Immunotherapy is revolutionizing oncology, with a simple guiding principle: the host immune system has the potential to eradicate cancer, treatment consisting in optimizing immune actors' functions. Although significant results were demonstrated in patients with melanoma or lung cancer, objective response rate (ORR) is only 20% in digestive oncology. However, we can improve this situation by a better knowledge of anti-tumor immunity. For example, ORR is multiplied by two to three in case of PD-L1 (programmed death-ligand 1) overexpression or microsatellite instability (MSI). In a near future, we will certainly be able to take into account other biomarkers for building composite scores for assigning to each patient with digestive cancer an 'immune identity card' able to strongly predict immunotherapy efficacy.
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.
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.
Recently, a phase II clinical trial in hepatocellular carcinoma (HCC) has suggested that the combination of sorafenib and 5-fluorouracil (5-FU) is feasible and side effects are manageable. However, preclinical experimental data explaining the interaction mechanism(s) are lacking. Our objective is to investigate the anticancer efficacy and mechanism of combined sorafenib and 5-FU therapy in vitro in HCC cell lines MHCC97H and SMMC-7721.
Assessing the clinical utility of cancer genomic and proteomic data across tu...Gul Muneer
Molecular profiling of tumors promises to advance the clinical
management of cancer, but the benefits of integrating
molecular data with traditional clinical variables have not been
systematically studied. Here we retrospectively predict patient
survival using diverse molecular data (somatic copy-number
alteration, DNA methylation and mRNA, microRNA and protein
expression) from 953 samples of four cancer types from The
Cancer Genome Atlas project. We find that incorporating
molecular data with clinical variables yields statistically
significantly improved predictions (FDR < 0.05) for three
cancers but those quantitative gains were limited (2.2–23.9%).
Additional analyses revealed little predictive power across
tumor types except for one case. In clinically relevant genes,
we identified 10,281 somatic alterations across 12 cancer types
in 2,928 of 3,277 patients (89.4%), many of which would
not be revealed in single-tumor analyses. Our study provides
a starting point and resources, including an open-access
model evaluation platform, for building reliable prognostic and
therapeutic strategies that incorporate molecular data
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.
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.
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.
Recently, a phase II clinical trial in hepatocellular carcinoma (HCC) has suggested that the combination of sorafenib and 5-fluorouracil (5-FU) is feasible and side effects are manageable. However, preclinical experimental data explaining the interaction mechanism(s) are lacking. Our objective is to investigate the anticancer efficacy and mechanism of combined sorafenib and 5-FU therapy in vitro in HCC cell lines MHCC97H and SMMC-7721.
Assessing the clinical utility of cancer genomic and proteomic data across tu...Gul Muneer
Molecular profiling of tumors promises to advance the clinical
management of cancer, but the benefits of integrating
molecular data with traditional clinical variables have not been
systematically studied. Here we retrospectively predict patient
survival using diverse molecular data (somatic copy-number
alteration, DNA methylation and mRNA, microRNA and protein
expression) from 953 samples of four cancer types from The
Cancer Genome Atlas project. We find that incorporating
molecular data with clinical variables yields statistically
significantly improved predictions (FDR < 0.05) for three
cancers but those quantitative gains were limited (2.2–23.9%).
Additional analyses revealed little predictive power across
tumor types except for one case. In clinically relevant genes,
we identified 10,281 somatic alterations across 12 cancer types
in 2,928 of 3,277 patients (89.4%), many of which would
not be revealed in single-tumor analyses. Our study provides
a starting point and resources, including an open-access
model evaluation platform, for building reliable prognostic and
therapeutic strategies that incorporate molecular data
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.
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.
A KRAS-variant is a Biomarker of Poor Outcome, Platinum Chemotherapy Resistan...UCLA
Germ-line variants in the 3′ untranslated region (3′UTR) of cancer genes disrupting microRNA (miRNA) regulation have recently been associated with cancer risk. A variant in the 3′UTR of the KRAS oncogene, referred to as the KRAS-variant, is associated with both cancer risk and altered tumor biology. Here we test the hypothesis that the KRAS-variant can act as a biomarker of outcome in epithelial ovarian cancer (EOC), and investigate the cause of altered outcome in KRAS-variant positive EOC patients. As this variant appears to be associated with tumor biology, we additionally test the hypothesis that this variant can be directly targeted to impact cell survival.
EOC patients with complete clinical data were genotyped for the KRAS-variant and analyzed for outcome (n=536), response to neoadjuvant chemotherapy (n=125), and platinum resistance (n=306). Outcome was separately analyzed for women with known BRCA mutations (n=79). Gene expression was analyzed on a subset of tumors with available tissue. Cell lines were employed to confirm altered sensitivity to chemotherapy with the KRAS-variant. The KRAS- variant was directly targeted through siRNA/miRNA oligonucleotides in cell lines and survival was measured.
Post-menopausal EOC patients with the KRAS-variant were significantly more likely to die of ovarian cancer by multivariate analysis (HR=1.67, 95% CI=1.09–2.57, p=0.019, n=279). Possibly explaining this finding, EOC patients with the KRAS-variant were significantly more likely to be platinum resistant (OR=3.18, CI=1.31–7.72, p=0.0106, n=291). Additionally, direct targeting of the KRAS-variant led to a significant reduction in EOC cell growth and survival in vitro.
These findings confirm the importance of the KRAS-variant in EOC, and indicate that the KRAS- variant is a biomarker of poor outcome in EOC likely due to platinum resistance. In addition, this work supports the hypothesis that these tumors have continued dependence on such 3′UTR lesions, and that direct targeting may be a viable future treatment approach.
