scholarly journals Immunotherapy and Targeting the Tumor Microenvironment: Current Place and New Insights in Primary Pulmonary NUT Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiang Li ◽  
Hui Shi ◽  
Wei Zhang ◽  
Chong Bai ◽  
Miaoxia He ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Nuclear Protein ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Disease Stage ◽  
Innovative Strategies ◽  
Immunohistochemical Markers ◽  
Tumor Neovascularization ◽  
Tumor Mutational Burden ◽  
Nut Carcinoma

Primary pulmonary nuclear protein of testis carcinoma is a rare and highly aggressive malignant tumor. It accounts for approximately 0.22% of primary thoracic tumors and is little known, so it is often misdiagnosed as pulmonary squamous cell carcinoma. No effective treatment has been formed yet, and the prognosis is extremely poor. This review aims to summarize the etiology, pathogenesis, diagnosis, treatment, and prognosis of primary pulmonary nuclear protein of testis carcinoma in order to better recognize it and discuss the current and innovative strategies to overcome it. With the increasing importance of cancer immunotherapy and tumor microenvironment, the review also discusses whether immunotherapy and targeting the tumor microenvironment can improve the prognosis of primary pulmonary nuclear protein of testis carcinoma and possible treatment strategies. We reviewed and summarized the clinicopathological features of all patients with primary pulmonary nuclear protein of testis carcinoma who received immunotherapy, including initial misdiagnosis, disease stage, immunohistochemical markers related to tumor neovascularization, and biomarkers related to immunotherapy, such as PD-L1 (programmed death-ligand 1) and TMB (tumor mutational burden). In the meanwhile, we summarized and analyzed the progression-free survival (PFS) and the overall survival (OS) of patients with primary pulmonary nuclear protein of testis carcinoma treated with PD-1 (programmed cell death protein 1)/PD-L1 inhibitors and explored potential population that may benefit from immunotherapy. To the best of our knowledge, this is the first review on the exploration of the tumor microenvironment and immunotherapy effectiveness in primary pulmonary nuclear protein of testis carcinoma.

Mature tertiary lymphoid structures in lung adenocarcinoma are associated with better progression free survival

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S149-S149
Author(s):  
R Obeng ◽  
V Parihar ◽  
D Alexis ◽  
M Behera ◽  
T Owonikoko ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Lung Adenocarcinoma ◽  
Progression Free Survival ◽  
Germinal Centers ◽  
Disease Stage ◽  
Free Survival ◽  
Formalin Fixed Paraffin Embedded ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures ◽  
Lymphoid Aggregates

Abstract Introduction/Objective The presence of inducible lymphoid structures known as tertiary lymphoid structures in the tumor microenvironment has been shown to correlate with positive clinical outcome. However, the maturation states of lymphoid aggregates in lung adenocarcinoma are not completely understood. Methods/Case Report Seventy tumor samples from 69 patients diagnosed with lung adenocarcinoma (Stages I to III) between 2013 and 2015 were included in the study. The presence and maturation states of the lymphoid structures within the tumors were evaluated by conventional and 26 samples were further analyzed by multiplexed immunohistochemistry of formalin fixed paraffin embedded tissues and then quantified. Mature lymphoid follicles containing germinal centers were identified by the presence of CD21+ and BCL-6+ cells in an organized configuration within tight clusters of T and B cells. Results (if a Case Study enter NA) Samples with fully mature lymphoid structures (germinal centers) had larger tumors and higher disease stage. The number of mature lymphoid structures correlated with the total number of lymphoid aggregates present in the tumor microenvironment. Additionally, tumor samples with ≥10 mature lymphoid structures had more primary follicles. While there was no difference in overall survival, progression free survival was significantly longer in patients who had ≥10 mature lymphoid structures in comparison with patients who had <10 mature structures. Conclusion In conclusion, a spectrum of lymphoid aggregates in different stages of maturation are present in lung adenocarcinoma. An increase in the number of mature lymphoid structures may be associated with progression free survival in patients with lung adenocarcinoma.

scholarly journals Multidisciplinary Management of Hepatocellular Carcinoma in Clinical Practice

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Gemma Bruera ◽  
Katia Cannita ◽  
Aldo Victor Giordano ◽  
Rosa Manetta ◽  
Roberto Vicentini ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Practice ◽  
Liver Function ◽  
Rating Scale ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Disease Stage ◽  
Multidisciplinary Management ◽  
Disease Extension ◽  
Surgical Treatments

