OAE Publishing Inc.

Journal of Cancer Metastasis and Treatment

Published by OAE Publishing Inc.
Online ISSN: 2454-2857
Print ISSN: 2394-4722
Discipline: Oncology
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Aims and scope

Journal of Cancer Metastasis and Treatment concerns cancer metastasis and treatment, including the occurrence, development, progression, metastasis, and treatment of neoplastic diseases. Its coverage includes basic, translational and clinical studies related to cancer cell biology, genomics, precision medicine, medical oncology, radiation therapy and radiology, obstetrics and gynecology, pediatrics, surgery, hematology, neuro-oncology, etc.



Recent publications
Clinical indications for liquid biopsy of tumor markers throughout the patient journey.
Tumor protein biomarkers of various cancer types. AFP: Alpha-fetoprotein; B2M: beta 2-microglobulin; β-hCG: beta-human chorionic gonadotropin; CA: cancer antigen; CA 19-9: carbohydrate antigen 19-9; CEA: carcinoembryonic antigen; Cyfra 21-1: cytokeratin 19 fragments; HE4: human epididymis secretory protein 4; Ig: immunoglobulin; LG2m: laminin γ2 monomer; NMP22: nuclear matrix protein-22; NSE: neuron-specific enolase; PIVKA-II: protein induced by vitamin K absence-II; ProGRP: pro-gastrinreleasing peptide; PSA: prostate-specific antigen; SCCA: squamous cell carcinoma antigen; Tg: thyroglobulin.
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.
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.
VISTA expression in the periphery versus the tumor microenvironment. BALB/c mice were injected intradermally with 100k CT26 cells and were grown for two weeks. Tumors and spleens were dissociated and processed for flow cytometry. Cells from VISTA-deficient mice were used for staining controls. (A) Overlays showing VISTA expression on CD8+ T cells in the spleen or tumor. (B) VISTA expression as Mean Fluorescence intensity in spleen versus tumor within the indicated cell subsets. Data are represented as mean ± SD. VISTA: V-domain Ig Suppressor of T cell Activation.
The proposed effects of VISTA blockade in the TME. The administration of an anti-VISTA antagonist results in the recruitment of T cells to the TME, as well as a reduction in chemotaxis of MDSCs and macrophages into the TME. VISTA antagonism also results in decreased differentiation of MDSCs into TAMS is also decreased; reduced production of suppressive cytokines by MDSCs and macrophages, resulting in decreased T cell inhibition, and increased production of IFNγ and IL-2. DCs become more activated and upregulate Erk1/2 and Jnk1/2, potentially regulating the IL-23/IL-17 inflammatory axis. Neutrophil and PMN-MDSC levels are decreased in the TME by the reduction of chemotaxis after VISTA blockade. Altogether, these effects of VISTA antagonism result in reduced tumor burden. VISTA: V-domain Ig Suppressor of T cell Activation; TME: tumor microenvironment; MDSCs: myeloid-derived suppressor cells; TAMS: tumor associated macrophages.
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.
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.
Assigned lymph node levels of the lateral neck. Level IA: Submental nodes. Level IB: Submandibular nodes. Level IIA: Upper jugular nodes anterior to the spinal accessory nerve. Level IIB: Upper jugular nodes posterior to the spinal accessory nerve. Level III: Mid jugular nodes. Level IV: Lower jugular nodes. Level VA: Posterior triangle nodes superior to the level of the inferior border of cricoid cartilage. Level VB: Posterior triangle nodes inferior to the level of the inferior border of cricoid cartilage. Level VI: Central compartment nodes.
Patterns of metastatic spread to lateral neck lymph nodes from non-melanoma skin cancer of the head and neck.
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
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
WHO histologic classification of thymoma (A) Type A thymoma is characterized by a spindle cell proliferation with limited numbers of lymphocytes, (B) Type AB thymoma is characterized by a spindle cell population intimately admixed with increased numbers of lymphocytes, (C) Type B1 thymoma is characterized by sparse epithelioid cells in a dense immature lymphoid cell population, (D) Type B2 thymoma is characterized by an increased number of epithelioid cells with a relatively decreased proportion of lymphoid cells, (E) Atypical thymoma (WHO type B3 thymoma) is characterized by sheets of epidermoid appearing epithelioid cells with increased cytologic atypia and few lymphocytes, (F) Metaplastic thymoma is characterized by a pseudosarcomatous stromal component with an admixed epithelial component composed of neoplastic thymic epithelial cells. Note: Not shown here are numerous other subtypes of more esoteric thymomas that do not fit into any particular classification system and have limited documented molecular data.