Potential of Targeting Bone Metastases with Immunotherapies_Crimson PublishersCrimsonpublishersCancer
Cancer-related bone metastases are incurable and cause high mortality in patients. Immunotherapies have been evaluated in large-scale clinical trials with advanced cancer patients, but effects on bone metastases have not been specified. This mini review introduces case reports where patients with bone metastases have been treated with immunotherapies and local effects on tumor growth have been assessed. Potential skeletal-related adverse effects of immunotherapies are also discussed.
Multicentric and multifocal versus unifocal breast cancer: differences in the...Enrique Moreno Gonzalez
The aim of this study was to evaluate the expression of the cell adhesion-related glycoproteins MUC-1, β-catenin and E-cadherin in multicentric/multifocal breast cancer in comparison to unifocal disease in order to identify potential differences in the biology of these tumor types.
Sticky siRNAs targeting survivin and cyclin B1 exert an antitumoral effect on...Enrique Moreno Gonzalez
Melanoma represents one of the most aggressive and therapeutically challenging malignancies as it often gives rise to metastases and develops resistance to classical chemotherapeutic agents. Although diverse therapies have been generated, no major improvement of the patient prognosis has been noticed. One promising alternative to the conventional therapeutic approaches currently available is the inactivation of proteins essential for survival and/or progression of melanomas by means of RNA interference. Survivin and cyclin B1, both involved in cell survival and proliferation and frequently deregulated in human cancers, are good candidate target genes for siRNA mediated therapeutics.
Purpose: An inherited mutation in KRAS (LCS6-variant or rs61764370) results in altered control of the KRAS oncogene. We studied this biomarker’s correlation to anti-EGFR monoclonal antibody (mAb) therapy
response in patients with metastatic colorectal cancer.
Experimental Design: LCS6-variant and KRAS/BRAF mutational status was determined in 512 patients
with metastatic colorectal cancer treated with salvage anti-EGFR mAb therapy, and findings correlated with
outcome. Reporters were tested in colon cancer cell lines to evaluate the differential response of the LCS6-
variant allele to therapy exposure.
Results: In this study, 21.2% (109 of 512) of patients with metastatic colorectal cancer had the LCS6-
variant (TG/GG), which was found twice as frequently in the BRAF-mutated versus the wild-type (WT) group
(P = 0.03). LCS6-variant patients had significantly longer progression- free survival (PFS) with anti-EGFR
mAb monotherapy treatment in the whole cohort (16.85 vs. 7.85 weeks; P = 0.019) and in the double WT
(KRAS and BRAF) patient population (18 vs. 10.4 weeks; P = 0.039). Combination therapy (mAbs plus
chemotherapy) led to improved PFS and overall survival (OS) for nonvariant patients, and brought their
outcome to levels comparable with LCS6-variant patients receiving anti-EGFR mAb monotherapy. Combination
therapy did not lead to improved PFS or OS for LCS6-variant patients. Cell line studies confirmed a
unique response of the LCS6-variant allele to both anti-EGFR mAb monotherapy and chemotherapy.
Conclusions: LCS6-variant patients with metastatic colorectal cancer have an excellent response to anti-EGFR
mAb monotherapy, without any benefit from the addition of chemotherapy. These findings further confirm
the importance of thismutation as a biomarker of anti-EGFR mAb response in patients with metastatic colorectal cancer, and warrant further prospective confirmation.
Proteogenomic analysis of human colon cancer reveals new therapeutic opportun...Gul Muneer
We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development.
Integrative Cancer - New theories and Advances in Treatment From Hippocrates ...Sheldon Stein
Professor Serge Jurasunsas' recent paper on Integrative Cancer, From Hippocrates to the Human Genome - posted on his behalf. Discusses testing, protocols and case discussion.
Naiyer Rizvi, MD, Omid Hamid, MD, Solange Peters, MD, PhD, Thomas Powles, MBBS, MRCP, MD, and Nadeem Riaz, MD, MSc, prepared useful Practice Aids pertaining to immuno-oncology for this CME activity titled "Emerging Biomarkers, New Targets, and Rational Combinations: Are We on the Verge of the Next Generation of Immuno-Oncology?" For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2H2s92Y. CME credit will be available until June 17, 2019.
The outlook for cancer treatment options is a promising one. Researchers and physicians are discovering new ways to identify the best care for patients through targeted treatments. With the large number of cancer types, a treatment plan that works well for one person may not be the best plan for another. Through collaboration, rapidly evolving technology, and research in genetics and the molecular profiling of tumors, researchers and physicians have made astounding strides in the development of personalized cancer care.
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.
A KRAS-variant is a Biomarker of Poor Outcome, Platinum Chemotherapy Resistan...UCLA
Germ-line variants in the 3′ untranslated region (3′UTR) of cancer genes disrupting microRNA (miRNA) regulation have recently been associated with cancer risk. A variant in the 3′UTR of the KRAS oncogene, referred to as the KRAS-variant, is associated with both cancer risk and altered tumor biology. Here we test the hypothesis that the KRAS-variant can act as a biomarker of outcome in epithelial ovarian cancer (EOC), and investigate the cause of altered outcome in KRAS-variant positive EOC patients. As this variant appears to be associated with tumor biology, we additionally test the hypothesis that this variant can be directly targeted to impact cell survival.
EOC patients with complete clinical data were genotyped for the KRAS-variant and analyzed for outcome (n=536), response to neoadjuvant chemotherapy (n=125), and platinum resistance (n=306). Outcome was separately analyzed for women with known BRCA mutations (n=79). Gene expression was analyzed on a subset of tumors with available tissue. Cell lines were employed to confirm altered sensitivity to chemotherapy with the KRAS-variant. The KRAS- variant was directly targeted through siRNA/miRNA oligonucleotides in cell lines and survival was measured.
Post-menopausal EOC patients with the KRAS-variant were significantly more likely to die of ovarian cancer by multivariate analysis (HR=1.67, 95% CI=1.09–2.57, p=0.019, n=279). Possibly explaining this finding, EOC patients with the KRAS-variant were significantly more likely to be platinum resistant (OR=3.18, CI=1.31–7.72, p=0.0106, n=291). Additionally, direct targeting of the KRAS-variant led to a significant reduction in EOC cell growth and survival in vitro.
