Endometrial Serous Carcinoma: Its Molecular Characteristics and Histology-Specific Treatment Strategies

e20055 Background: Lung adenocarcinoma (LAC) is the most common histological type of non-small-cell lung cancer and is one of the malignancies with the most evolved personalized treatments based on molecular characteristics of the tumor. Mutations in EGFR, HER2 and BRAF, specific translocations of ALK, ROS1, RET and amplification of MET all have standard diagnostic importance and lead to specific treatment options for the individual LAC patients. Recently, in 2-4% of LAC MET gene mutations leading to skipping of exon 14 were found. These mutations were described to occur more frequently in tumors with sarcomatoid histology. LAC with MET exon 14 skipping mutations showed impressive, although temporary, responses to MET tyrosine kinase inhibitors (TKI) crizotinib, cabozantinib and capmatinib. We will present our experience with routine molecular diagnostic detection of the most common MET exon 14 skipping mutations. Methods: In January 2016 we included in our standard, DNA based, molecular diagnostics custom-made NGS analyses 4 amplicons for detection of MET skipping mutations. The analyses were performed on microdissected FFPE tissue sections or routine histology or cytology stained preparations. Nine different mutations were validated for their effect on splicing by RT-PCR on RNA isolated from the same tissue samples. Results: Between January 2016 and January 2017 676 routine molecular diagnostic analyses on LAC were performed. In 18 (2.7%) cases MET mutations were detected possibly resulting in exon 14 skipping. Nine out of 16 different mutations were tested by RT-PCR and all 9 were demonstrated to result in MET exon 14 skipping. Conclusions: MET exon 14 skipping mutations can reliably be detected in routine pathology tissue samples. These analyses can easily be included in routine molecular diagnostic NGS. When necessary, confirmation of the mutational effect on RNA splicing can be implemented as well. Routine identification of MET skipping mutations (2.7% of cases) adds substantially to the personalized targeted treatment strategies for LAC patients.

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Managing sarcoma: where have we come from and where are we going?

Therapeutic Advances in Medical Oncology ◽

10.1177/1758834017728927 ◽

2017 ◽

Vol 9 (10) ◽

pp. 637-659 ◽

Cited By ~ 18

Author(s):

Jenna S. Bleloch ◽

Reyna D. Ballim ◽

Serah Kimani ◽

Jeannette Parkes ◽

Eugenio Panieri ◽

...

Keyword(s):

Molecular Mechanisms ◽

Single Agent ◽

Treatment Strategies ◽

Specific Treatment ◽

Primary Treatment ◽

Response To Treatment ◽

Molecular Characteristics ◽

Mortality And Morbidity ◽

Children And Young Adults ◽

Robust Response

Sarcomas are a heterogeneous group of neoplasms of mesenchymal origin. Approximately 80% arise from soft tissue and 20% originate from bone. To date more than 100 sarcoma subtypes have been identified and they vary in molecular characteristics, pathology, clinical presentation and response to treatment. While sarcomas represent <1% of adult cancers, they account for approximately 21% of paediatric malignancies and thus pose some of the greatest risks of mortality and morbidity in children and young adults. Metastases occur in one-third of all patients and approximately 10–20% of sarcomas recur locally. Surgery in combination with preoperative and postoperative therapies is the primary treatment for localized sarcoma tumours and is the most promising curative possibility. Metastasized sarcomas, on the other hand, are treated primarily with single-agent or combination chemotherapy, but this rarely leads to a complete and robust response and often becomes a palliative form of treatment. The heterogeneity of sarcomas results in variable responses to current generalized treatment strategies. In light of this and the lack of curative strategies for metastatic and unresectable sarcomas, there is a need for novel subtype-specific treatment strategies. With the more recent understanding of the molecular mechanisms underlying the pathogenesis of some of these tumours, the treatment of sarcoma subtypes with targeted therapies is a rapidly evolving field. This review discusses the current management of sarcomas as well as promising new therapies that are currently underway in clinical trials.