Background. Hepatocellular carcinoma (HCC) patients require different treatment strategies according to disease extension, liver function, and patient’s fitness. We evaluated HCC multidisciplinary management in clinical practice.Methods. Consecutive patients were followed and treated with tailored medical, locoregional, and surgical treatments, according to disease stage and patient’s fitness (age, Cumulative Illness Rating Scale (CIRS)). Activity, efficacy, and safety were evaluated.Results. Thirty-eight patients were evaluated: median age, 74; elderly 92%; CIRS secondary 28 (74%); Child-Pugh A 20 (53%), B 11 (29%); and Barcelona Clinic Liver Cancer (BCLC) 0 2 (5%), A 9 (24%), B 10 (26%), C 13 (34%), and D 4 (11%). Overall survival (OS) was 30 months. At 9 months median follow-up, among 25 unresectable HCC, OS was 10 months; BCLC B–D unfit for sorafenib showed OS 3 months. Ten patients (40%) received sorafenib: Child-Pugh A 5 (50%) and B 5 (50%) and disease control rate 89%, progression-free survival 7 months, and OS 9 months. G3-4 toxicities: anorexia, hypertransaminaemia, hyperbilirubinemia, and hypercreatininemia. Limiting toxicity syndromes were 40%, all multiple sites.Conclusion. HCC patients require multidisciplinary clinical management to properly select tailored treatments according to disease stage, fitness, and liver function. Patients suitable for sorafenib should be carefully selected, monitored for individual safety, and prevalently characterized by limiting toxicity syndromes multiple sites.

scholarly journals Current Trends in Non-Invasive Imaging of Interactions in the Liver Tumor Microenvironment Mediated by Tumor Metabolism

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3645
Author(s):  
Isabel Theresa Schobert ◽  
Lynn Jeanette Savic
Keyword(s):  
Tumor Microenvironment ◽  
Liver Cancer ◽  
Cancer Cells ◽  
Imaging Techniques ◽  
Treatment Strategies ◽  
Tumor Metabolism ◽  
Resistance Mechanisms ◽  
Metabolic Reprogramming ◽  
Non Invasive

With the increasing understanding of resistance mechanisms mediated by the metabolic reprogramming in cancer cells, there is a growing clinical interest in imaging technologies that allow for the non-invasive characterization of tumor metabolism and the interactions of cancer cells with the tumor microenvironment (TME) mediated through tumor metabolism. Specifically, tumor glycolysis and subsequent tissue acidosis in the realms of the Warburg effect may promote an immunosuppressive TME, causing a substantial barrier to the clinical efficacy of numerous immuno-oncologic treatments. Thus, imaging the varying individual compositions of the TME may provide a more accurate characterization of the individual tumor. This approach can help to identify the most suitable therapy for each individual patient and design new targeted treatment strategies that disable resistance mechanisms in liver cancer. This review article focuses on non-invasive positron-emission tomography (PET)- and MR-based imaging techniques that aim to visualize the crosstalk between tumor cells and their microenvironment in liver cancer mediated by tumor metabolism.

scholarly journals Estrogen/ER in anti-tumor immunity regulation to tumor cell and tumor microenvironment

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Tiecheng Wang ◽  
Jiakang Jin ◽  
Chao Qian ◽  
Jianan Lou ◽  
Jinti Lin ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Tumor Immunity ◽  
Immune Cells ◽  
Target Genes ◽  
Target Therapy ◽  
Treatment Strategies ◽  
Signal Transduction Pathway ◽  
Pathway Activation ◽  
Immune System Regulation

AbstractAs the essential sexual hormone, estrogen and its receptor has been proved to participate in the regulation of autoimmunity diseases and anti-tumor immunity. The adjustment of tumor immunity is related to the interaction between cancer cells, immune cells and tumor microenvironment, all of which is considered as the potential target in estrogen-induced immune system regulation. However, the specific mechanism of estrogen-induced immunity is poorly understood. Typically, estrogen causes the nuclear localization of estrogen/estrogen receptor complex and alternates the transcription pattern of target genes, leading to the reprogramming of tumor cells and differentiation of immune cells. However, the estrogen-induced non-canonical signal pathway activation is also crucial to the rapid function of estrogen, such as NF-κB, MAPK-ERK, and β-catenin pathway activation, which has not been totally illuminated. So, the investigation of estrogen modulatory mechanisms in these two manners is vital for the tumor immunity and can provide the potential for endocrine hormone targeted cancer immunotherapy. Here, this review summarized the estrogen-induced canonical and non-canonical signal transduction pathway and aimed to focus on the relationship among estrogen and cancer immunity as well as immune-related tumor microenvironment regulation. Results from these preclinical researches elucidated that the estrogen-target therapy has the application prospect of cancer immunotherapy, which requires the further translational research of these treatment strategies.