These findings confirm the importance of the KRAS-variant in EOC, and indicate that the KRAS- variant is a biomarker of poor outcome in EOC likely due to platinum resistance. In addition, this work supports the hypothesis that these tumors have continued dependence on such 3′UTR lesions, and that direct targeting may be a viable future treatment approach.
Potential of Targeting Bone Metastases with Immunotherapies_Crimson PublishersCrimsonpublishersCancer
Cancer-related bone metastases are incurable and cause high mortality in patients. Immunotherapies have been evaluated in large-scale clinical trials with advanced cancer patients, but effects on bone metastases have not been specified. This mini review introduces case reports where patients with bone metastases have been treated with immunotherapies and local effects on tumor growth have been assessed. Potential skeletal-related adverse effects of immunotherapies are also discussed.
Multicentric and multifocal versus unifocal breast cancer: differences in the...Enrique Moreno Gonzalez
The aim of this study was to evaluate the expression of the cell adhesion-related glycoproteins MUC-1, β-catenin and E-cadherin in multicentric/multifocal breast cancer in comparison to unifocal disease in order to identify potential differences in the biology of these tumor types.
Sticky siRNAs targeting survivin and cyclin B1 exert an antitumoral effect on...Enrique Moreno Gonzalez
Melanoma represents one of the most aggressive and therapeutically challenging malignancies as it often gives rise to metastases and develops resistance to classical chemotherapeutic agents. Although diverse therapies have been generated, no major improvement of the patient prognosis has been noticed. One promising alternative to the conventional therapeutic approaches currently available is the inactivation of proteins essential for survival and/or progression of melanomas by means of RNA interference. Survivin and cyclin B1, both involved in cell survival and proliferation and frequently deregulated in human cancers, are good candidate target genes for siRNA mediated therapeutics.
Purpose: An inherited mutation in KRAS (LCS6-variant or rs61764370) results in altered control of the KRAS oncogene. We studied this biomarker’s correlation to anti-EGFR monoclonal antibody (mAb) therapy
response in patients with metastatic colorectal cancer.
Experimental Design: LCS6-variant and KRAS/BRAF mutational status was determined in 512 patients
with metastatic colorectal cancer treated with salvage anti-EGFR mAb therapy, and findings correlated with
outcome. Reporters were tested in colon cancer cell lines to evaluate the differential response of the LCS6-
variant allele to therapy exposure.
Results: In this study, 21.2% (109 of 512) of patients with metastatic colorectal cancer had the LCS6-
variant (TG/GG), which was found twice as frequently in the BRAF-mutated versus the wild-type (WT) group
(P = 0.03). LCS6-variant patients had significantly longer progression- free survival (PFS) with anti-EGFR
mAb monotherapy treatment in the whole cohort (16.85 vs. 7.85 weeks; P = 0.019) and in the double WT
(KRAS and BRAF) patient population (18 vs. 10.4 weeks; P = 0.039). Combination therapy (mAbs plus
chemotherapy) led to improved PFS and overall survival (OS) for nonvariant patients, and brought their
outcome to levels comparable with LCS6-variant patients receiving anti-EGFR mAb monotherapy. Combination
therapy did not lead to improved PFS or OS for LCS6-variant patients. Cell line studies confirmed a
unique response of the LCS6-variant allele to both anti-EGFR mAb monotherapy and chemotherapy.
Conclusions: LCS6-variant patients with metastatic colorectal cancer have an excellent response to anti-EGFR
mAb monotherapy, without any benefit from the addition of chemotherapy. These findings further confirm
the importance of thismutation as a biomarker of anti-EGFR mAb response in patients with metastatic colorectal cancer, and warrant further prospective confirmation.
Proteogenomic analysis of human colon cancer reveals new therapeutic opportun...Gul Muneer
We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development.
Integrative Cancer - New theories and Advances in Treatment From Hippocrates ...Sheldon Stein
Professor Serge Jurasunsas' recent paper on Integrative Cancer, From Hippocrates to the Human Genome - posted on his behalf. Discusses testing, protocols and case discussion.
Naiyer Rizvi, MD, Omid Hamid, MD, Solange Peters, MD, PhD, Thomas Powles, MBBS, MRCP, MD, and Nadeem Riaz, MD, MSc, prepared useful Practice Aids pertaining to immuno-oncology for this CME activity titled "Emerging Biomarkers, New Targets, and Rational Combinations: Are We on the Verge of the Next Generation of Immuno-Oncology?" For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2H2s92Y. CME credit will be available until June 17, 2019.
The outlook for cancer treatment options is a promising one. Researchers and physicians are discovering new ways to identify the best care for patients through targeted treatments. With the large number of cancer types, a treatment plan that works well for one person may not be the best plan for another. Through collaboration, rapidly evolving technology, and research in genetics and the molecular profiling of tumors, researchers and physicians have made astounding strides in the development of personalized cancer care.
Co-Chairs, Nasser Altorki, MD, and Jonathan D. Spicer, MD, PhD, FRCSC, prepared useful Practice Aids pertaining to NSCLC for this CME/MOC activity titled “How to Integrate Perioperative Immunotherapy Into Multimodal Treatment Plans to Improve Outcomes in Resectable NSCLC.” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/3xb6WS1. CME/MOC credit will be available until June 14, 2023.
Chair & Moderator, Prof. Solange Peters, MD, PhD, Mark M. Awad, MD, PhD, and Jonathan D. Spicer, MD, PhD, FRCSC, prepared useful Practice Aids pertaining to Cancer Immunotherapy for this CME/MOC/CC activity titled “Parsing the Practicalities of Pathologic Response Assessment After Neoadjuvant Immunotherapy to Facilitate Progress in Early-Stage Cancers.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/CC information, and to apply for credit, please visit us at https://bit.ly/3uRHyjk. CME/MOC/CC credit will be available until May 9, 2023.
