The treatment of metastatic urothelial cancer (mUC) has been transformed by recent progress in clinical trials and drug development. There are now three therapeutic classes with proven benefits in mUC: chemotherapy, immunotherapy, and targeted therapy. The optimal sequence and combination of these classes remain to be defined. Biomarker development is essential to guide treatment selection at each therapeutic juncture. Two biomarkers, programmed death-ligand 1 expression and fibroblast growth factor receptor alterations, have been incorporated into the mUC treatment paradigm thus far. This review discusses predictive biomarkers in development and their potential to influence mUC treatment selection moving forward.
The dysregulation of Membrane - type 1 matrix metalloproteinase (MT1-MMP) has been extensively studied in numerous cancer types, and plays key roles in angiogenesis, cancer progression, and metastasis. MT1-MMP is a predictor of poor prognosis in osteosarcoma (OS), yet the molecular mechanisms of disease progression are unclear. This review provides a summary of the literature relating to the gene and protein expression of MT1-MMP (MMP-14) in OS clinical samples, evaluates the expression in cell lines and experimental models, and analyses its potential role in the progression and metastasis of OS. In addition, the therapeutic potential of MT1-MMP as a drug target has been assessed. Due to the biological complexity of MMPs, inhibition has proven to be challenging. However, exploiting the expression and proteolytic capacity of MT1-MMP could open new avenues in the search for novel, safer and selective drugs for use in OS.
The management of metastatic bladder cancer is palliative. Best outcomes are achieved in those who are fit enough for systemic therapies. The place of radiotherapy in these patients is mainly for symptom control, in particular haematuria. However, a small proportion, especially those with oligometastases, will benefit from more radical treatment. In this review, we look at the evidence currently available for radiotherapy in this setting.
Aim: Definitive chemoradiotherapy (dCRT) is the standard treatment for locally advanced unresectable esophageal squamous cell carcinoma (LU-ESCC). This study aimed to describe the results of dCRT for T4 ESCC and evaluate the pretherapeutic predictive factors of the outcomes.
Methods: A total of 133 patients with T4 ESCC who received dCRT were grouped into those who achieved a complete response (CR) or those who had residual disease (RD). The clinicopathologic variables were compared between the groups and the overall survival (OS) was evaluated. The predictive factor of RD was assessed and the prognostic factor for OS was identified.
Results: Among the 133 patients, 31 (23%) achieved CR. The CR group had a significantly better OS than the RD group (89.9 months vs. 10.7 months; hazard ratio = 0.096; 95% confidence interval: 0.05-0.19; P < 0.001). Multivariate analysis showed that a supracarinal tumor (OR = 3.21; P = 0.016), higher pretherapeutic serum
Conclusions: Among the patients who underwent dCRT for LU-ESCC, 23% achieved CR, and the long-term outcome of these patients was favorable. Increased levels of pretherapeutic serum squamous cell carcinoma antigen were also found to be predictive of treatment failure.
The immune cellular components of the tumour microenvironment are a diverse group of cells that paradoxically are now appreciated to have a coordinated opposing duality of either promoting or retarding tumour growth. Manipulating this seemingly dynamic interaction for therapeutic benefit is a hotbed of much research. Recent findings in tumour immunology (both preclinical and clinical) build on more than a century of insights and provide a way forward to improving patient outcomes, long term survival and the predictability of “cures”. This opinion piece attempts to summarise some of these historical and contemporary insights with a view to describing eminently testable therapeutic solutions.
The updated, recently published 2021 WHO classification of thymic tumors incorporates the most recent advances in the field of thymic pathology, with particular emphasis on primary thymic epithelial neoplasms. This new edition retains the basic format of previous editions for the classification of primary thymic epithelial neoplasms reaffirming the schema originally proposed in the first edition, which utilized a combination of letters and numbers for the designation of these tumors. Only minimal changes have been incorporated in the new edition compared with the previous ones. A new helpful feature is a summary in each chapter of recommendations for “essential” and “desirable” criteria to facilitate the diagnosis. A few issues in this classification, however, still require clarification. In this review, the changes and advances in the classification of thymoma presented in the latest WHO book on Thoracic Tumors will be reviewed along with some of the areas that may still benefit from the additional investigation.
A new generation of novel, effective targeted drugs and cellular therapies include monoclonal antibodies directed at the cell surface, such as the anti-CD-19 tafasitamab which, combined with lenalidomide, is the first therapy approved by the Food and Drug Administration for second-line treatment of diffuse large B-cell lymphoma. Other agents interfere with pro-survival intracellular signaling pathways including drugs that inhibit Bruton tyrosine kinase, phosphatidylinositol-3 kinase (PI3-kinase), and bcl-2. An increasing number of therapies impact the microenvironment, notably checkpoint inhibitors and bispecific antibodies. Chimeric antigen receptor-T cell therapy has improved the outcome of patients with a variety of histologies of lymphoma. Whereas in the past, such therapies would be used inrelapsed and refractory settings, they are now being evaluated as initial treatment in selected patients. With an improved ability to individualize treatment approaches, chemo-free will be a reality for lymphoma patients.