scholarly journals Therapeutic Sequencing in ALK+ NSCLC

2021 ◽  
Vol 14 (2) ◽  
pp. 80
Author(s):  
Mei Elsayed ◽  
Petros Christopoulos
Keyword(s):  
Disease Progression ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Treatment Strategies ◽  
Fourth Generation ◽  
Cell Therapies ◽  
Anaplastic Lymphoma ◽  
Phase Ii Studies ◽  
Tumor Mutational Burden ◽  
Potential Clinical Utility

Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC) is a model disease for the use of targeted pharmaceuticals in thoracic oncology. Due to higher systemic and intracranial efficacy, the second-generation ALK tyrosine kinase inhibitors (TKI) alectinib and brigatinib have irrevocably displaced crizotinib as standard first-line treatment, based on the results of the ALEX and ALTA-1L trials. Besides, lorlatinib and brigatinib are the preferred second-line therapies for progression under second-generation TKI and crizotinib, respectively, based on the results of several phase II studies. Tissue or liquid rebiopsies at the time of disease progression, even though not mandated by the approval status of any ALK inhibitor, are gaining importance for individualization and optimization of patient management. Of particular interest are cases with off-target resistance, for example MET, HER2 or KRAS alterations, which require special therapeutic maneuvers, e.g., inclusion in early clinical trials or off-label administration of respectively targeted drugs. On the other hand, up to approximately half of the patients failing TKI, develop anatomically restricted progression, which can be initially tackled with local ablative measures without switch of systemic therapy. Among the overall biologically favorable ALK+ tumors, with a mean tumor mutational burden uniquely below 3 mutations per Mb and the longest survival among NSCLC currently, presence of the EML4-ALK fusion variant 3 and/or TP53 mutations identify high-risk cases with earlier treatment failure and a need for more aggressive surveillance and treatment strategies. The potential clinical utility of longitudinal ctDNA assays for earlier detection of disease progression and improved guidance of therapy in these patients is a currently a matter of intense investigation. Major pharmaceutical challenges for the field are the development of more potent, fourth-generation TKI and effective immuno-oncological interventions, especially ALK-directed cell therapies, which will be essential for further improving survival and achieving cure of ALK+ tumors.

scholarly journals Emerging Trends for Radio-Immunotherapy in Rectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1374
Author(s):  
Claudia Corrò ◽  
Valérie Dutoit ◽  
Thibaud Koessler
Keyword(s):  
Rectal Cancer ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Infiltration ◽  
Emerging Trends ◽  
Tumor Mutational Burden ◽  
Microsatellite Stability

Rectal cancer is a heterogeneous disease at the genetic and molecular levels, both aspects having major repercussions on the tumor immune contexture. Whilst microsatellite status and tumor mutational load have been associated with response to immunotherapy, presence of tumor-infiltrating lymphocytes is one of the most powerful prognostic and predictive biomarkers. Yet, the majority of rectal cancers are characterized by microsatellite stability, low tumor mutational burden and poor T cell infiltration. Consequently, these tumors do not respond to immunotherapy and treatment largely relies on radiotherapy alone or in combination with chemotherapy followed by radical surgery. Importantly, pre-clinical and clinical studies suggest that radiotherapy can induce a complete reprograming of the tumor microenvironment, potentially sensitizing it for immune checkpoint inhibition. Nonetheless, growing evidence suggest that this synergistic effect strongly depends on radiotherapy dosing, fractionation and timing. Despite ongoing work, information about the radiotherapy regimen required to yield optimal clinical outcome when combined to checkpoint blockade remains largely unavailable. In this review, we describe the molecular and immune heterogeneity of rectal cancer and outline its prognostic value. In addition, we discuss the effect of radiotherapy on the tumor microenvironment, focusing on the mechanisms and benefits of its combination with immune checkpoint inhibitors.

scholarly journals Challenging Diagnosis in NUT Carcinoma

2021 ◽  
pp. 106689692110195
Author(s):  
Grosse Claudia ◽  
Grosse Alexandra
Keyword(s):  
Nuclear Protein ◽  
Hematological Malignancy ◽  
Undifferentiated Carcinoma ◽  
Squamous Differentiation ◽  
Poorly Differentiated Carcinoma ◽  
Poorly Differentiated ◽  
Nut Carcinoma ◽  
Disseminated Disease ◽  
Generation Sequencing