Background : During the conference of ASCO 2015, there was no consensus about TIL role in beast cancer and no recommendations concerning the microscopic assessment of TIL. In fact, the patients could be put on anti-PD1 drugs without the necessity of highlighting PD1 positive cells by using immunohistochemistry. Nevertheless, many questions about the prognostic impact of TIL, the methods of assessment, the type of TIL to count remain unresolved. Material and Methods : We performed a review of the literature on the sites : Pubmed and Cochrane. We used the key-words : �TIL in cancer�; �TIL in breast cancer� and �prognostic impact of TIL in breast cancer�. Results : According to our inclusion and exclusion criteria, thirty eight articles were retained. Our review of the literature showed that assessing TIL in high grade tumors seem unnecessary. They seem available in intermediate graded tumors. In neo-adjuvant and adjuvant conditions, CD3+ lymphocytes seem to be correlated to a good response to chemotherapy. After a chemotherapy, quantification T reg lymphocytes CD4 + FOXP3+ seems helpful because the decrease of their number is correlated to a good prognosis. Conclusion : The role of TIL in breast cancer is clearly established. The mechanisms of immune escape induced to discovery of immune therapy. The role of the microscopic examination and the subtyping of TIL using immunohistochemistry hasn�t been clearly established. Through this review of the literature, we tried to establish a diagram highlighting the different subtypes of TIL to evaluate and their prognostic impact.
How to Understand and Treat Cancer with Molecular MarkersSheldon Stein
How to Understand and Treat Cancer with Molecular Markers by Professor Serge Jurasunas, N.D., M.D. (Hom)
This is the first in a series of presentations on Naturopathic Oncology.
For More Information Visit: www.sergejurasunas.com
Immunotherapy is based in reactivating the patient immune system specifically against the neoplasia, tumors have immunosuppression mechanisms that allow them to control and evade the immune response.
There are different immunotherapy approaches like tumor-targeting monoclonal antibodies, adoptive T cell transfer, anticancer vaccines, checkpoint inhibitors, most of these in important clinical trials in which the effects and toxicities are still evaluated. They are also beginning tested on a combination of immunotherapies and other non-immunological therapies in order to increase the survival of patients. Immunotherapy is still a young area and it needs to reach its peak, but it will surely be a great tool to treat and cure cancer.
Co-Chairs, Nasser Altorki, MD, and Jonathan D. Spicer, MD, PhD, FRCSC, prepared useful Practice Aids pertaining to NSCLC for this CME/MOC activity titled “Can the Addition of Immunotherapy to Multimodal Management of Stage I-III NSCLC Help Break the Stalled Cycle of Poor Outcomes?” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/3m1OV2m. CME/MOC credit will be available until February 27, 2023.
Alcoholic Chronic Pancreatitis or Intraductal Papillary Mucinous Neoplasm: Wh...CrimsonGastroenterology
Intraductal Papillary Mucinous Neoplasm (IPMN) is an intraductal mucin-producing neoplasm, with
an increasing incidence. IPMNs may have clear malignant potential and exhibit a broad histological
spectrum ranging from adenoma to invasive carcinoma. In contrast to the ductal adenocarcinoma, IPMNs
have in general a better clinical prognosis. The clinical presentation of IPMN and Chronic Pancreatitis
(CP) are often indistinguishable. Misdiagnosis of IPMN in patients with CP can lead to serious delays in
the appropriate management. In patients with history of alcoholic CP, the possible presence of IPMN
could not to be excluded. Due the high frequency of malignancy in IPMN, surgical approach should be
considered. Assessment for potential IPMN is mandatory in patients with CP. All patients with CP must
have a clinical assessment at least every 6 months, with abdominal US at least every year. In symptomatic
patients with IPMN and severe abdominal pain, early pancreaticoduodenectomy must be strongly
considered.
Anti-CTLA-4 Induced Inflammatory Bowel Disease: Is There A More Etiological T...CrimsonGastroenterology
Anti-CTLA-4 Induced Inflammatory Bowel Disease: Is There A More Etiological Treatment? Lessons From CTLA-4 Haploinsufficiency by Georgios Germanidisin Gastroenterology Medicine & Research: Structure
We read with great interest the article by Bamias G et al. [1] entitled “Immunological Characteristics of Colitis Associated with Anti-CTLA-4 Antibody Therapy’’ [1], and we would like to address some issues regarding possible future use of a more etiological treatment for this colitis, namely abatacept. The immunological characteristics of anti-CTLA-4 and anti-PD-1-related colitis have been up to now poorly described [1,2].
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory T cell receptor, similar to CD28 in structure, expressed by activated and regulatory T cells (Tregs). CTLA-4 is constitutively expressed on CD4+CD25+ Tregs, and such expression is important for Tregmediated suppression of T cell proliferation. Abatacept is a soluble fusion protein which links the CTLA-4 extracellular domain to the Fc region of the IgG molecule. CTLA-4 immunoglobulin (Ig) fusion protein and neutralizing CTLA-4 antibody are used to modulate immunity in autoimmune and cancer patients, respectively.
Crimson Publishers-Herring Bone Stitch: Knitting to Secure Abdominal Wall Clo...CrimsonGastroenterology
Herring Bone Stitch: Knitting to Secure Abdominal Wall Closure for Emergency Midline Laparotomy by Dhananjaya Sharma in Gastroenterology Medicine & Research: Laparotomy
Introduction: 5-26% of patients develop incisional hernia (IH) after midline laparotomy. We hypothesized that a simple ‘herring bone’ stitch repair can provide secure abdominal wall closure and minimize the incidence of IH in patients undergoing emergency midline laparotomy.