Lollipop plot from St. Judes PECAN database demonstrating somatic point mutations across the GTF2I gene. GTF2I gene (transcript RM_032999) is shown with overlayed data from the COSMIC database. Each individual dot corresponds to a documented mutation. The majority of the mutations are of missense type (blue dots). GTF2I p.L424H is one of the most commonly occurring mutations. Source of data and image: https://pecan.stjude.cloud/ and https://cancer.sanger.ac.uk/cosmic[77-79].
Numbers of non-synonymous mutations in atypical (type B3) thymomas. A bar plot of next-generation sequencing data is shown from 47 atypical thymomas (unpublished data) using the AmpliSeq Cancer Hotspot Panel v2 (Illumina, product number 20019161) using paired-end 2 x 300 read format with an average 500X depth per sample. The bar plot demonstrates a low number of non-synonymous mutations, with the majority of samples showing only two or fewer mutations.
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.
Steps of angiogenesis. (A) The hypoxic tumour core induces the production of hypoxia-inducible factor-1 and the consequent release of pro-angiogenic factors from tumour cells. (B) Hypoxia upregulates matrix metalloproteinase production, leading to basement membrane and perivascular extracellular matrix degradation. (C) Pro-angiogenic factors activate the endothelial cells of adjacent vessels, and a tip cell migrates along the angiogenic factor gradient. (D) This tip cell is followed by highly proliferative stalk cells, which form the new vascular tubule. (E) Platelet-derived growth factor stimulates the recruitment of pericytes and smooth muscle cells (not shown here) and the vessel matures, allowing for blood flow that stimulates further tumour growth. VEGF: Vascular endothelial growth factor; FGF: fibroblast growth factor; EGF: epidermal growth factor; MMP: matrix metalloproteinase; PDGF: platelet-derived growth factor; PDGFR: platelet-derived growth factor receptor.
Resistance mechanisms to anti-angiogenic therapies.
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.
Combined mechanism of oncolytic virus and radiation therapy.
Clinical studies on oncolytic viruses and radiation therapy
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.
CT of the thorax presents a large tumor (14.5 cm × 9.4 cm) of the posterior mediastinum infiltrating Th6-Th12 vertebrae and prolapsing into the spinal canal. CT: Computed tomography.
Mediastinal (A-C) and maxillary sinus (D-F) plasmacytomas stained immunohistochemically to visualize microvessel density (MVD) and expression of osteopontin (OPN). On hematoxylin-eosin staining, the poorly differentiated plasma cells can be seen in both extramedullary plasmacytomas (A,D), while immunostaining confirmed high grade of MVD (B,E) and high expression of OPN in plasma cells.
Brain MRI showed a 62 mm × 37 mm large tumor that infiltrated the right orbit, eroded the skull base, protruded into the middle cranial fossa suppressing the brain, and infiltrating the sphenoid and maxillary sinus. MRI: Magnetic resonance imaging.
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.
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.
Progression-free survival correlated with hormonal therapy (survival median time of HIT 33 months (95%CI: 24-42); survival median time of HT 18 months (95%CI: 12-23)) (A). Overall survival correlated with hormonal therapy [survival median time of HIT 81 months (95%CI: 64-99); survival median time of HT 62 months (95%CI: 54-70)] (B).
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.
Disease free survival for the matched cohort (n = 174).
Overall survival for the matched cohort (n = 174).
Disease free survival for open and minimally invasive Surgery (MIS) (propensity matched).
Overall survival for open and minimally invasive surgery (MIS) (propensity matched).
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.
Novel Agents Targeting Specific Biological Pathways in Diffuse Large B-cell Lymphoma. B-cell receptor (BCR) pathway is affected in both GC- and ABC-DLBCL subtypes. Chronic BCR signaling, as manifested by BCR clustering, is a hallmark of ABC-DLBCL, and mimics antigen-dependent BCR activation. Tonic BCR signaling (antigen-independent, no BCR clustering) is a characteristic of GC-DLBCL, and is NF-κB-independent. Mutations in proteins involved in BCR signaling and interrelated pathways include CD79B, CARD11, A20, and LYN. MYD88 L265P mutations lead to lymphomagenesis through activation of the TLR and IL1R pathways independent of ligand stimulation and have been highlighted in newer molecular classifications. Small molecule inhibitors (IRAK4, BTK, MALT1, PI3K, BCL2), protein degraders (IRAK4), antibody/antibody-conjugates (Polatuzumab-vedotin, Tafasitamab, magrolimab), and cellular therapy (CAR-T) have been developed in order to target these specific aberrations to mitigate lymphomagenesis. BCL2: B-cell lymphoma 2; BCR: B-cell receptor; BsAb: Bispecific antibodies; BTK: Bruton tyrosine kinase; ILR: Interleukin receptor; MALT1: mucosa-associated lymphoid tissue lymphoma translocation protein; PI3K: phosphoinositide 3-kinase; SIRPα: signal-regulatory protein alpha. Created with BioRender.com.