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Symposium 1 “Department-specific Treatment Strategies for Reflux Disease” — Introduction

Nihon Kikan Shokudoka Gakkai Kaiho ◽

10.2468/jbes.69.83 ◽

2018 ◽

Vol 69 (2) ◽

pp. 83-83

Author(s):

H. Kuwano ◽

N. Oridate

Keyword(s):

Reflux Disease ◽

Treatment Strategies ◽

Specific Treatment

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Immune Sensing and Potential Immunotherapeutic Approaches to Control Chromoblastomycosis

Journal of Fungi ◽

10.3390/jof7010003 ◽

2020 ◽

Vol 7 (1) ◽

pp. 3

Author(s):

Leandro C. D. Breda ◽

Isabela G. Menezes ◽

Larissa N. M. Paulo ◽

Sandro Rogério de Almeida

Keyword(s):

Social Stigma ◽

Treatment Strategies ◽

Specific Treatment ◽

Treatment Interruption ◽

Lower Limbs ◽

Disease Treatment ◽

Immune Sensing ◽

Skin Immunology ◽

Anti Fungal ◽

Made In

Chromoblastomycosis (CBM) is a neglected, chronic, and progressive subcutaneous mycosis caused by different species of fungi from the Herpotrichiellaceae family. CBM disease is usually associated with agricultural activities, and its infection is characterized by verrucous, erythematous papules, and atrophic lesions on the upper and lower limbs, leading to social stigma and impacts on patients’ welfare. The economic aspect of disease treatment is another relevant issue. There is no specific treatment for CBM, and different anti-fungal drug associations are used to treat the patients. However, the long period of the disease and the high cost of the treatment lead to treatment interruption and, consequently, relapse of the disease. In previous years, great progress had been made in the comprehension of the CBM pathophysiology. In this review, we discuss the differences in the cell wall composition of conidia, hyphae, and muriform cells, with a particular focus on the activation of the host immune response. We also highlight the importance of studies about the host skin immunology in CBM. Finally, we explore different immunotherapeutic studies, highlighting the importance of these approaches for future treatment strategies for CBM.

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Molecular Subtypes and Precision Oncology in Intrahepatic Cholangiocarcinoma

Journal of Clinical Medicine ◽

10.3390/jcm10132803 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2803

Author(s):

Carolin Czauderna ◽

Martha M. Kirstein ◽

Hauke C. Tews ◽

Arndt Vogel ◽

Jens U. Marquardt

Keyword(s):

Clinical Care ◽

Treatment Options ◽

Treatment Strategies ◽

Specific Treatment ◽

Growth Factor Receptor ◽

Treatment Modalities ◽

Precision Oncology ◽

Recurrence Rates ◽

Isocitrate Dehydrogenase 1 ◽

Liver Cancers

Cholangiocarcinomas (CCAs) are the second-most common primary liver cancers. CCAs represent a group of highly heterogeneous tumors classified based on anatomical localization into intra- (iCCA) and extrahepatic CCA (eCCA). In contrast to eCCA, the incidence of iCCA is increasing worldwide. Curative treatment strategies for all CCAs involve oncological resection followed by adjuvant chemotherapy in early stages, whereas chemotherapy is administered at advanced stages of disease. Due to late diagnosis, high recurrence rates, and limited treatment options, the prognosis of patients remains poor. Comprehensive molecular characterization has further revealed considerable heterogeneity and distinct prognostic and therapeutic traits for iCCA and eCCA, indicating that specific treatment modalities are required for different subclasses. Several druggable alterations and oncogenic drivers such as fibroblast growth factor receptor 2 gene fusions and hotspot mutations in isocitrate dehydrogenase 1 and 2 mutations have been identified. Specific inhibitors have demonstrated striking antitumor activity in affected subgroups of patients in phase II and III clinical trials. Thus, improved understanding of the molecular complexity has paved the way for precision oncological approaches. Here, we outline current advances in targeted treatments and immunotherapeutic approaches. In addition, we delineate future perspectives for different molecular subclasses that will improve the clinical care of iCCA patients.

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Molecular subtype-specific efficacy of anti-EGFR therapy in colorectal cancer is dependent on the chemotherapy backbone

British Journal of Cancer ◽

10.1038/s41416-021-01477-9 ◽

2021 ◽

Author(s):