Methods: This prospective observational study was done from March 2015 to December 2017 in a teaching hospital in Central India. Consecutive patients undergoing emergency midline laparotomy were included. Study group (patients undergoing single layer continuous herring bone closure of rectus sheath with Polypropylene no. 1 suture) was compared with control group (patients undergoing standard single layer continuous closure of rectus sheath with Polypropylene no. 1 suture). Patients were followed up till 1 year. Outcomes noted were surgical site infection (SSI), proline knot granuloma or sinus formation, superficial wound dehiscence, fascial dehiscence and IH.
Results: There were 112 patients in study group and 108 in control group with comparable demographics.Vector physics of Herring bone stitch showed that any tension on the suture line is preferentially distributed parallel to the wound. Incidence of SSI, proline knot granuloma and superficial wound dehiscence was comparable among the two groups. The incidence of fascial dehiscence (0.045) and IH was less (p = 0.009) in study group.
Discussion: The Herring bone stitch is technically easy, reproducible, safe and can be performed quickly. The present study shows superiority of ‘herring bone suture’ over conventional closure of rectus sheath in emergency midline laparotomy.
Cyclical Vomiting Syndrome in Children by Maheeba Abdulla in Gastroenterology Medicine & Research: Endoscopic Testing
Cyclic vomiting is considered a variant of migraine, first described by Gee in 1881[1]. Cyclic vomiting syndrome (CVS) is a disorder characterized by recurrent, discrete, self-limited episodes of vomiting and is defined by symptom-based criteria and the absence of positive laboratory, radiographic, and endoscopic testing [2]. The attacks of vomiting are interspersed with normal periods. The duration of vomiting episodes is from hours to days, with spontaneous resolution if left untreated. The episodic occurrence of emesis may be precipitated by stress and fatigue. The attacks begin in childhood and often wane in frequency with progression into young and middle adult life [3].The differential diagnoses include idiopathic CVS, gastrointestinal disorders, and extraintestinal disorders, including brain stem neoplasm, abdominal epilepsy, and metabolic disorders.
Crimson Publishers-Alcohol Abstinence and Relapse in ALD Patients, Predicting...CrimsonGastroenterology
Alcohol Abstinence and Relapse in ALD Patients, Predicting the Unpredictable by Neeraj Nagaich in Gastroenterology Medicine & Research: Liver Disease
Objectives: Alcoholism is a chronic relapsing disorder. Alcoholism is common, and continues to be the source of great cost to afflicted individuals, their families and the community at large. Alcohol dependence is characterized by a prolonged course of alcohol-related problems and a persistent vulnerability to relapse. Even though there is an improvement in multiple domains of life after alcohol treatment, the risk of relapse remains high following treatment. This prospective and retrospective study of 451 patients with alcohol use disorders was done with an intent to assess various factors affecting remission and relapse and improve outcome for individuals with alcohol dependence. Demographic variables, clinical parameters and certain psychosocial factors were evaluated. Early identification of risk factors may help us in defining a more rigorous follow up protocol in these sub group of patients.
Method: Patients with ethanol related liver disease and alcohol dependence were enrolled after their presentation in gastroenterology clinic and followed thereafter at 1, 3, 6, and 12 months. Initial assessments included USG abdomen LFT RFT, UGI Endoscopy and other relevant investigations. Semi structured clinical interviews, the Symptom Checklist 90-Revised (SCL90-R), Addiction Severity Index (ASI), the Beck Depression Inventory (BDI) were recorded. High-Risk Alcoholism Relapse Scale based score was calculated.2Patients were reassessed at six and twelve months to determine treatment outcome (abstinence status and duration of continuous abstinence). Data were coded, validated and analyzed using descriptive statistics.
Results: A majority of the sample 70 percent (n=315) had significant psychiatric symptoms at intake: 22 percent (N=70) presented with depressive symptoms, 17 percent (N=15) with anxiety symptoms, and 41 percent (N=192) with combined depressive and anxiety symptoms. Forty percent of patients who presented with combined depression and anxiety symptoms were abstinent at six months. These patients had worse prognosis than less symptomatic cohort at intake, including those who presented with depression symptoms alone; in the latter group, 60 percent were abstinent at six months. Key predictor variables included days in treatment, primary drug of abuse, frequency of drug use, and report of concurrent depression or anxiety symptoms at intake.
Crimson Publishers: Radiation Proctitis-Experience at a Tertiary Care Centre ...CrimsonGastroenterology
Radiation Proctitis-Experience at a Tertiary Care Centre of North India by Parveen Malhotra in Gastroenterology Medicine & Research: Radiotherapy
Introduction: Proctitis is a troublesome complication in patients receiving radiotherapy in pelvic malignancies. This is a prospective study done to evaluate the efficacy of 4% formalin in treatment of radiation proctitis and complications associated with it.
Method: Patients with rectal bleeding post radiotherapy for gynaecological malignancy were analysed in our institution from June 2010-May 2011. 50ml of 4% formalin was sprayed through colonoscopy with mucosal contact time of 10 min and observed for 4hrs for any complication.
Results: A total of 22 patients with mean age 57 (range 40-65) years, moderately built with radiation proctitis were subjected to 4% formalin and followed up for 12 (range 1-36) months. Mean interval between radiotherapy and presenting symptoms was 15 (range 6 -24) months. Cessation of bleeding occurred in 77.27% cases after mean of 2(range 1-4) cycles of spray with hemoglobin rise of 2gm% (range 1.1-2.9). 5 patients complained of intense pain relieved with analgesics and one had seizure. There was only one mortality in a patient who got operated for recto-vaginal fistula and expired on 5th post-operative day due to septicemia.