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) nucleosome 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.
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.
Influence of different sources of tumor and/or viral antigens on the expression of costimulatory/CCR7 molecules of DCs and their cytokine profile. (A) The number of CD80- and CD86-positive DCs in the cell population after treatment with LPS, live VV (VV), or heat-inactivated VV (hiVV) for 24 h. (B) The number of CD80-, CD86-, and CCR7-positive DCs generated five or seven days after treatment with tumor and/or viral antigens: L + LPS in violet; iL in blue; L + hiVV in green; hiVV in dark green; LPS in grey; negative control (immature DCs) in white. (C) The level of IL-12, IL-6, and TNF-α in the conditioned media of DCs loaded with tumor/viral antigens after 24 h of incubation [experimental group color set is the same as in (B)]. Data are presented as mean ± S.E.M.*P < 0.05, ***P < 0.001. DCs: Dendritic cells; VV: vaccinia virus; LPS: lipopolysaccharide.
The cytotoxicity of mouse splenocytes primed in vivo with tumor/viral antigen-loaded DCs with respect to B16 melanoma cells. The viability of B16 melanoma cells was monitored in real time with an xCELLigence system. (A, C) The viability of infected (A) or uninfected (C) B16 cells incubated alone (control) or with primed splenocytes at an effector-to-target cell ratio of 20/1 is shown as an RTCA graph. (B, D) Bar diagrams represent the cytotoxicity of primed splenocytes against infected (B) or uninfected (D) B16 melanoma cells at an effector-to-target cell ratio of 20/1 or 10/1, corresponding to the 70 h time point in (A, C). Control⁻ (intact B16 cells) in red; control⁺ (live VV infected B16 cells) in brown; DCs loaded with L + LPS in violet; with iL in blue; and with L + hiVV in green. Data are presented as mean ± S.E.M. *P < 0.05, **P < 0.01, ***P < 0.001. DCs: Dendritic cells; VV: vaccinia virus; RTCA: real-time cell analysis; hiVV: heat-inactivated vaccinia virus.
Antitumor effects of therapy based on DCs and oncolytic VV in a murine melanoma B16 model. (A) Experimental setup. B16-bearing C57BL/6 mice (n = 10) on Day 8 after tumor transplantation were subcutaneously (s/c) injected with antigen-loaded DCs (a); on Day 10 with VV intratumorally (i/t) administered (b); or on Day 8 DCs (s/c) followed by intratumoral injection with VV on Day 10 (c). (B) Progress curves of melanoma B16 growth. (C) The levels of cytokines in the blood serum of B16-bearing C57BL/6 mice receiving either of the monotherapies with DCs or oncolytic VV or combination therapy. (L + LPS)-loaded DCs in violet; iL-loaded DCs in dark blue; iL-loaded DCs + VV in blue; VV in green; and control in red. Data from two independent experiments are presented as mean ± S.E.M. *P < 0.05. DCs: Dendritic cells; VV: vaccinia virus; LPS: lipopolysaccharide.
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.
The effects of aging and extrinsic and intrinsic stressors for the bone marrow microenvironment ecosystem: implications for clonal hematopoiesis. ROS: Reactive oxygen species; HSC: hematopoietic stem cell.
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.
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.
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.
Kaplan-Meier curves of overall survival (A) and cancer-specific survival (B) according to the sites of metastases in patients with single metastatic site (Reproduced from Ref.[71]).
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.
Flow diagram of patient selection and analysis. SALV: Salvage surgery.
Overall survival of the CR and RD groups. CR: Complete response; RD: residual disease.
Overall survival of the study population stratified by serum SCC antigen levels (> 1.6 ng/mL). SCC: Squamous cell carcinoma.
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 SCC-Ag level (> 1.6 ng/mL) (OR = 2.86; P = 0.018), and metastatic node invasion (OR = 3.19; P = 0.048) were independent predictors of RD. The increased level of pretherapeutic serum squamous cell carcinoma antigen (> 1.6 ng/mL) (OR = 1.61; P = 0.022) was an independent predictor of poor survival. 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.