Inflammation and its effects in the bone marrow microenvironment represent a paradigmatic condition in which the hematopoietic niche and the immune systems, thought to properly sustain blood cell production and distinguish between friend and foe, can actively sustain a corrupted neighborhood within a chronic aberrant inflamed state. The bone marrow niche hijacks the physiologic hematopoiesis. The interactions between the hematopoietic stem cells and the niche in the bone marrow are critical determinants of quiescence. We examined several approaches to confront the available evidence; three key points emerged, pointing to the chronic inflammation process, especially the chronic infection and systemic inflammatory states, as leading causes of hematopoietic stem cell depletion. Clonal hematopoiesis, defined as a relative expansion of individual clones, is caused by somatic alterations in essential hematopoietic genes, which increase stem cell fitness. Moreover, terminal differentiation plays a significant role in progenitor loss and inflammatory signaling, promoting clonal selection and clonal hematopoiesis conditions. Specific myeloid malignancies as paradigmatic examples are discussed as a condition associated with inflammation, including the 5q- syndrome, Philadelphia negative myeloproliferative neoplasms, and chronic myeloid leukemia. Aging with increased fitness and hematopoietic stem cell attrition, extrinsic stress, enhanced stressor-specific fitness, and intrinsic defect across the hematopoietic process represent the route for novel insights in defective hematopoiesis. The discussion in this review also points out that the hematopoietic niches’ inflammatory stimulation may affect differentiation patterns and the function of downstream cells.
Aim: We aimed to test the hypothesis that loading of dendritic cells (DCs) with both viral and tumor-specific antigens would enhance the efficacy antitumor DC-based therapy applied simultaneously with oncolytic virus.
Methods: Vaccinia virus LIVP/GFP and melanoma B16-F10 were used in this study. DCs were pulsed with various combinations of viral and tumor-associated antigens. The maturation status of DCs was verified by expression of the markers CD80, CD86, and CCR7 and assessment of IL-6, TNF-α, and IL-12 secretion. The most efficient combination of antigens for DC loading was selected based on the analysis of the cytotoxic activity of T lymphocytes. Combination therapy using vaccinia virus LIVP/GFP and DCs pulsed with viral and tumor-specific antigens was administered to the B16-F10 melanoma/mouse C57Bl tumor model.
Results: We found that loading of DCs with viral antigens, or with a combination of viral and tumor antigens, resulted in similar levels of expression of DC maturation markers. The maximal in vitro cytotoxicity against virus-infected and non-infected B16 melanoma cells exhibited T lymphocytes activated by DCs loaded with the heat inactivated lysate of vaccinia virus LIVP/GFP infected tumor cell. The results show that the combination of vaccinia virus LIVP/GFP and DCs loaded with both tumor and viral antigens inhibit tumor growth of B16-F10 murine melanoma by more than two-fold.
Conclusions: Combination therapy with oncolytic vaccinia virus LIVP/GFP and tumor/virus antigen-loaded DCs limited the growth of established melanoma B16-F10, but no synergistic antitumor effects were observed. We propose that optimization of the therapy regimen could enhance the efficiency of combination therapy.
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease comprising multiple genetic subtypes that translates and impacts clinical outcomes after standard chemoimmunotherapy. Our initial understanding of the complex biological subtypes of DLBCL began with the identification of cell of origin (COO), and now has evolved to include even more specific subtypes defined by genetic signatures and mutations. These newer classifications lend themselves to the application of precision-based medicine, allowing us to tailor new treatment platforms that target specific oncogenic drivers in order to improve DLBCL outcomes. Essential to this is the development of genetic assays and tools that are reliable and readily available to assist in the application of these molecular classifications to real-world use. In this review, we discuss the history of DLBCL classification systems and their implication on clinical investigation as well as novel therapeutic options in DLBCL.
The mucin 1 (MUC1) gene emerged in mammals to afford protection of barrier epithelial tissues from the external environment. MUC1 encodes a transmembrane C-terminal (MUC1-C) subunit that is activated by loss of homeostasis and induces inflammatory, proliferative, and remodeling pathways associated with wound repair. As a consequence, chronic activation of MUC1-C promotes lineage plasticity, epigenetic reprogramming, and carcinogenesis. In driving cancer progression, MUC1-C is imported into the nucleus, where it induces NF-κB inflammatory signaling and the epithelial-mesenchymal transition (EMT). MUC1-C represses gene expression by activating (i) DNA methyltransferase 1 (DNMT1) and DNMT3b, (ii) Polycomb Repressive Complex 1 (PRC1) and PRC2, and (iii) the nucleosome remodeling and deacetylase (NuRD) complex. PRC1/2-mediated gene repression is counteracted by the SWI/SNF chromatin remodeling complexes. MUC1-C activates the SWI/SNF BAF and PBAF complexes in cancer stem cell (CSC) models with the induction of genome-wide differentially accessible regions and expressed genes. MUC1-C regulates chromatin accessibility of enhancer-like signatures in association with the induction of the Yamanaka pluripotency factors and recruitment of JUN and BAF, which promote increases in histone activation marks and opening of chromatin. These and other findings described in this review have uncovered a pivotal role for MUC1-C in integrating lineage plasticity and epigenetic reprogramming, which are transient in wound repair and sustained in promoting CSC progression.
Aim: We conducted a pilot study that combines immunotherapy (cyclic interleukin-2 interferon-beta sequence) and hormone therapy (HT) to overcome endocrine resistance in metastatic breast cancer.
Methods: The final results of a 2:1 control-case retrospective observational study are here shown following 22 additional months of postoperative follow-up and 6 further controls. There were 95 controls and 42 cases in total. The 95 controls were ER+/HER2- metastatic breast cancer patients who underwent first-line HT with aromatase inhibitors (AIs) or fulvestrant. Twenty-eight of them (28.9%) also received biological drugs including cyclin kinase inhibitors (CKIs). The 42 cases were ER+ metastatic breast cancer patients who received interferon beta-interleukin-2 immunotherapy in addition to first-line HT. Selective estrogen receptor modulators/down-regulators (SERMs/SERDs) were used for HT in 39 (92.9%) of them and AIs in the remaining 3.