Nuclear protein in testis (NUT) carcinoma represents a highly aggressive, poorly differentiated carcinoma that is genetically defined by rearrangement of NUT gene. The histomorphological appearance ranges from entirely undifferentiated carcinoma to carcinoma with prominent squamous differentiation. NUT carcinoma can display neuroendocrine features. Although it is typically distributed along the midline axis, it may manifest in nonmidline locations. The majority of patients develop rapidly disseminated disease. We illustrate 2 cases of NUT carcinoma, one located in the lung, which closely resembled a neuroendocrine carcinoma, and the other one with assumed lung origin demonstrating metastatic dissemination with diffuse bone involvement, which was clinically first suspected to be a hematological malignancy. Due to its undifferentiated nature, NUT carcinoma may be confused with many entities. NUT immunohistochemistry is considered to be sufficient for the diagnosis. Fluorescence in-situ hybridization analysis and next-generation sequencing are currently used to confirm the diagnosis.

scholarly journals Immunotherapy in Adrenocortical Carcinoma: Predictors of Response, Efficacy, Safety, and Mechanisms of Resistance

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 304
Author(s):  
Marta Araujo-Castro ◽  
Eider Pascual-Corrales ◽  
Javier Molina-Cerrillo ◽  
Teresa Alonso-Gordoa
Keyword(s):  
Adrenocortical Carcinoma ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Mechanisms Of Resistance ◽  
Response Efficacy ◽  
Predictors Of Response ◽  
Primary Endpoints ◽  
Tumor Mutational Burden

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options in the advanced stages. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in advanced ACC has been investigated in different studies. With the aim clarifying the role of immunotherapy in ACC we performed a comprehensive review about this topic focusing on the predictors of response, efficacy, safety, and the mechanisms of resistance. Five clinical trials with four immune checkpoint inhibitors (pembrolizumab, avelumab, nivolumab, and ipilimumab) have investigated the role of immunotherapy in advanced ACC. Despite, the different primary endpoints used in these studies, the reported rates of overall response rate and progression free survival were generally poor. Three main potential markers of response to immunotherapy in ACC have been described: Expression of PD-1 and PD-L1, microsatellite instability and tumor mutational burden. However, none of them has been validated in prospective studies. Several mechanisms of ACC immunoevasion may be responsible of immunotherapy failure, and a greater knowledge of these mechanisms might lead to the development of new strategies to overcome the immunotherapy resistance. In conclusion, although currently the role of immunotherapy is limited, the identification of immunological markers of response and the implementation of strategies to avoid immunotherapy resistance could improve the efficacy of this therapy.

scholarly journals Unique Genomic Landscape of High-Grade Neuroendocrine Cervical Carcinoma: Implications for Rethinking Current Treatment Paradigms

2020 ◽  
pp. 972-987
Author(s):  
Ramez N. Eskander ◽  
Julia Elvin ◽  
Laurie Gay ◽  
Jeffrey S. Ross ◽  
Vincent A. Miller ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Current Treatment ◽  
High Grade ◽  
Novel Treatment ◽  
Sample Average ◽  
Genomic Landscape ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Sample Range ◽  
Novel Treatment Strategies

PURPOSE High-grade neuroendocrine cervical cancer (HGNECC) is an uncommon malignancy with limited therapeutic options; treatment is patterned after the histologically similar small-cell lung cancer (SCLC). To better understand HGNECC biology, we report its genomic landscape. PATIENTS AND METHODS Ninety-seven patients with HGNECC underwent comprehensive genomic profiling (182-315 genes). These results were subsequently compared with a cohort of 1,800 SCLCs. RESULTS The median age of patients with HGNECC was 40.5 years; 83 patients (85.6%) harbored high-risk human papillomavirus (HPV). Overall, 294 genomic alterations (GAs) were identified (median, 2 GAs/sample; average, 3.0 GAs/sample, range, 0-25 GAs/sample) in 109 distinct genes. The most frequently altered genes were PIK3CA (19.6% of cohort), MYC (15.5%), TP53 (15.5%), and PTEN (14.4%). RB1 GAs occurred in 4% versus 32% of HPV-positive versus HPV-negative tumors ( P < .0001). GAs in HGNECC involved the following pathways: PI3K/AKT/mTOR (41.2%); RAS/MEK (11.3%); homologous recombination (9.3%); and ERBB (7.2%). Two tumors (2.1%) had high tumor mutational burden (TMB; both with MSH2 alterations); 16 (16.5%) had intermediate TMB. Seventy-one patients (73%) had ≥ 1 alteration that was theoretically druggable. Comparing HGNECC with SCLC, significant differences in TMB, microsatellite instability, HPV-positive status, and in PIK3CA, MYC, PTEN, TP53, ARID1A, and RB1 alteration rates were found. CONCLUSION This large cohort of patients with HGNECC demonstrated a genomic landscape distinct from SCLC, calling into question the biologic and therapeutic relevance of the histologic similarities between the entities. Furthermore, 73% of HGNECC tumors had potentially actionable alterations, suggesting novel treatment strategies for this aggressive malignancy.

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

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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