Conclusion: In the context of improving health care quality, it was indicated that multifaceted interventions are more effective than simpler interventions and that the insistence on change requires a multi-layered approach. A major focus of health policy is the effective management of long term diseases both for reducing the burden on patients and professionals as well as of the health services also. Studying the Group of patients with IBD could be an important example of study as the patients themselves are chronic patients with 20 years being the peak age onset of the diseases and life expectancy of healthy individuals.
Crimson Publishers: The Impact of Chronic Diseases on Patients and Their Fami...CrimsonGastroenterology
The Impact of Chronic Diseases on Patients and Their Families: Case of Ulceratice Colitis and Crohn’s Disease by Maria Tsoukka in Gastroenterology Medicine & Research: Bowel Disease
Background: The purpose of the study is to identify the potential psychological effects of ulcerative colitis and Crohn’s disease on patients and their family environment.Aim: The objective aims of this current research are to identify the causal factors creating psychological problems among patients and their family members, exploring ways to eliminate them and create a general picture for their psychological condition in relation to the diseases at a Pancyprian level.Methods: The Greek translation of the Hospital Anxiety and Depression Scale (HADS) and the Greek translation of the Health Survey (SF-12) will be used for evaluating the psychological effects of ulcerative colitis and Crohn disease on patients and their families. In addition, the Greek translation of the inflammatory Bowel Disease Questionnaire will be used only on the patients. The questionnaires will be handed out to the patients and their attendants in Gastroenterology dispensaries all over Cyprus. Conclusion: In the context of improving health care quality, it was indicated that multifaceted interventions are more effective than simpler interventions and that the insistence on change requires a multi-layered approach. A major focus of health policy is the effective management of long term diseases both for reducing the burden on patients and professionals as well as of the health services also. Studying the Group of patients with IBD could be an important example of study as the patients themselves are chronic patients with 20 years being the peak age onset of the diseases and life expectancy of healthy individuals.
Crimson Publishers: Insulin Therapy and Cardiovascular Outcome Trials (CVOTs)...CrimsonGastroenterology
The therapeutic management of diabetes may on its own increase the risk of cardiovascular (CV) risk markers – directly or indirectly – through their pharmacological actions (e.g. side effects as hypoglycaemia), or some metabolic changes (e.g. Weight-Gain, increased BP, etc.). As these risks may not have been anticipated or immediately noticed during clinical trials, 1 post hoc analyses and epidemiological follow up of clinical trials have raised concerns about the CV safety of some drugs used in the management of diabetes.
Crimson Publishers: Improved Version of Cancer Evo-Dev, a Novel Scientific Hy...CrimsonGastroenterology
Chronic but active inflammation, which is activated and maintained by stimulants such as infection and the interactions of stimulants with genetic predisposition, facilitates the occurrence and recurrence of cancers of various histotypes. Chronic inflammation, apparent or unapparent, is indispensible for the development of most malignancies, which has been clarified in hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC). Based on our previous work and the advances of researches on HBV-induced HCC and other inflammation-associated cancers, we presented the framework of a novel cancer theory termed Cancer Evolution and Development (Cancer Evo-Dev) [1-3]. Actually, Cancer Evo-Dev can be applied in cancers of many histotypes.
Transgastric ERCP with Rendezvous Technique by Mikkel Jessen in Gastroenterology Medicine & Research
Two patients with gastric bypass Roux-en-Y (GBY) presented symptoms of post-prandial upper abdominal pain. Both patients had elevated liver enzyme levels and hyperbilirubinemia. MRCP was performed on both patients demonstrating cholecystolithiasis and gallstones in the common bile duct (CBD). A combined procedure was planned for both patients with laparoscopic cholecystectomy and perioperative Transgastric Rendezvous ERCP.
Crimson Publishers: Dietary Supplements as a Possible Trigger of Autoimmune H...CrimsonGastroenterology
Introduction: Autoimmune hepatitis (AIH) etiology remains unknown, but in genetically predisposed individuals, diverse agents may trigger the disease. Herbal and drug induced AIH have been reported in recent years probable due to the increase in self-medication. More studies are necessary to define if drugs and herbal/dietary supplements unmask and induce AIH or drug-induced hepatitis with autoimmune features.
Purpose: We report an autoimmune hepatitis case possibly induced by herbal/dietary supplements intake.
Case-report: A 55-year-old female presented with a 15-day course of jaundice and increased aminotransferases. Immunologic panel showed antinuclear antibody titer of 1:320 and serum immunoglobulin G (IgG) level approximately 2 times the upper limit of normal. She reported regular daily ingestion of Herbalife® products for 6 months which were discontinued when symptoms began. Laboratory tests worsened despite the fact that patient had stopped supplements usage, and a liver biopsy was performed. Histology was suggestive of both AIH and drug induced liver disease. The patient fulfilled criteria for probable AIH based on the revised criteria for diagnosing autoimmune hepatitis, and improved with prednisolone and azathioprine therapy, with progressive laboratory improvement and symptoms remission.
Discussion: Herbal/dietary supplements induced AIH has been previously reported, but the causality is not yet well established. Worsening of aminotransferases despite supplement suspension, histological findings and favorable response with corticosteroid treatment, supported the hypothesis of AIH induced by the used supplement. This case report aims to demonstrate the possible causality between herbal/dietary supplements and liver injury, including autoimmune hepatitis.
Crimson Publishers: Reply To: Comments on "Transabdominal Preperitoneal (TAPP...CrimsonGastroenterology
Reply To: Comments on “Transabdominal Preperitoneal (TAPP) Versus Totally Extraperitoneal (TEP) for Laparoscopic Hernia Repair: A Meta-Analysis” by Feng Xian Wei in Gastroenterology Medicine & Research
Crimson Publishers: Interferon-Free Therapy for Hepatits C in Brazil and Sust...CrimsonGastroenterology
Introduction: Hepatitis C has been treated with interferon and ribavirin for over a decade with described global sustained virological response rates of 33% to 56%. Direct acting antiviral drugs available since 2013 in USA and 2015 in Brazil are changing this reality.