Results: Median progression-free survival (PFS) and overall survival (OS) were significantly longer in the 42 studied patients who received hormone immunotherapy (HIT) than in the 95 controls (median time 33 vs. 18 months, P = 0.002, and 81 vs. 62 months, P = 0.019). In the analysis adjusted for disease-free interval (DFI), hormone receptor, HER2 status, visceral involvement, AIs, and biological therapy, the PFS and OS hazard ratio (HR) further increased in favor of the 42 cases (P = 0.004 and P = 0.044 respectively). In the same ER+/HER2- metastatic breast cancer patients treated with both AIs and CKIs, a median PFS ranging from 25.3 to 28.18 months and a median OS of 37.5 months were observed.
Conclusions: This study strongly suggests multi-center randomized clinical trials should be performed to enter our proposed immunotherapy into clinical practice.
Aim: The aim of this study is to compare disease-free survival (DFS) and overall survival (OS) in patients with stage I cervical cancer (≤ 4cms, lymph node-negative) undergoing open radical hysterectomy (ORH) vs. minimally invasive radical hysterectomy (MIRH).
Methods: All patients undergoing radical hysterectomy between January 2012-December 2018 from the largest tertiary referral cancer centre were included. A 1:1 propensity matching was done based on four independent prognostic factors to compare DFS and OS with the route of surgery.
Results: One hundred and ninety-nine patients were included during the study period. The median age of the cohort was 50 years. The median follow-up of patients was 47 months. Following 1:1 propensity matching, a total of 174 patients were analysed for DFS and OS in ORH (n = 87) and MIRH (n = 87) groups. Protective measure was used in two-thirds of the patients during MIRH. Twenty-nine patients (16.7%) had recurrences. For the matched cohort (n = 174), the DFS at 36 and 60 months was 84.8% (78.1%-89.6%) and 81% (73.4%-86.6%) respectively and the OS was 96.5% (91.7%-98.5%) and 95.6% (90.3%-98%) respectively. There was no statistically significant difference in DFS or OS between ORH and MIRH.
Conclusion: The present study showed no difference in oncological outcomes in MIRH compared to ORH. Retrospective audits on patient characteristics such as screening/vaccination history along with surgical technique/load and matching for crucial risk factors should be factored in future studies to eliminate the possible methodological errors.
Thymic carcinoma (TC) is a rare thymic epithelial neoplasm with an aggressive clinical course. There are many recognized histologic subtypes as described by the fifth edition of the World Health Organization (WHO) Classification of Thoracic Tumors; however, given the rarity of this tumor group, diagnosis remains a challenge, especially on limited tissue samples. Additionally, rare variants of TC are continuing to be established, particularly in the era of molecular diagnostics. Herein, histologic subtypes are described as the rare subtypes of TC in the context of their immunoprofile, cytogenetic or molecular features, clinical presentation, and ensuing challenges.
Extramedullary disease (EMD) of multiple myeloma (MM) can present as paraskeletal (paraosseous) plasmocytoma (PP) that arise from skeletal focal lesions or extramedullary plasmacytomas (EMP) that derive from hematogenous spread. The pathogenetic mechanisms that distinguish classical MM, PP, and EMP are still insufficiently known, as are the therapies that would be effective in EMD. The aim of this study was to evaluate immunohistochemically the angiogenesis, determined as microvessel density (MVD) and osteopontin expression in PP, of two patients with MM of plasmablastic morphology and an aggressive course of disease. We found high levels of MVD and osteopontin expression in both cases of PP. The role of angiogenesis and osteopontin in EMD should be clarified in future investigations, especially since there are no satisfactory therapeutic protocols for this form of multiple myeloma, and both of these biological factors can be the potential targets of new therapies.
Cancer has caused a tremendous burden in developing countries. Oncolytic virus (OV) therapy is an emerging modality with the potential to be a single or combination agent with radiation therapy (RT). Following entry of OV to the cell, OV will replicate and assemble before exiting from tumor cells. Construction of OV can be done by modifying the capsid, genome, and chemical material of viruses. Irradiation will induce double-strand breaks, and further integration of OV with DNA damage response pathway will interact with the MRE11-Rad50-Nbs1 complex to regulate the mobilization of E4 open reading frame 6, protein phosphatase 2A, poly(ADP-ribose) polymerase, apoptosis-inducing factor, and topoisomerase-IIβ-binding protein 1. Degradation of DNA-dependent protein kinase catalytic subunits via human simplex virus-1-infected cell polypeptide 0 will inhibit DNA repair. OV and RT have a synergistic interaction to cause viral oncolysis and upregulation of immune response. In the clinical setting, most studies have demonstrated that OV is a safe treatment with less toxicity. Moreover, OV + RT resulted in longer median survival (62.4 vs. 37.7 weeks) in malignant glioma.
Cancer is a group of diseases with significant morbidity and mortality. In cancer cells, where energy requirements are exceptionally high, angiogenesis, which is the sprouting of new blood vessels from pre-existing ones, is an important process for tumour survival and progression. Hence, extensive research in recent years focuses on the discovery of new anticancer drugs that target angiogenesis. Several methodologies have been developed preclinically, including the inhibition of pro-angiogenic factors and their receptors via micromolecular agents or monoclonal antibodies and the inhibition of other compensatory pathways beyond the traditional angiogenic ones. The purpose of the literature review is to present new anticancer drugs that target the process of angiogenesis and have been under preclinical or clinical investigation during the last five years. Many new anticancer drugs targeting angiogenesis are identified in the literature. The results of the in vitro and in vivo evaluation of these drugs show that, apart from inhibiting angiogenesis, they also affect cancer cell proliferation and tumour growth. Recent clinical studies show that these drugs increase the overall or disease-free survival of patients, even those with persistent, chemotherapy-resistant and metastatic types of cancer, although treatment-related side effects are not uncommon. Drugs that target the process of angiogenesis are likely to be the future of anticancer therapy, especially in cases where more traditional treatments do not produce the desired results and where combination regimens of anti-angiogenic agents with standard chemotherapeutics increase patient survival.