Expression of MT1-MMP in Sarcoma. (A) MMP-14 (the gene for MT1-MMP) expression in various cancer types (www.cbioportal.org/)[4,5]. (B) MMP-14 expression in various types of sarcoma (http://ist.medisapiens.com/)[6]. (Figure adapted from Figure 1 in Ref 7[7]).
Schematic representation of potential MT1-MMP regulatory mechanisms in OS. Several growth factors (including Wnt, PEDF, TGF, EGF) activate downstream signal transduction pathways (including SRC, RAS, PI3K/Akt, Rho/ROCK) that are responsible for the transcriptional regulation of a variety of MMPs, including MT1-MMP. EGF: Epidermal growth factor; ERK: extracellular signal-regulated kinases; PEDF: pigment epithelium-derived factor; PI3K: phosphoinositide 3-kinases; ROCK: Rho-associated protein kinase; SRC: proto-oncogene tyrosine-protein kinase; TGF: transforming growth factor.
Structures of BT1718, ICT2588 and Cy-SS-MTX.
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.
Current landscape. Current metastatic urothelial carcinoma (mUC) treatment landscape. Clinical factors which influence treatment selection, such as cisplatin-eligibility, are highlighted in green. Biomarkers are highlighted in yellow. Treatment options are shown in blue. In the second line, erdafitinib is an FDA-approved option but results from the phase III THOR trial (NCT03390504) comparing it against pembrolizumab are not yet available, thus it is shown with a dotted outline. PD-L1: Programmed death-ligand 1; ICI: immune checkpoint inhibitor; 1L: first-line; 2L: second-line; 3L: third-line.
Potential landscape. Potential metastatic urothelial carcinoma (mUC) treatment landscape. Clinical factors which influence treatment selection, such as cisplatin-eligibility, are highlighted in green. Biomarkers are highlighted in yellow. Current FDA-approved treatments are in blue while investigational treatment options are in purple. The combination of chemotherapy and atezolizumab (Chemo-ICI) showed PFS benefits in the IMvigor130 (NCT02807636) trial but OS results are still pending. The combination of enfortumab vedotin with pembrolizumab (EV/P) is being tested in various settings, including first-line against platinum chemotherapy (EV-302, NCT04223856), first-line cisplatin-ineligible (EV-103, NCT03288545), and second-line (EV-103; EV-201, NCT03219333). Other combinations and targeted therapies are under investigation. PD-L1: Programmed death-ligand 1; ICI: immune checkpoint inhibitor; 1L: first-line; 2L: second-line; 3L: third-line.
Treatment Classes. Summary of biomarkers for metastatic urothelial carcinoma by therapeutic classes.
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.
(A) Monocytic population on the CD45xSSC plot. The blue population is classic monocytes and the pink population is activated monocytes. (B) CD16 expression on monocytes (CD16xSSC). The blue population is classical monocytes and pink represents CD16-positive activated monocytes.
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.
Intraoperative nerve monitoring (IONM) has evolved into an objective tool not only for the identification but also for the preservation and prognostication of function of the recurrent laryngeal nerve in thyroid surgeries. Technical improvements have resulted in the increasing incorporation of IONM into operating rooms around the world. The importance of adherence to recommended standards is also recognized as being vital in optimizing the efficacy of IONM. The advent of continuous IONM has made real-time nerve monitoring possible, thus providing the surgeon with an ally in difficult surgeries. Additionally, as thyroid surgeries are evolving into remote access and minimally invasive procedures, so also is the applicability of IONM. This review focuses on the use of IONM for nerve monitoring in thyroidectomies for neoplastic conditions while discussing the rationale, technique, and interpretation of findings and their implications.
Meta-analysis of reported short-term (perioperative and 30-day) mortality[38].
Difference in median survival between extrapleural pneumonectomy and pleurectomy decortication among 17 studies[38].
Malignant pleural mesothelioma (MPM) is a primary solid malignancy related to inhalational asbestos exposure. Despite advances in therapy, MPM remains challenging to treat with a post-treatment survival of only 15% at 5-year. In recent years, extra-pleural pneumonectomy has decreased in popularity due to a high morbidity rate and mortality compared to pleurectomy/decortication and other therapeutic alternatives. In this review, we will discuss both procedures, outcomes, ongoing studies, and the roles of surgery in the future treatment of this disease.