Purpose: Analyze the real-life efficacy and safety of interferon-free therapy.
Methods: Repot six cases of different treatments guided by north-american and european guildelines.
Results: Every reported patient achieved sustained virological response. The only adverse event was anemia in one patient.
Conclusion: Direct-acting antiviral drugs will dramatically change the population which can be treated and increase sustained virological response rates.
Crimson Publishers: Safety of Everolimus in Living Donor Liver Transplantatio...CrimsonGastroenterology
Safety of Everolimus in Living Donor Liver Transplantation Recipients with Severe Renal Dysfunction with Low Estimated Glomerular Filtration Rate: Can Everolimus Help in Renal Recovery? by Long-Bin Jeng* in Gastroenterology Medicine & Research
Liver transplantation is the best solution for patients suffering from end stage liver disease. The magnitude of liver disease in Egypt in remarkable due to HCV infection. The pool of donors does not cover the increasing need for this modality. Deceased program although it has been approved legally since 2010 but still not activated and the detailed regulations are not yet established due to resistance of some groups as religious and human rights. In this review, we show the progress of liver transplantation in Egypt since its start in 1991 and aiming to start the deceased program soon.
Liver Fibrosis: Difficulties in Diagnostic and Treatment: A Review-Crimson Pu...CrimsonGastroenterology
Early discovery of liver fibrosis and cirrhosis is becoming more relevant because of enhanced incidence of hepatocellular carcinoma. There a many underlying factors in developing liver fibrosis (i.e. viral hepatitis, steatohepatitis). Diagnosis of liver fibrosis is difficult; chronic liver failure and less distinct fibrosis stages can be underestimated, when laboratory routine parameters and native ultrasound of the liver are unsuspicious. Liver biopsy is a common element of diagnostic workup in hepatic cirrhosis, alongside clinical examination and abdominal ultrasound, and is the accepted diagnostic gold standard. But there is no unitary system of histological classification used to evaluate the degree of fibrosis, and individual systems are often validated only for individual disease entities. On the other hand liver biopsy is of less tolerance for patients. In the last years serological markers for detecting liver fibrosis were developed with different validity. Various imaging modalities have been proposed as methods for assessing liver fibrosis
by liver stiffness measurement. They are sufficient to approve the suspicious of liver fibrosis and/or to uncover unknown chronic liver failure. Studies showed the clinical usefulness of acoustic radiation force impulse shear wave elasticity imaging (ARFI-SWEI) is efficient as a preventive screening method to uncover fibrosis. The ARFI-SWEI system is integrated in an ultrasound device has a good accuracy and high reproducibility. Therapy of liver fibrosis depends on underlying disease and degree of liver failure. When liver failure can be cured liver fibrosis can regress. Direct antifibrotic drugs are
actually not available but in progress.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
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.
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
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
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.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
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
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
2. How to cite this article: Lopez A. Can we Optimize Immune Checkpoint Inhibitors Efficacy in Digestive Oncology?. Gastro Med Res. 1(2). GMR.000508. 2018.
DOI: 10.31031/GMR.2018.01.000508
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(OS) is approximatively 7 months [4-14]. However, three scenarios
seem more favorable. First, in the phase II KEYNOTE-059 trial,
the association of pembrolizumab (anti-PD-1 antibody) and
conventional chemotherapy based on 5-fluorouracil and cisplatin
in 25 naïve patients with metastatic HER2-negative gastric or
gastroesophageal junction cancer was associated with an ORR
of 60%, a median progression-free survival (PFS) of 6.6 months
and a median OS of 13.8 months [8]. The phase III is ongoing
(NCT02494583 or KEYNOTE-062). Second, very good results
were obtained in third-line or more with pembrolizumab as single
agent therapy in patients with metastatic MSI colorectal cancer
(CRC) [10]. ORR was 62% whereas median PFS and median OS
were not reached. Finally, in patients with advanced anal canal
carcinoma in second-line or more, nivolumab (anti-PD-1 antibody)
and pembrolizumab were associated with ORR of 24% and 17%,
respectively [13,14].
Can We Improve the Efficacy of Immune Checkpoint
Inhibitors?
PD-L1 status is generally measured on tumor cells with
immunochemistry and most of the studies used a threshold of 1%
for considering a tumor as PD-L1 positive. Data on the predictive
status of tumor PD-L1 positivity has become increasingly evident.
ORR is thus multiplied by two to three in patients with PD-L1
positive tumors compared with those with PD-L1 negative tumors.
However, these results must be confirmed on larger populations.
Interestingly, the difference in response was only 7% in 74 patients
with MSI metastatic CRC treated with nivolumab in a second-line
setting, suggesting that MSI status would be a stronger predictive
factor than PD-L1 [11].
About 15% of the patients with CRC and 22% of those with
gastric cancer have a MSI tumor, which is associated with a better
prognosis. In preliminary and ongoing studies, ORR was roughly
60% in patients with MSI tumors compared with less than 10%
in case of microsatellite stability (MSS). Recently, Le et al. [15]
analyzed the efficacy of pembrolizumab in 86 patients with MSI
cancers (76% of digestive tumors). ORR was 53%. After 2 years
of follow-up, half of the patients were not progressive and 64%
were still alive (median PFS and median OS were not reached).
Impressive results of immune checkpoint inhibitors in case of MSI
tumor could be explained by higher mutational load leading to
higher neoantigens number. In the seminal work of Le et al. [15]
mean number of mutations in MSI tumors was 1782 compared with
73 in MSS tumors (p=0.007), suggesting that high mutational, even
beyond MSI status, could be a major predictive factor.
Contrary to lung cancer patients, data on the relationship
between neoepitopes load and ORR in digestive oncology are
lacking. In a study including 619 CRC patients, those with a MSI
tumor,butalsothosewithaMSStumorwithPolEandPolDmutations
had significantly more mutations, and this was correlated with T
cell infiltration and specific survival [16]. Tumor phenotype is a
recent concept including different parts of anti-tumor immunity.