Thymic epithelial tumors (TETs) comprise a heterogeneous group of epithelial-derived thymic neoplasms with diverse clinical behavior and underlying molecular genetic features. Owing to their rare nature, the molecular classification of TETs has only recently begun to be fully explored. The advent of advanced molecular studies, particularly the ability to sequence the DNA and RNA of tumors in a massively parallel fashion, has led to an increased understanding of the molecular underpinnings of thymic neoplasia. Thymomas, characterized by a heterogeneous group of molecular alterations, tend to have low mutational burdens and various copy number abnormalities including a characteristic loss of chromosomal material in the region of 6q25.2-p25.3, a recurrent, specific point mutation GTF2I p.L424H, and specific expression of certain microRNAs. Thymic carcinomas, in contrast, are generally characterized by increased tumor mutational burdens, multiple copy number alterations, and varied, non-recurrent, somatic mutations. Advances in molecular knowledge of TETs allow for more precise molecular classification of these tumors, and the presence of specific alterations aids in the diagnosis of borderline lesions. In the future, additional molecular studies will better delineate the molecular landscape of these tumors and may one day allow for more targeted treatment algorithms. This review aims to cover the current understanding of the molecular alterations thus far identified in thymomas and thymic carcinomas.
Due to occupational activities, many people are exposed to carcinogenic airborne pollutants, such as benzene. Furthermore, benzene is also present in cigarette smoke. The main cancers associated with benzene, toluene, ethylbenzene, and xylenes (BTEX) are lung cancer and malignancies of the blood. At initial stages, lung cancer is often asymptomatic, but progression into metastasis is a huge clinical concern. We performed a review on possible biomarkers for monitoring increased genome instability and downregulation of the immune system in connection with overexposure to BTEX in a subgroup of workers being exposed to BTEX at Brazilian gas stations. The workers are subject to routine blood exams every semester; however, early genomic assessment is not routine. We evaluated available tests to be applied, including measuring benzene-derived metabolites in urine, determination of oxidative and inflammatory markers in blood, immunophenotypical profiling, micronucleus test, comet (single-cell gel electrophoresis) assay, (molecular) cytogenetics, chromosomal microarray, epigenetic-changes oriented tests, determination of mitochondrial (mt)DNA copy numbers, and studies on miRNA-level. However, no consensus was reached about their application and which test combination might be suited best.
Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma, accounting for 70% of cases in Western countries. Despite this unique name, FL is an extremely heterogeneous disease, both clinically and biologically. The basis of FL heterogeneity lies in the different biological pathways which can be activated, because of the variety of gene mutations that can occur. Today, there is a growing interest in the knowledge of these activated pathways, which is also testified by the presence of a new model that incorporates FL mutations to define patient’s prognosis (m7-FLIPI). These evaluations are also appealing because of the recent possibility of using “targeted therapies”. Targeted therapies are new tools, currently applicable in the setting of relapse/refractory (R/R) disease, where we can find a great variety of “chemo-free” combinations. As in other hematologic malignancies, “cellular therapy” enriches FL drug scenario, including T-cell dependent bispecific antibodies and chimeric antigen receptor (CAR) T-cell. Since FL heterogeneity is the basis of the difference in therapeutic efficacy and disease course among patients, the hope for the future is to understand FL biology more deeply, to better comprehend how to obtain more representative samples and pre-treatment prognostic information in order to individualize the treatment strategy as early as frontline therapy.
The management of non-melanoma skin cancers metastatic to the neck is challenging due to variability in biological behavior and patterns of regional lymphatic spread. Metastatic non-melanoma skin cancers to the parotid and neck often behave aggressively, with a high incidence of local recurrence after treatment and reduced five-year survival outcomes. Patterns of lymphatic spread are different from those seen in mucosal squamous cell carcinoma, with higher prevalence of disease in the parotid and superficial lymphatics. These factors require that treatment is individualized to achieve optimal outcomes. Traditionally, the management of non-melanoma skin cancers metastatic to lymph nodes has involved surgical excision followed by adjuvant radiation therapy. However, novel systemic therapies are showing promising results and their role in the management of these cancers is evolving.
Aim: Cancer stem cells (CSCs) are highly resistant to chemotherapy and γ-irradiation. Neutrons have a high linear energy transfer, which can lead to extensive damage to the DNA of tumor cells and CSCs. The aim of this work was to compare the sensitivity of MCF-7 human breast adenocarcinoma cells and CSCs to γ- and γ,n-irradiation.
Methods: To increase the number of CSCs, MCF-7 cells were cultured as mammospheres. γ-irradiation was carried out in a GUT-200M device (60Co source) in the dose range of 1-8 Gy at a dose rate of 0.75 Gy/min. γ,n-irradiation was carried out in an IR-8 reactor in the dose range of 0.05-2 Gy at a dose rate of 0.06 Gy/min. DNA DSB formation was assessed by the level of γH2AX foci using fluorescence microscopy and flow cytometry. CSCs were identified by flow cytometry as CD44+/CD24-/low cells.
Results: We showed that γ,n-irradiation induced the formation of γH2AX foci of a larger size than did γ-irradiation and led to more severe DNA damage per 1 Gy. Moreover, γ,n-radiation was found to have a high relative biological effectiveness (RBE) as assessed by the cell survival rate, the number of CSCs in culture, and the ability of CSCs to repopulate. The highest RBE of neutron radiation was observed at low doses, when cell survival rate decreased by only 5%-10%. With an increase in the radiation dose, the RBE value decreased for all studied parameters, but it remained as high as 5.