Select phase III ongoing clinical trials for systemically treatment-naïve RCC
The last decade has brought about major advances in systemic therapy for patients with advanced clear cell renal cell carcinoma. The introduction of angiogenesis targeting agents, immune checkpoint inhibitors, and combinations thereof has resulted in a multitude of therapeutic standards for patients with newly diagnosed advanced disease. With the rapid adoption and increasing number of available options for patients, selection amongst treatment regimens has become complex. Further, a new balance is also being sought to optimize treatment outcomes and limit treatment-related toxicities. With a rising bar against which novel therapeutics are being measured, the field looks toward an evolved understanding of tumor biology to help pave new ways forward for individualized therapy. Here, we review pivotal studies that led to regulatory approvals and ongoing clinical trials conducted in patients with systemically untreated clear cell renal cell carcinoma and provide perspective on how newly emerging data can be integrated into this rapidly changing landscape.
Treatment flowchart of ENKL patients. *CCRT-VIPD and CCRT-VIDL regimens are included. ♰AspaMetDex regimen is included only in relapsed or refractory ENKL patients. ‡The definition of limited stage in this flowchart is a little different from that in the conventional Lugano/Ann Arbor classification. UAT: Upper aerodigestive tract; LN: lymph node; RT: radiotherapy; DeVIC: dexamethasone, etoposide, ifosfamide, carboplatin; CR: complete response; PR: partial response; PD: progressive disease; SMILE: steroid, methotrexate, ifosfamide, L-asparaginase, etoposide; L-asp: L-asparaginase; HSCT: hematopoietic stem cell transplantation.
The scheme of molecular pathways and promising treatments for ENKL patients. LMP: Latent membrane protein; EBV: Epstein-Barr virus; HDAC: histone deacetylase.
Natural killer (NK)/T cell lymphoma includes two major subtypes of disease, specifically extranodal NK/T cell lymphoma, nasal type (ENKL) and aggressive NK cell leukemia (ANKL). Both are strongly associated with Epstein-Barr virus and are prevalent in East Asia and Latin America. Except for that of limited-stage ENKL, the prognosis of both diseases was poor in the previous decade. The advent of non-anthracycline-based chemoradiotherapy has contributed to an improvement in ENKL prognosis, but there is still room for further treatment progress. Recently, the high efficacy of PD-1 antibody was reported in relapsed or refractory ENKL patients. This was later supported by the finding that PD-L1/PD-L2 genetic alterations are frequently observed in ENKL and ANKL patients. Due to the rarity of the disease, a standard treatment for ANKL remains to be established. Currently, allogeneic stem cell transplantation is the only curative treatment, and this is even applicable to chemo-resistant ANKL patients. In this review, we focus on recent treatment approaches for NK/T cell lymphomas including novel agents.
Metastasectomy was initially described in the 1970s as a therapeutic strategy for patients with metastatic renal cell carcinoma. Since that time, systemic therapy options have grown exponentially, most recently with the introduction of immunotherapy. We aimed to review the contemporary literature regarding the role of metastasectomy in the era of targeted therapy and immunotherapy. Historically, metastasectomy has benefited patients with small volume, single-organ metastases, with favorable outcomes amongst younger, healthier patients with metastases to specific sites. The interplay between the employment of metastasectomy and systemic therapy has been limited to small, retrospective series with significant patient selection bias. More recently, investigators have conducted randomized controlled trials exploring the use of targeted therapies in the adjuvant setting after metastasectomy. Initial randomized data suggested no benefit in using sorafenib in this setting, and a subsequent study demonstrated possible harm in using pazopanib after metastasectomy. However, the role of other novel systemic therapies, including immunotherapy, nor the timing of use, have been meaningfully explored. Metastasectomy appears to be a valuable therapeutic option in the properly selected patient, requiring a multi-disciplinary management strategy and, pending future trials, a multimodal treatment approach.
Reasons for exclusion.
Additional investigations and relapse in mrCR and mrPR.
Overall survival illustrated using Kaplan-Meier curves.