It would exist three tumor phenotypes, with variable responses
to immunotherapy. Inflamed tumors can demonstrate infiltration
by a number of subtypes of immune cells (e.g. immune-inhibitory
regulatory T cells, myeloid-derived suppressor cells, suppressor
B cells and cancer-associated fibroblasts). Tumor-infiltrating
lymphocytes (TILs) that express CD8 may also demonstrate a
dysfunctional state such as hyperexhaustion [3]. In patients with
metastatic melanoma, response to pembrolizumab was associated
with CD8+ TILs density at the invasive tumor margin [17]. In CRC,
this parameter seemed correlated with ORR and tumor stability
(p=0.017) [10], but these findings must be confirmed in larger
studies. In immune-excluded phenotype, T cells are present at the
boundaryofthetumorbuttheydonotpenetrateinsidebecausethey
are peripherally blocked by the stroma. In this situation, efficacy of
immune checkpoint inhibitors seems uncertain. In immune-desert
phenotype, very few or no CD8+ T cells are present, suggesting the
absence of pre-existing antitumor immunity. This tumor type rarely
responds to immunotherapy.
Increasing data are available concerning the relationship
between gut microbiota and carcinogenesis. In germ-free mice,
immune checkpoint inhibitors were ineffective for treating
subcutaneous tumors [18]. This defect was overcome by gavage
with Bacteroides fragilis, by immunization with B. fragilis
polysaccharides, or by adoptive transfer of B. fragilis-specific T cells.
Even if these results must be confirmed in humans, gut microbiota
seems involved in immune checkpoint inhibitors’ sensitivity.
Other factors such as tumor genetic and epigenetic (e.g. TGF-
β), host genetic (e.g. TLR4 polymorphisms) or environmental
factors (e.g. exposure to sunlight) could also be predictive factors of
immune checkpoint inhibitors efficacy.
Perspectives
Immunotherapy recently generated considerable hopes, but
results in digestive oncology seem disappointing. However, it was
probably necessary to go back to basics of antitumor immunity.
With this essential preclinical work, first (dramatic) results were
described in patients with MSI tumors. The relationship between
mutational load, neoantigens, immunity, and immune checkpoint
inhibitors efficacy was made. Tomorrow we will go further,
creating for each patient a ‘tumor immune ID’ available to predict
his response to immunotherapy. Recently, a composite score (the
immunopheno score) showed a stronger ability for predicting
immune checkpoint inhibitors efficacy compared with ‘checkpoint’
molecules considered on their own [19]. This seminal work is
paving the way to a personalized immunotherapy based on a
comprehensive analysis of tumor immune environment.
References
1. Yadav M, Jhunjhunwala S, Phung QT, Lupardus P, Tanguay J, et al.
(2014) Predicting immunogenic tumour mutations by combining mass
spectrometry and exome sequencing. Nature 515(7528): 572-576.
2. Jiricny J (2006) The multifaceted mismatch-repair system. Nat Rev Mol
Cell Biol 7(5): 335-346.
3. Chen DS, Mellman I (2017) Elements of cancer immunity and the cancer-
immune set point. Nature 541(7637): 321-330.
3. How to cite this article: Lopez A. Can we Optimize Immune Checkpoint Inhibitors Efficacy in Digestive Oncology?. Gastro Med Res. 1(2). GMR.000508. 2018.
DOI: 10.31031/GMR.2018.01.000508
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Gastro Med ResGastroenterology Medicine & Research
4. Doi T, Piha-PSA, Jalal SI, Hieu MD, Sanatan S, et al. (2016) Updated
results for the advanced esophageal carcinoma cohort of the phase
Ib KEYNOTE-028 study of pembrolizumab (MK-3475). J Clin Oncol
34(Suppl 4): 7.
5. Kang YK, Satoh T, Ryu MH, Yee C, Ken K, et al. (2017) Nivolumab (ONO-
4538/BMS-936558) as salvage treatment after second or later-line
chemotherapy for advanced gastric or gastro-esophageal junction
cancer (AGC): A double-blinded, randomized, phase III trial. J Clin Oncol
35(Suppl 4): 2.
6. Janjigian YY, Ott P, Calvo E, Joseph WK, Paolo AA, et al. (2017)
Nivolumab±ipilimumab in pts with advanced (adv)/metastatic
chemotherapy-refractory (CTx-R) gastric (G), esophageal (E), or
gastroesophageal junction (GEJ) cancer: CheckMate 032 study. J Clin
Oncol 35: 4014.
7. Fuchs CS, Doi T, Jang RWJ, Kei M, Taroh S, et al. (2017) KEYNOTE-059
cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy
in patients with previously treated advanced gastric cancer. J Clin Oncol
35: 4003.
8. Bang YJ, Muro K, Fuchs C, Talia G, Ravit G, et al. (2017) KEYNOTE-059
cohort 2: Safety and efficacy of pembrolizumab (pembro) plus
5-fluorouracil (5-FU) and cisplatin for first-line (1L) treatment of
advanced gastric cancer. J Clin Oncol 35: 4012.
9. Chung HC, Arkenau HT, Wyrwicz L, Do-Youn Oh, Keun-WL, et al. (2016)
Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced
gastric or gastroesophageal junction cancer from JAVELIN solid tumor
phase Ib trial: Analysis of safety and clinical activity. J Clin Oncol 34:
4009.
10. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, et al. (2015) PD-1
blockade in tumors with mismatch repair deficiency. N Engl J Med
372(26): 2509-2520.
11. Overman MJ, Lonardi S, Leone F, Raymond S McDermott, Michael AM, et
al. (2017) Nivolumab in patients with DNA mismatch repair deficient/
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