Conclusion: γ,n-radiation is highly effective against CSCs. Our results explain the efficacy of neutron therapy for resistant forms of breast cancer.
V-domain Ig Suppressor of T cell Activation (VISTA) is a negative immune checkpoint that is expressed on multiple immune cell subsets and has been characterized in T cells, macrophages, and myeloid-derived suppressor cells. As the only immune checkpoint expressed on naïve T cells, VISTA contributes to the maintenance of T cell quiescence and tolerance. VISTA also regulates multiple myeloid cell activities such as chemotaxis, differentiation, and migration. In the context of cancer, antagonistic monoclonal antibody targeting of VISTA has been shown to aid anti-tumor immunity. Furthermore, combination therapies that include other immune checkpoints such as PD-1 or CTLA-4 with VISTA blockade may enhance therapeutic efficacy in a variety of cancers. Combination therapy may help overcome adaptive resistance to individual checkpoint therapies, thereby improving patient outcomes and survival. Here, we summarize the role of VISTA in myeloid cells and T cells within the tumor microenvironment. We discuss the proposed counter-receptors for VISTA, VISTA antibodies currently in development, and the potential for combination therapies with checkpoint inhibitors such as PD-1 and CTLA-4.
Peripheral T-cell lymphomas (PTCL) are uncommon and aggressive diseases that are difficult to study. Combination chemotherapy such as cyclophosphamide, doxorubicin, vincristine, and prednisone has been the mainstay of treatment for almost 30 years, but outcomes remain poor. The development of new targeted therapies is changing the landscape of how we treat patients with these difficult diseases. For instance, the addition of brentuximab vedotin to combination chemotherapy enhanced the outcomes in patients with CD30-positive anaplastic large cell lymphomas, but there is still a need for better therapies in the other numerous subtypes. Here we discuss the data for the existing treatment paradigm of PTCL as well as the merits of shifting toward a chemotherapy-free approach.
Early diagnosis of cancer can significantly improve treatment and survival outcomes. Imaging and tissue biopsy are the gold standard diagnostic approaches but are costly, invasive, and often unable to detect early-stage tumors. The past decade has marked an acceleration in the discovery and development of liquid biopsy tests for aiding in the detection of various types of tumor markers in non-tissue samples, such as blood. Liquid biopsy markers include circulating tumor cells, as well as tumor cell fragments, nucleic acids, and proteins. Liquid biopsy may be useful in screening patients considered to be at high risk of developing cancer, for refining diagnosis when combined with other test results, and for early detection of recurrence. Advances in big data analytics, informatics, and artificial intelligence will make it possible to combine patient history, clinical data, and liquid biopsy marker profiles to achieve more accurate and earlier diagnosis. In this review, we summarize the current use of liquid biopsy in cancer care, including the development of multi-analyte panels to improve diagnostic accuracy and detect several cancer types in a single assay. We highlight recent advances for potential future applications of liquid biopsy to aid in the diagnosis of early-stage lung cancer. We also discuss the opportunities and challenges of integrating liquid biopsy into current algorithms for cancer screening and diagnosis.
The dynamic interplay between tumor cells and immune cells in the microenvironment plays a crucial role in determining disease severity and therapeutic outcome in cancer. Myeloid cells are the most abundantly available cell population in the tumor microenvironment. Myeloid cells have been shown to exist in diverse phenotypes and play both antitumoral and protumoral roles in cancer. Understanding the biology of myeloid cells can lay the foundation for the development of therapeutic strategies aimed at enhancing the antitumoral role of myeloid cells. This article presents an overview of the role of myeloid cells in tumor development and various mechanisms by which myeloid cells aid tumor progression. Existing drugs against cancer that utilize myeloid cells and the role of myeloid cells in drug resistance are also discussed.
Malignant mesothelioma (MM) is a rare, aggressive solid tumor with limited therapeutic options and poor therapeutic response. The role of immunotherapy in MM is now well established and therapeutic options, such as checkpoint inhibitors, are increasingly being approved. Chimeric antigen receptor (CAR)-T cell therapy is successfully implemented in several hematologic cancers, but currently has inadequate effect in solid tumors, owing to several limitations, such as trafficking and infiltration, limited T cell persistence and exhaustion, the immunosuppressive TME and tumor antigen heterogeneity. The lack of uniform and universal expression of tumor-associated antigens (TAAs) on tumor cells, as well as TAA heterogeneity following tumor editing post-therapy, are issues of significant importance to CAR-T cell and associated antigen-targeting therapies. Our review discusses the concept of tumor antigen heterogeneity in MM, the consequences for CAR-T cell therapies and the strategies to overcome it.
Background: The measurement of circulating tumor DNA (ctDNA) has been studied in several malignancies, including metastatic pancreatic cancer, but less is known about its utility in monitoring treatment response and recurrence in resectable pancreatic cancer. Methods: We conducted a systematic review of the literature examining the association of ctDNA with overall survival (OS) and disease-free survival. Results: Five articles met our exclusion criteria. Baseline and/or postoperative ctDNA was found to be associated with decreased OS and recurrence-free survival. Discussion: ctDNA has the potential to be used as a prognostic biomarker and to guide therapy in resectable pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease, even in patients whose cancer is localized and non-metastatic. Surgical resection provides the only option for cure, but long-term survival rates remain dismal. For patients with borderline resectable (BR) disease who undergo upfront resection, many patients are either too unwell for subsequent adjuvant systemic therapy, develop recurrence soon after, or are found to have unresectable disease intra-operatively. There is increasing evidence for a neoadjuvant approach, using more conventional multi-agent chemotherapy regimens, which have demonstrated higher activity in the metastatic setting compared to single agents. For patients with locally advanced (LA) disease, which is unresectable by current definitions, there is mounting evidence that effective neoadjuvant systemic therapy is able to convert some patients’ disease to a resectable state, offering the potential for long-term survival and cure. Herein we present a review of key trials focusing on prospective, randomized studies to provide high-level evidence supporting a neoadjuvant approach to both BR and LA PDAC. However, many knowledge gaps exist, such as the optimal neoadjuvant multi-agent chemotherapy regimen, the role of radiotherapy, and the safety and efficacy of adding immunotherapy to chemo/radiation therapy. Future challenges in determining the optimal approach to patients with BR or LA PDAC include not only overcoming the inherent difficulties in conducting complex, multidisciplinary, multicentre randomized trials in patients with a high-morbidity and mortality disease, but also trying to standardize disease definitions, treatment regimens, and outcome measures.