Sanne ten Hoorn ◽

Dirkje W. Sommeijer ◽

Faye Elliott ◽

David Fisher ◽

Tim R. de Back ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Subtype ◽

Primary Tumour ◽

Treatment Strategies ◽

Specific Treatment ◽

Progression Free Survival ◽

First Line ◽

Free Survival ◽

Tumour Location ◽

Selection For

Abstract Background Patient selection for addition of anti-EGFR therapy to chemotherapy for patients with RAS and BRAF wildtype metastatic colorectal cancer can still be optimised. Here we investigate the effect of anti-EGFR therapy on survival in different consensus molecular subtypes (CMSs) and stratified by primary tumour location. Methods Retrospective analyses, using the immunohistochemistry-based CMS classifier, were performed in the COIN (first-line oxaliplatin backbone with or without cetuximab) and PICCOLO trial (second-line irinotecan with or without panitumumab). Tumour tissue was available for 323 patients (20%) and 349 (41%), respectively. Results When using an irinotecan backbone, anti-EGFR therapy is effective in both CMS2/3 and CMS4 in left-sided primary tumours (progression-free survival (PFS): HR 0.44, 95% CI 0.26–0.75, P = 0.003 and HR 0.12, 95% CI 0.04–0.36, P < 0.001, respectively) and in CMS4 right-sided tumours (PFS HR 0.17, 95% CI 0.04–0.71, P = 0.02). Efficacy using an oxaliplatin backbone was restricted to left-sided CMS2/3 tumours (HR 0.57, 95% CI 0.36–0.96, P = 0.034). Conclusions The subtype-specific efficacy of anti-EGFR therapy is dependent on the chemotherapy backbone. This may provide the possibility of subtype-specific treatment strategies for a more optimal use of anti-EGFR therapy.

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Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1320611111 ◽

2015 ◽

Vol 112 (3) ◽

pp. 851-856 ◽

Cited By ~ 201

Author(s):

Mona Meyer ◽

Jüri Reimand ◽

Xiaoyang Lan ◽

Renee Head ◽

Xueming Zhu ◽

...

Keyword(s):

Functional Significance ◽

Treatment Strategies ◽

Specific Treatment ◽

Clonal Analysis ◽

Specific Drug ◽

Drug Resistant ◽

Naive Patient ◽

Functional Behavior ◽

Proliferation And Differentiation ◽

Genomic Analyses

Glioblastoma (GBM) is a cancer comprised of morphologically, genetically, and phenotypically diverse cells. However, an understanding of the functional significance of intratumoral heterogeneity is lacking. We devised a method to isolate and functionally profile tumorigenic clones from patient glioblastoma samples. Individual clones demonstrated unique proliferation and differentiation abilities. Importantly, naïve patient tumors included clones that were temozolomide resistant, indicating that resistance to conventional GBM therapy can preexist in untreated tumors at a clonal level. Further, candidate therapies for resistant clones were detected with clone-specific drug screening. Genomic analyses revealed genes and pathways that associate with specific functional behavior of single clones. Our results suggest that functional clonal profiling used to identify tumorigenic and drug-resistant tumor clones will lead to the discovery of new GBM clone-specific treatment strategies.

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Cancer-Associated Fibroblasts in Breast Cancer Treatment Response and Metastasis

Cancers ◽

10.3390/cancers13133146 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3146

Author(s):

Patricia Fernández-Nogueira ◽

Gemma Fuster ◽

Álvaro Gutierrez-Uzquiza ◽

Pere Gascón ◽

Neus Carbó ◽

...

Keyword(s):

Breast Cancer ◽

Hormone Receptors ◽

Treatment Strategies ◽

Specific Treatment ◽

Growth Factor Receptor ◽

Cancer Associated Fibroblasts ◽

Luminal A ◽

Luminal B ◽

Number Of Patients ◽

Current Therapies

Breast cancer (BrCa) is the leading cause of death among women worldwide, with about one million new cases diagnosed each year. In spite of the improvements in diagnosis, early detection and treatment, there is still a high incidence of mortality and failure to respond to current therapies. With the use of several well-established biomarkers, such as hormone receptors and human epidermal growth factor receptor-2 (HER2), as well as genetic analysis, BrCa patients can be categorized into multiple subgroups: Luminal A, Luminal B, HER2-enriched, and Basal-like, with specific treatment strategies. Although chemotherapy and targeted therapies have greatly improved the survival of patients with BrCa, there is still a large number of patients who relapse or who fail to respond. The role of the tumor microenvironment in BrCa progression is becoming increasingly understood. Cancer-associated fibroblasts (CAFs) are the principal population of stromal cells in breast tumors. In this review, we discuss the current understanding of CAFs’ role in altering the tumor response to therapeutic agents as well as in fostering metastasis in BrCa. In addition, we also review the available CAFs-directed molecular therapies and their potential implications for BrCa management.

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Ranscriptome Analysis Reveals the Molecular Mechanism of Yiqi Rougan Decoction in Reducing CCl4-induced Liver Fibrosis in Rats

10.21203/rs.3.rs-919251/v1 ◽

2021 ◽

Author(s):

Yu Xiong ◽

Jinyuan Hu ◽

Chen Xuan ◽

Jiayu Tian ◽

Kaiyue Tan ◽

...