Clinical and histopathological characteristics
Aim: The aim of this study was to evaluate the impact of MRI performed three months after treatment on further follow-up interventions and outcome in patients with uterine cervical carcinoma treated with definitive chemoradiotherapy. Methods: Sixty consecutive women diagnosed with uterine cervical cancer FIGO 2009 stage IB1-IVA during 2011-2012 treated with definitive chemoradiotherapy/radiotherapy with curative intent at the Department of Gynaecological Oncology at Karolinska University Hospital were retrospectively included. A review of MRI reports and medical records with focus on follow-up interventions associated to imaging was performed. Results: On follow-up MRI three months post treatment, 29/60 women had complete remission (mrCR), 24/60 women had partial remission (mrPR) and 7/60 had progressive disease (mrPD). In patients with mrCR, no additional procedures were performed. The group with mrPR had 27 additional MRIs, 3 PET/CT examinations and 9 biopsy procedures, none leading to diagnosis of residual tumour. Locoregional control rate was 96% after 6.5 months (median). No patient had cervical relapse only; 2/53 had cervical relapse in combination with non-regional lymph nodes and distant relapse. There was no statistically significant difference in overall survival between patients with mrCR and mrPR (HR = 2.2, P = 0.21). Conclusion: Patients with residual changes on MRI at three months post treatment have a low risk for locoregional recurrence. If this is not recognised, follow-up MRI results in unnecessary additional procedures with low impact on treatment outcome. Further studies are needed regarding the most appropriate imaging modality and timing of post-treatment evaluation.
Temporal occurrence of signature mutations in pancreatic cancer and its effect on G1 to S transition. Driver mutations occur in KRAS of normal pancreatic cells initiating tumor formation. These mutations promote cell proliferation by upregulating cyclin D1. During the stages of low grade PanIN, INK4A mutations are acquired. It inactivates p16 tumor suppressor. As the tumor progresses to high grade PanIN, TP53 and SMAD4 are mutated mediating the inactivation of p21 and p27 CKIs. All these events deregulate G1 to S transition promoting uncontrolled proliferation and pancreatic cancer proceeds to full blown adenocarcinoma.
The gemcitabine metabolism and its mechanism of resistance. Gemcitabine is taken into cells by nucleoside transporters and converted by a series of reactions into dFCTP. It is incorporated into replicating DNA resulting in chain termination. The incorporated dFdCTP leads to dislodgement of DNA polymerase one nucleotide downstream of the dFdCTP. This extra nucleotide masks the break site and makes it imperceptible to the DNA repair enzymes leading to DNA damage[49]; whereas dFdCDP inhibits ribonucleotide reductase (RNR) enzyme leading to reduced pools of dCTP thus creating a positive feedback loop ensuring gemcitabine incorporation. The steps affected by the resistance mechanisms are starred (*) in blue.
Most commonly occurring mutations in different stages of pancreatic cancer
Mechanisms of gemcitabine resistance Factors affecting gemcitabine metabolism
Studies showing targeting different components of pancreatic stroma
Pancreatic cancer is a deadly disease and the third-highest cause of cancer-related deaths in the United States. It has a very low five-year survival rate (< 5%) in the United States as well as in the world (about 9%). The current gemcitabine-based therapy soon becomes ineffective because treatment resistance and surgical resection also provides only selective benefit. Signature mutations in pancreatic cancer confer chemoresistance by deregulating the cell cycle and promoting anti-apoptotic mechanisms. The stroma-rich tumor microenvironment impairs drug delivery and promotes tumor-specific immune escape. All these factors render the current treatment incompetent and prompt an urgent need for new, improved therapy. In this review, we have discussed the genetics of pancreatic cancer and its role in tumor evolution and treatment resistance. We have also evaluated new treatment strategies for pancreatic cancer, like targeted therapy and immunotherapy.
Local cancer fields for carcinoma of the uterine cervix determined by development. (A) Lineage specification pathway of cervical epithelial and stromal cells from nephrogenic cord precursor cells. (B) Ontogenetic anatomy of the uterine cervix displayed in a midpelvic transverse section as indicated by the sagittal inset. Mature tissue derivatives from the morphogenetic units of the three generations of precursor cells are coded light, middle, and dark grey, respectively. Mature derivatives of the Müllerian compartment and its cervical subcompartment are colored light and dark green, respectively. The color code corresponds to (A). (C) Local cancer fields of cervical carcinoma depicted as red areas in the same midpelvic plane as in (B) for stepwise malignant progression of the transformed cells from ontogenetic stage oT1 to oT4. Modified from Höckel et al.[15].
Survey of cancer field operations for the treatment of cervix carcinoma. Resection lines and resected tissues shown in the same midpelvic plane as in Figure 1 are colored dark and light red, respectively. TMMR: Total mesometrial resection; EMMR: extended mesometrial resection; LEER: laterally extended endopelvic resection.
Regional cancer fields for cervix carcinoma. First-, second-, and third-line lymph node regions are colored dark green, light green, and yellow, respectively. Cervical cancers invading the uterine corpus exhibit first-line lymph node regions both in the pelvis and in the mesenteric periaortic region (dark green stripes). (A) parietal node regions; (B) intercalated node regions. ei: External iliac; pv: paravisceral; ci: common iliac; ps: presacral; ab: aortic bifurcation; pm: perimesenteric; ir: infrarenal; mm: meosmetrial. From Höckel et al.[13].