Soft tissue sarcoma (STS) most often occurs sporadically, but can also arise in the setting of a germline cancer predisposition syndrome (CPS). There is significant diversity amongst STS diagnoses as these tumors exhibit a variety of histologies, occur in all age groups, and can occur in any location in the body. This diversity is also reflected in the many known associated germline cancer predisposition associations. Some STS diagnoses, such as anaplastic rhabdomyosarcoma, are associated with high heritability and other STS, such as Ewing sarcoma, are notably absent from known CPS. Recognizing when a STS is more likely to be hereditary can influence clinical management. Individuals diagnosed with STS due to CPS may be at risk for other malignancies and should undergo additional surveillance for early detection. Additionally, family members should undergo genetic testing as they also may be at risk to develop STS and other CPS-associated malignancies. Some underlying cancer predisposition diagnoses may have implications for the treatment of a concurrent malignancy as in the case of PARP inhibitor therapy in the setting of homologous recombination deficiency. This review summarizes current knowledge of selected STS and their associations with CPS.
Cellular plasticity, the dynamic ability of cells to adopt distinct transcriptional states, plays a well-known role in the pancreas during the initiation of pancreatic ductal adenocarcinoma (PDA), the most common form of pancreatic cancer. It is now becoming clear that plasticity also plays an important role after the emergence of PDA. PDA is composed of two major transcriptional subtypes, classical and basal-like, with important biological differences. Recent work has indicated that individual tumors can be comprised of cells of each subtype, and that tumor subtype can change during the evolution of a tumor. This suggests that PDA cells can transit between transcriptional states, with important implications for disease progression. This review discusses what is currently known about inter-subtype plasticity and how this process is controlled.
Aims: Palbociclib has been approved in combination with endocrine therapy (ET) for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), regardless of age. Even though ABC is one of the most prevalent cancers in older patients, very few patients ≥ 65 years old were included in pivotal trials. Therefore, the current study evaluated the safety and efficacy of palbociclib in
Methods: Data were collected on patients > 70 years old who were treated with palbociclib plus ET for HR+/HER2- ABC in our institution. We analyzed safety data (CTCAE v4.0 criteria) and outcomes, such as progression-free survival (PFS) and overall survival (OS), as well as any associations between main geriatric characteristics and our results. Furthermore, we assessed safety at a national level by analyzing all palbociclib-related adverse events (AEs) reported in the French Pharmacovigilance Database (FPVD) during the same period.
Results: From February 2016 to July 2019, 52 patients were identified with a median age of 80.9 years, of whom 88% presented an AE. The most common grade 3-4 AE was neutropenia (64%). Median PFS and OS were nine months and not reached, respectively. The FPVD reports 227 cases of palbociclib-related AEs, with older and younger patients sharing similar characteristics.
Conclusion: Palbociclib is well tolerated in older patients with efficacy comparable to that in younger patients. However, the addition of palbociclib to ET should be evaluated individually in this older and frailer subgroup.
The treatments for metastatic urothelial carcinoma (mUC) have advanced substantially since 2016. Prognostic tools have been used to inform clinical trial designs and treatment decisions. Historically, prognostic tools were developed for mUC based on older clinical trials involving cytotoxic chemotherapy. As novel therapies emerged, there are studies investigating prognostic factors in the era of immune checkpoint inhibitors (ICI), antibody-drug conjugates, and targeted therapies. This review aims to highlight prognostic factors in mUC and their potential in clinical decision-making and research. In the setting of chemotherapy, patient performance status, site of metastatic burden, and specific laboratory findings were found to have prognostic value in mUC. In the era of ICI, newer models identified variables such as neutrophil to lymphocyte ratio, platelet count, and lactate dehydrogenase to also have potential prognostic value. In addition to clinical biomarkers, molecular biomarkers, such as PD-L1 assay and fibroblast growth factor receptor 2 and 3 genomic testings, may have promising prognostic and predictive implications. Current methods of identifying clinical and molecular prognostic factors involve clinician insight. As large complex datasets emerge, machine learning and artificial intelligence may help data analysis and detect important prognostic features. With careful validation, such machine learning-based strategies may help create more robust prognostic and/or predictive models in the future.
Cervical cancer is the fourth most common cancer in women worldwide, with a global incidence of 604,127 and an annual death rate of 341,831 in 2020. Patients with recurrent, persistent, or metastatic disease not amenable to curative therapy represent a patient population with a dismal prognosis. Until recently, the standard of care for these patients was based on platinum doublet chemotherapy with or without bevacizumab. However, significant advances in the treatment landscape of this disease have recently been achieved with the incorporation, among others, of immunotherapy in the therapeutic armamentarium. This review summarizes the main treatment approaches developed throughout the past decades, with particular emphasis on immunotherapy and novel targeted therapies.
