (95% CI)
57.6
(53.8-61.7)
69.2
(66.6-71.9)
75.4
(72.0-79.0)
HR (95% CI)
P value
Int vs high: 0.69 (0.60-0.80)
Low vs high: 0.52 (0.43-0.62)
< .0001
5-yr OS, % (95% CI)
66.9
(63.4-70.7)
77.3
(75.0-79.7)
81.5
(78.5-84.6)
HR (95% CI)
P value
Int vs high: 0.73 (0.63-0.85)
Low vs high: 0.59 (0.49-0.71)
< .0001
Galon J, et al. ASCO 2016. Abstract 3500.
31. Deciphering the tumor immune microenvironment:
Clinical implications
CD3
Tumor
Clinical implications
Predictions Response to immunotherapies
(CTLA4, PD1, PDL1, …)
“Cold” Tumor
I 0
“Hot” Tumor
I 4
Need T-cell priming
Cancer vaccine
CAR-T cells
But it is not as simple since biology is complex and is not dichotomized in good & bad
32. Pembrolizumab (Anti–PD-1) in MMRD CRC:
Study Design
Eligibility for cohorts A and B:
Metastatic or locally advanced CRC, with or
without MMRD (defined as: deficiency in MLH1,
MSH2, MSH6 or PMS2 by IHC, or MSI in ≥ 2 loci
by PCR)
≥ 2 previous cancer therapy regimens
ECOG PS ≤ 1
No previous checkpoint inhibitor therapy
Treatment: pembrolizumab 10 mg/kg Q2W
MMR testing using standard PCR-based assay
for detection of MSI
Current report: updated data from cohort A3
Cohort A (n = 28)
MMRD CRC
Cohort B (n = 25)
MMRP CRC
Cohort C (n = 30)
MMRD non-CRC
Le DT, et al. ASCO 2016. Abstract 103.
33. Pembrolizumab in MMRD CRC: Efficacy
Le DT, et al. ASCO 2016. Abstract 103.
Outcome
MMRD CRC
(n = 28)
MMRP CRC
(n = 25)
Median follow-up, mos 9.3 6
ORR, % (95% CI) 57 (39-73) 0 (0-13)
Response, %
CR
PR
SD (Wk 12)
PD
NE (no 12-wk scan)
11
46
32
4
7
0
0
16
44
40
Disease control rate, %
(95% CI)
89 (73-96) 16 (6-35)
Median PFS, mos NR 2.3
Median OS, mos NR 5.98
34. Pembrolizumab in MMRD CRC: OS and PFS
Le DT, et al. ASCO 2016. Abstract 103.
OS(%)
PFS(%)
Mos
MMRD
(mOS: NR)
OS PFS
10
0
50
0
0 3 6 12 15 1
8
21 24 27 30
MMRP
(mOS: 5.98 mos)
9
Mos
MMRD
(mPFS: NR)
10
0
50
0
0 3 6 12 15 1
8
21 24 27 30
MMRP
(mPFS: 2.3 mos)
9
35. Pembrolizumab in MMRD CRC: Duration of
Disease Control
Complete and durable responses observed in > 50% of
pts with MMRD CRC
Le DT, et al. ASCO 2016. Abstract 103.
125
75
50
25
0
-25
-50
-75
-100
ChangeFromBaseline(%)
-125
100
365 73
0
MMRP CRC
MMRD CRC
36. Phase II CheckMate-142: Nivolumab +
Ipilimumab in MSI-H CRC
Primary endpoint: ORR per investigator (RECIST 1.1)
Secondary endpoint: ORR per IRC
Exploratory endpoints: safety, tolerability, PFS, OS, biomarkers
Nivo 3
mg/kg
Q2W
(n = 19)
1st:
mStage 1
≥
7/19
Respon
ses ≥
7/1
9
MSI-H
CONTINUE
Nivo 3 mg/kg
Q2W
(n = 19 + 29 add’l
pts)
3rd:
mStage 2
• Nivo 3 mg/kg + Ipi
1 mg/kg (Q3W x 4)
• Then Nivo 3 mg/kg
(Q2W)
(n = 19 + 29 add’l
pts)
4th: cStage
2*
Second-line
CRC MSI-H; ≥
1 prior
treatment for
metastatic
disease;
≥ 1 target
lesion; ECOG
PS: 0-1
(N = 120)
3-
6/19
Nivo 3 mg/kg
Nivo 3 mg/kg
+ Ipi 1 mg/kg
(Q3W x 4)
Then Nivo 3
mg/kg (from
W13, Q2W)
(n = 19)
2nd:
cStage 1
Respon
ses
Respon
ses
*Currently
enrolling
Overman M, et al. ASCO 2016. Abstract 3501.