Keyword(s):

Protein Kinase ◽

Liver Fibrosis ◽

Liver Injury ◽

Molecular Mechanism ◽

Treatment Strategies ◽

Specific Treatment ◽

Mitogen Activated Protein Kinase ◽

Signalling Pathways ◽

High Dose ◽

Peroxisome Proliferator

Abstract BackgroundLiver fibrosis develops from various chronic liver diseases, and there is currently a lack of specific treatment strategies. Yiqi Rougan decoction (YQRG) is a traditional Chinese medicine that has shown durative effects in the treatment of liver fibrosis; however, the mechanism associated with YQRG-related improvements in liver fibrosis remains to be experimentally determined. This study evaluated the therapeutic effect of YQRG on carbon tetrachloride (CCl4)-induced liver fibrosis in rats and its molecular mechanism. MethodsWe used low-, medium-, and high-dose YQRG to treat CCl4-induced liver fibrosis in rats, followed by assessment of liver injury and fibrosis according to liver appearance, body weight, liver mass index, histopathologic examination, and serum testing. Additionally, we performed transcriptome analysis using RNA-sequencing (RNA-seq) technology, including cluster, Gene Ontology (GO), and pathway analyses, to identify differentially expressed genes (DEGs), and protein and gene expression were detected by immunofluorescence (IFC), western blot, and real-time quantitative PCR. ResultsThe results showed that YQRG effectively alleviated CCl4-induced liver injury and fibrosis in rats, including observations of improved liver function, decreased activity of hepatic stellate cells (HSCs), and decreased extracellular matrix (ECM) deposition. Moreover, we identified downregulated and upregulated DEGs in the model group relative to the control and YQRG-treated groups, with GO analysis revealing their enrichment in biological processes, such as endoplasmic reticulum stress (ERS), apoptosis, and autophagy. Furthermore, pathway analysis showed that YQRG treatment downregulated the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/Akt (PI3K/AKT) signalling pathways and upregulated other signalling pathways, including those related to peroxisome proliferator-activated receptors(PPAR) and AMP-activated protein kinase(AMPK), with these finding subsequently verified experimentally. ConclusionThese findings showed that YQRG improved CCl4-induced liver fibrosis through multiple mechanisms and pathways, offering critical insight into the YQRG-related therapeutic mechanism and promoting further research into its potential application.

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Stratifying Sepsis in Uganda Using Rapid Pathogen Diagnostics and Clinical Data: A Prospective Cohort Study

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.21-0138 ◽

2021 ◽

Author(s):

Matthew J. Cummings ◽

Barnabas Bakamutumaho ◽

Nicholas Owor ◽

John Kayiwa ◽

Joyce Namulondo ◽

...

Keyword(s):

Prospective Cohort ◽

Treatment Strategies ◽

Specific Treatment ◽

Sub Saharan Africa ◽

Rapid Diagnostics ◽

Suspected Sepsis ◽

Laboratory Capacity ◽

Antimicrobial Management ◽

Sub Saharan ◽

Tb 32

The global burden of sepsis is concentrated in sub-Saharan Africa, where extensive pathogen diversity and limited laboratory capacity challenge targeted antimicrobial management of life-threatening infections. In this context, established and emerging rapid pathogen diagnostics may stratify sepsis patients into subgroups with prognostic and therapeutic relevance. In a prospective cohort of adults (age ≥18 years) hospitalized with suspected sepsis in Uganda, we stratified patients using rapid diagnostics for HIV, tuberculosis (TB), malaria, and influenza, and compared clinical characteristics and 30-day outcomes across these pathogen-driven subgroups. From April 2017 to August 2019, 301 adults were enrolled (median age, 32 years [interquartile range, 26–42 years]; female, n = 178 [59%]). A total of 157 patients (53%) were HIV infected. Sixty-one patients (20%) tested positive for malaria, 52 (17%), for TB (including 49 of 157 [31%] HIV-infected patients), and 17 (6%), for influenza. Co-infection was identified in 33 (11%) patients. The frequency of multi-organ failure, including shock and acute respiratory failure, was greatest among patients with HIV-associated TB. Mortality at 30 days was 19% among patients with malaria, 40% among patients with HIV-associated TB, 32% among HIV-infected patients without microbiological evidence of TB, 6% among patients with influenza, and 11% among patients without a pathogen identified. Despite improvements in anti-retroviral delivery, the burden of sepsis in Uganda remains concentrated among young, HIV-infected adults, with a high incidence of severe HIV-associated TB. In parallel with improvements in acute-care capacity, use of rapid pathogen diagnostics may enhance triage and antimicrobial management during emergency care for sepsis in sub-Saharan Africa, and could be used to enrich study populations when trialing pathogen-specific treatment strategies in the region.

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