Malignant mesothelioma (MM) is an aggressive cancer that affects the pleural and peritoneal mesothelial lining of the lungs and abdomen. Survival rates for patients with MM remain extremely low and effective treatments are limited. MM tumors harbor both genotypic and phenotypic features that indicate MM tumor cells are under increased oxidative stress, similar to other aggressive cancers. This increased oxidative stress in MM cells supports aggressive growth while providing a therapeutic vulnerability exploitable by redox-modulating compounds. MM tumor cells also exhibit altered mitochondrial structure and function that contribute to the disease through perturbations in metabolism and reactive oxygen species (ROS) production and metabolism. Targeting the altered redox status in cancer through increasing cellular ROS levels directly or inhibiting cellular antioxidant pathways and disrupting ROS scavenging mechanisms has become an exciting area for therapeutic intervention. This review discusses ROS sources and signaling, mitochondrial structure and function and targeting mitochondria ROS as a therapeutic approach for the treatment of MM.
Mesothelioma is a rare malignant tumor of the serosal membranes that can be challenging to diagnose, especially on small biopsy specimens. There are updated guidelines on the diagnosis and classification of mesothelioma, which incorporate advancements in understanding mesothelioma biology published in the literature over recent years. This review will discuss marked developments and/or improvements that have been made, including: (1) to the histologic classifications of mesothelioma; (2) the use of such classifications and nuclear grading in prognosis; (3) the indispensability of ancillary studies in the diagnosis of mesothelioma; (4) the application of these pleural based classifications and diagnostic schemes in peritoneal mesothelioma; and (5) the potential for diagnosis of mesothelioma in situ.
Pancreatic ductal adenocarcinoma is a highly aggressive malignancy with a poor prognosis. Effective treatment with acceptable outcomes is yet to be found, with chemo- and radioresistance comprising major impediments towards this goal. Although upfront surgery is the established therapeutic approach for resectable and borderline resectable disease, neoadjuvant treatment has recently monopolized the interest in clinical trials. This also applies to locally advanced pancreatic adenocarcinomas that could potentially be rendered operable. Chemotherapy and chemoradiotherapy are the most utilized therapeutic modalities in the neoadjuvant setting, while immunotherapy and targeting agents have been gaining significant attention. This critical review focuses on the clinical experience gained from retrospective and phase II/III randomized trials, reporting on the outcomes of neoadjuvant chemotherapy and chemoradiotherapy for pancreatic adenocarcinoma. Moreover, the ongoing trials, including those that involve immunotherapy and targeting agents, are summarized.
Therapeutic radiation plays an important role in the management of thymoma and thymic carcinoma. These two tumor types differ substantially in their aggressiveness and prognosis. The most pressing issue in radiotherapy is which thymoma and thymic carcinoma patients need radiation. Given that these are rare cancers, few randomized trials have been published. Controversy remains regarding which patients benefit from adjuvant radiation therapy. Existing literature spans patients treated over nearly 50 years, during which time radiation therapy has evolved from rudimentary 2-dimensional based planning to conformal 3-dimensional planning to yet more conformal dose painting techniques such as intensity-modulated radiation therapy and proton therapy. If the effect of radiation is small and the natural history of a disease long, as is the case for stage I favorable histology thymoma, then differences in techniques and toxicities may have as much of an impact as whether radiation was given or not.
The approval of immune checkpoint inhibitors (ICIs) has changed the treatment landscape in many aspects of urothelial cancer (UC), in both non-muscle-invasive bladder cancer and muscle-invasive bladder cancer and has introduced the concept of long-term remission for some patients in the metastatic setting. Front-line chemotherapy remains superior at achieving initial control of disease compared to front-line immune therapy. However, long-term durable responses are limited by chemotherapy resistance. The maintenance approach, sequencing chemotherapy with ICIs, could be considered a best of both worlds approach, achieving initial control with chemotherapy, which is maintained in some individuals with avelumab. However, outcomes for patients with metastatic UC remain poor. There are three steps to improving outcomes for these patients; the first is to develop better drugs and combinations of therapies, the second is the development of novel biomarkers and techniques to better select patients for treatment, and the third area of development is to give the drugs in the most optimal setting.
Telemedicine is being incorporated into routine healthcare, including oncology. The integration of telemedicine with patient electronic medical records and the adoption of virtual provider-patient encounters was accelerated by the SARS-CoV2 worldwide pandemic. Although telemedicine has existed for more than 50 years, the impact of telemedicine on patient care and health outcomes is relatively understudied, and little research has been conducted on telehealth in the care of patients with sarcoma. This review discusses the potential applications of telemedicine to the care of patients with sarcoma and some of the data available on patient and provider preferences for telemedicine vs. in-person healthcare encounters. Some of the areas of care in which greater adoption of telemedicine may be beneficial to patients with sarcoma are also discussed.
Over the past decade, researchers have identified and characterized the diverse cell populations within the tumor microenvironment of pancreatic cancer. The interplay between these cells in the TME either promotes or inhibits the malignant behavior of pancreatic cancer cells. Cancer-associated fibroblasts, previously thought to be one main subset, can now be broadly subclassified into three main types: inflammatory, myofibroblastic, and antigen-presenting, with the former and the latter two exerting pro-tumoral and anti-tumoral functions, respectively. Myeloid cells include myeloid-derived suppressor cells and tumor-associated macrophages. Myeloid-derived suppressor cells can be further divided into polymorphonuclear and monocytic and exhibit pro-tumoral activities. Tumor-associated macrophages exhibit M1 (anti-tumoral) or M2 (pro-tumoral) phenotypes, which are present in a dynamic fashion between the two phenotypes. Other constituents of the immune make-up of the tumor microenvironment include T and B cells and less described subsets which include natural killer cells, γδ T cells, and group 2 innate lymphoid cells. This review provides an overview of the studies that lead to the discovery of those cellular populations and highlights the recent efforts to utilize them as therapeutic targets in pancreatic cancer.