37. Nivolumab + Ipilimumab in MSI-H Colon
Cancer: ORR per Investigators
Nivolumab 3 mg/kg + Ipilimumab
1 mg/kg100
0 6 12182430364248546066727884
75
50
25
0
-25
-50
-75
-100
Wks
PercentChangeFromBaseline
Off treatment
Nivolumab +
ipilimumab
treatment
ongoing
First occurrence of new l
CR or PR
Response
Nivolumab 3
mg/kg +
Ipilimumab 1
mg/kg (n = 27*)
ORR, n (%) [95%
CI]
CR
PR
SD
PD
Unable to
determine
9 (33.3) [18.6-
50.9]
0
9 (33.3) [16.5-
54.0]
14 (51.9)
3 (11.1)
0
Median time to
response, mos
(range)
2.73 (1.2-6.9)
Median duration
of response, mos
(range)
NE (NE-NE)
*Pts with ≥ 12 wks of follow-up.
Overman M, et al. ASCO 2016. Abstract 3501.
38. Nivolumab + Ipilimumab in MSI-H Colon Cancer:
Best Reduction in Target Lesion Size
*Confirmed responses.
56% pts with reduction 81% pts with reduction
Nivolumab 3 mg/kg +
Ipilimumab 1 mg/kg
Nivolumab 3 mg/kg100
75
50
25
0
-25
-50
-75
-100
BestReductionFromBaseline
inTargetLesion(%)
Pts
100
75
50
25
0
-25
-50
-75
-100
BestReductionFromBaseline
inTargetLesion(%)
Pts
***
*****
****
**
****
*
**% change truncated to 100%
Overman M, et al. ASCO 2016. Abstract 3501.
39. Nivolumab70 19 13 9 5 0
Nivo + Ipi30 21 7 0 0 0
Pts at Risk, n
0
13 1
0
0 3 6 9 12 15 21
Mos
0
20
40
60
80
100
PFS(%)
18
Nivolumab + Ipilimumab in MSI-H Colon Cancer:
PFS per Investigators
Nivo 3 mg/kg
(n = 70)
Nivo 3 mg/kg
+
Ipi 1 mg/kg
(n = 30)
PFS rate, % (95% CI)
6 mos
9 mos
12 mos
45.9 (29.8-
60.7)
45.9 (29.8-
60.7)
45.9 (29.8-
60.7)
66.6 (45.5-
81.1)
NE
NE
Median PFS, mos (95%
CI)
5.3 (1.5-NE) NE (3.4-NE)
Overman M, et al. ASCO 2016. Abstract 3501.
40. P = .05 (t-test)
TMB=229: POLE
(P286R; L1915I)
TMB=176: POLE
(V411L)
P < .0001 (t-test)
Salem ME, et al. ASCO GI 2017. Abstract 530.
2 MSI-Stable CRCTumors With High TMB Carried POLE Mutations
1
10
100
500
400
300
200
80
60
50
40
30
20
7
5
4
3
2
0.7
MSI High MSI Stable
FA MSI
TMBperMB
10
30
20
7
5
4
3
6
MSI High MSI Stable
FA MSI
TMBperMB
9
8
Tumor Mutation Burden and MSI Are Highly
Correlated in GI Cancers
41. Nivolumab Provides Durable Responses in
PatientsWith Metastatic DNA Mismatch
Repair–Deficient or MSI-High Colorectal
Cancer
July 27, 2017
This phase II study was designed to evaluate
response with nivolumab in patients with
MSI-high metastatic CRC.
42. Of the 74 patients who were enrolled
between March 12, 2014, and March 16, 2016,
40 (54%) had received three or more
previous treatments.
43. 23 (31·1%, 95% CI 20·8-42·9) of 74 patients
achieved an investigator-assessed objective
response
and 51 (69%, 57-79) patients had disease
control for 12 weeks or longer.
44. Median duration of response was not yet
reached; all responders were alive,
and eight had responses lasting 12 months or
longer
45. Response to pembrolizumab in patients
with mismatch repair deficient (dMMR)
colorectal cancer (CRC).
Citation:
J Clin Oncol 35, 2017 (suppl; abstr 3558)
Nineteen pts were included in this analysis
46. DCR at first assessment was 68%,
with 5% CR,
47% PR
and 16% SD
47. Median follow-up from diagnosis was 29 months
(95% CI 18-42).
Median OS was 103 months (95% CI 85-103);
12-month OS was 89%.
Median OS from PD-1 therapy was 16.1 months
(95% CI 16-NR);
12-month OS from PD-1 therapy was 79%.
48. Median PFS was NR (95% CI 5-NR);
12-month PFS was 54%.
At time of analysis, 9 pts remain on PD-1
therapy;
5 pts have died;
3 have received subsequent therapy.