As the current standard, surgery is applied to treat early-stage cervical cancer and selected post-irradiation pelvic relapses. Surgical therapy for local disease is based on a model of unlimited isotropic cancer cell propagation and dissection artifacts such as subperitoneal “ligaments” and “spaces”. For regional disease, the role of traditional surgery is diagnostic and eventually cytoreductive. However, the isotropic local tumor propagation model has to be rejected due to numerous inconsistencies with clinical facts. Likewise, the “ligament and space” approach to the subperitoneum is too crude and variable to accurately cover both local spread and intercalated lymph node metastases of cervical cancer. The ontogenetic cancer field model is fully in line with the locoregional spread patterns of carcinoma of the female genital tract. Developmentally derived (ontogenetic) anatomy enables unbiased and accurate dissection of the complex tissue structures within the subperitoneum. Cancer field surgery founded on these insights has a high potential to improve the treatment outcome of cervical carcinoma.
Angiogenesis mediators in CLL niches. In lymphoid tissues, CLL cells establish bidirectional interactions with immune and resident cells. Crosstalk with stromal cells induces an angiogenic switch in CLL cells. Conversely, CLL cells secrete the indicated angiogenic factors, which influence the behavior of immune and resident cells to favor angiogenesis. CLL cells are also able to recruit and induce a proangiogenic phenotype in immune cells by secreting soluble factors, such as GM/CSF (granulocyte-macrophage colony stimulating factor), CCL3 (C-C Motif Chemokine Ligand 3), CCL4 (C-C Motif Chemokine Ligand 4), and NAMPT (Nicotinamide phosphoribosyltransferase). Both CLL and stromal cells also release exosomes, whose cargo (proteins and miRNAs) allows neovascularization and angiogenesis. CLL: Chronic lymphocytic leukemia; PDGF: platelet-derived growth factor; VEGF: vascular endothelial growth factor; ANG2: angiopoietin-2; TSP-1: thrombospondin-1; MMP-9: matrix metalloproteinase-9; bFGF: basic fibroblast growth factor.
Molecular components of stromal and CLL-derived exosomes
Progression of chronic lymphocytic leukemia (CLL) is determined by the localization of malignant cells in lymphoid tissues, where they receive growth and survival signals. CLL cells produce angiogenic factors that are regulated by internal and external stimuli and whose levels vary according to the clinical stage of the disease. Stromal cellular and molecular components in CLL niches disturb the balance of pro- and antiangiogenic molecules in CLL cells and induce an angiogenic switch. Additionally, CLL cells also influence the behavior of microenvironmental cells, inducing endothelial cell proliferation and increasing the angiogenic capacity of macrophages, neutrophils, and other cells present in CLL niches. As a result of these reciprocal functional interactions, bone marrow angiogenesis is frequently increased in CLL and has been proposed as a prognostic marker in early disease. Besides their role in regulating angiogenesis, angiogenic factors are also involved in CLL cell migration and survival, all contributing to disease progression. Angiogenic factors, particularly vascular endothelial growth factor, have therefore been attractive therapeutic targets in CLL and many clinical trials were established in the past years. However, the results of these trials reveal that anti-angiogenic therapies alone are not as efficient as expected and should rather be used in combination with other treatments.
Triple-negative breast cancer (TNBC) represents the subtype of breast cancer with the most aggressive biological behavior and the worst prognosis compared to other breast cancers. Metastatic TNBC is characterized by a high proliferative index, rapid progression with metastases to the viscera and central nervous system, and generally an unfavorable prognosis with a survival of about one year. It is, therefore, necessary to identify specific targets and more effective treatments for patients with TNBC. Evidence of the effect of the tumor immune microenvironment on clinical outcomes is considered a significant issue in breast cancer therapeutics. Compared to other subtypes of breast cancer, TNBC is characterized by a higher mutational burden and is recognized as the most immunogenic among them. Based on these findings, immune checkpoint inhibition was evaluated in TNBC with encouraging results. Indeed, enhancing antitumor immunity in TNBC by blocking the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) axis or the programmed cell death-1 (PD-1) receptor/programmed death-ligand 1 (PD-L1) pathway is a promising treatment option. In this review, we examine the role of monoclonal antibodies targeting CTLA-4 and PD-1/PD-L1 in this breast cancer subtype and discuss combination approaches for early and advanced disease.
Mechanism of production of VEGF and possible mechanism of action in the pathogenesis of POEMS syndrome. VEGF: Vascular endothelial growth factor; VEGF-R: VEGF receptor.