This review provides an overview of articles about peritoneal mesothelioma (PM) to analyze the effect of treatment modalities on response rates, post-treatment side effects, morbidity and mortality, and survival. Median survival in months following systemic chemotherapy (SC) ranged from 8.7 to 26.8 months. However, no patient was reported to have survived for more than five years with SC alone. In contrast, comprehensive treatment that included cytoreductive surgery (CRS) + perioperative chemotherapy (POC) showed a significantly longer median survival time than SC alone. Additionally, CRS + POC demonstrated 10-year survival rates of 12%-35%. Accordingly, CRS + POC is an innovative treatment that provides long-term survival in selected patients with PM. Selection criteria are performance status (ECOG PS ≤ 1), the absence of extraperitoneal metastasis, PCI less than cutoff levels (from < 10 to < 28), MIB-1 index (< 10), and histologic type (epithelioid type). Postoperative morbidity and mortality rates after CRS + POC were significantly higher than with more conventional operations. Accordingly, CRS and POC should be done at the specialized peritoneal surface malignancy centers.
Malignant pleural mesothelioma (MPM) is an aggressive and rare disease, mainly due to asbestos exposure, characterized by a poor prognosis. For almost two decades, platinum-based chemotherapy has been the only approved therapeutic regimen for first-line MPM, with an overall survival of 12 months. In the last years, the therapeutic scenario of different tumor types, including MPM, has dramatically changed due to immune checkpoint inhibition. The promising results of this approach have promoted new efforts into clinical research, and many trials investigating novel therapeutic combinations are currently ongoing. The aim of the present review is to provide a comprehensive overview of the most promising immunotherapeutic-based strategies currently under investigation for advanced MPM.
Radiological imaging has a critical role in the diagnosis of sarcomas and in evaluating therapy response assessment. The current gold standard for response assessment in solid tumors is the Response Evaluation Criteria in Solid Tumors, which evaluates changes in tumor size as a surrogate endpoint for therapeutic efficacy. However, tumors may undergo necrosis, changes in vascularization or become cystic in response to therapy, with no significant volume changes; thus, size assessments alone may not be adequate. Such morphological changes may give rise to radiographic phenotypes that are not easily detected by human operators. Fortunately, recent advances in high-performance computing and machine learning algorithms have enabled deep analysis of radiological images to extract features that can provide richer information about intensity, shape, size or volume, and texture of tumor phenotypes. There is growing evidence to suggest that these image-derived or “radiomic features” are sensitive to biological processes such as necrosis and glucose metabolism. Thus, radiomics could prove to be a critical tool for assessing treatment response and may present an integral complement to existing response criteria, opening new avenues for patient assessment in sarcoma trials.
Clinical development of new treatment options for patients with pancreatic cancer has been slow and expensive and resulted in few effective therapies. With a dismal five-year survival rate of 11% in the U.S., pancreatic cancer remains the third leading cause of cancer-related deaths and is poised to move to second by 2030. Standard clinical trials typically compare one investigational treatment to one standard of care, encompass one phase of clinical investigation at a time, and treat one patient population. Accrual and data analysis are often very slow, and unfortunately, the vast majority of clinical trials targeting pancreatic cancer patients are unsuccessful. More efficient clinical trial designs can include combining phases I and II or phases II and III, and trials that involve a master protocol approach can also answer multiple clinical questions simultaneously. These modern clinical trial designs can allow a faster, more efficient and cost-effective approach to testing investigational therapies in patients with pancreatic cancer and, most importantly, fewer patients may be required to determine the efficacy of treatment. Herein we summarize some of the recent innovative clinical trials in pancreatic cancer to provide meaningful data toward developing new treatment options to benefit patients with a dismal disease like pancreatic cancer.
Malignant pleural mesothelioma (MPM) is an aggressive and recalcitrant surface neoplasm that defies current multimodality treatments. MicroRNAs (miRNAs) are small noncoding RNAs that epigenetically regulate multiple gene networks and cellular processes. In cancer, miRNA dysregulation is associated with tumorigenesis, with tumor suppressor miRNAs underexpressed or lost, while oncogenic miRNAs are overexpressed. Consequently, miRNAs have emerged as potential therapeutic candidates. Because loss of tumor suppressors predominates the pathophysiology of MPM, re-expressing tumor suppressor miRNAs could be an effective therapeutic strategy. This review highlights the most promising MPM-specific tumor suppressor miRNAs that could be developed into novel therapeutics, the supporting data, and what is known about their molecular mechanism(s).
Aim: Lymph node (LN) metastases are associated with poor outcomes in patients with recurrent larynx squamous cell carcinoma (LSCC). Neck dissection (ND) is therefore commonly performed along with salvage total laryngectomy (STL). Here, we assess the rate of occult LN metastases and the diagnostic value of MRI and PET/CT for detecting them in recurrent LSCC.
Methods: This retrospective study included patients with recurrent LSCC after primary (chemo)radiotherapy [(C)RT] who were re-staged by MRI and/or PET/CT and treated with STL and ND between 2004 and 2019. The histopathology of ND samples was used as the reference standard.
Results: Forty-one patients were included. The prevalence of occult metastases in MRI-negative and
Conclusion: Both MRI and PET/CT afforded good negative predictive values for nodal staging in patients with recurrent LSCC after (C)RT prior to STL. In selected patients, these radiological modalities, particularly PET/CT, could help to avoid unnecessary surgery to the neck and its associated morbidity.