POEMS syndrome is a rare paraneoplastic disorder due to an underlying clone of aberrant plasma cells. The name POEMS is an acronym for some of the major disease manifestations, namely polyneuropathy, organomegaly, endocrinopathy, presence of monoclonal component, and skin changes. The clinical presentation can be various and could lead to delayed diagnosis and treatment. Little is known about the pathogenic mechanism, although the neoangiogenesis due to overproduction of vascular endothelial growth factor (VEGF) by plasma cells seems to play a key role. The latest evidence suggests that the blood concentration of this cytokine correlates with the activity of the syndrome: VEGF could then be used as a therapeutic target and a marker to monitor response. Several case reports have shown the efficacy of this approach, but extended studies are required to better define the use of anti-VEGF in patients affected by POEMS syndrome.
Creating subtotal stomach reconstruction. (A) Cut line of the stomach. (B) Pull in the direction of the blue arrow to eliminate the bulge peculiar to the stomach, as indicated by the red dashed arrows. (C) Deflection of the stomach is present above the diaphragm especially at the greater curvature side, as indicated by the red dashed arrow, so we pull in the direction of the blue arrow to eliminate it. (D) The number of stiches used to fix the stomach to the diaphragmatic leg should be seven.
Example of three timings of ONS (oral nutritional supplementation).
Body weight change after surgery.
EORTC QLQ-OES18 scoring. EORTC QLQ-OES-18: The European organization for research and treatment of cancer quality of life questionnaire C30 (EORTC QLQ-30) and supplemental esophageal cancer-specific questionnaires.
Aim: Many therapeutic means have emerged to treat esophageal cancer. Factors relating to nutritional status such as body weight maintenance are important to the continuation of these treatments. In this study, we investigated methods to extend the administration of diversified treatments for patients with esophageal cancer, especially regarding measures to suppress body weight loss after surgery. Methods: We retrospectively evaluated a strategy for preventing postoperative body weight loss which can hinder the continuation of treatment via a reconstruction method aimed at safety and comfort combined with postoperative dietary intake and nutritional support for esophageal cancer patients. Results: The subjects comprised 386 patients who underwent subtotal stomach reconstruction during esophageal cancer surgery performed from January 2008 to January 2021 at Gifu University Hospital. The anastomotic leakage rate was 0.5%. By administering oral nutritional supplementation under strict rules using ENSURE® H during the perioperative period, the percentage of body weight loss after 5 years could be limited to 4.78% compared to that before treatment. Scores assessing early feeling of fullness measured using the EORTC QLQ-OES18 at postoperative months 3, 12, 24, 36, 48, and 60 were 1.7 ± 0.3, 2.0 ± 0.2, 1.2 ± 0.3, 1.3 ± 0.2, 1.5 ± 0.2, and 1.4 ± 0.1, respectively. Conclusion: Considering methods to eliminate the factors that prevent continuation of treatment may lead to sustainable treatment against esophageal cancer. Proper surgical reconstruction and nutritional management will allow maintenance of body weight and good quality of life.
Dose-depth curves of (6 MV FFF) photons (blue dotted line) vs. (130 MeV) proton (red line) vs. (270 MeV) carbon ion (orange line).
An example of a photon treatment plan (A) vs. proton treatment plan (B) of a primary RCC in the upper pole of the right kidney.
For both primary and metastatic renal cell carcinoma (RCC), treatment with stereotactic body radiotherapy (SBRT) has found its way into clinical practice. Being a non-invasive outpatient procedure, SBRT requires only a few visits to the radiation department and may be of interest for the elderly or, in the case of primary RCC, for patients who are not considered surgical candidates due to technical limitations, medical comorbidities, or in the event that the maintenance of kidney function is compromised. In the treatment landscape of oligometastatic RCC, SBRT shows promise in eradicating metastatic disease and delaying the initiation of systemic treatment. Technical advancements in the planning and administration of radiation treatment and improvements in movement management allow irradiating the tumor and/or metastatic lesions with very high doses in few fractions while maximally sparing the surrounding organs at risk, thus minimizing toxicity. In that context, the increasing availability of particle therapy, such as proton beam radiotherapy or carbon ion radiotherapy, could further optimize the delivery of radiation treatment in order to reduce toxicity and improve outcome.
Schematic representation of the EGFR signaling axis and its most important downstream targets in the AML microenvironment. EGFR ligands in the bone marrow microenvironment phosphorylate EGFR receptors on the surface of LSPC or CD8⁺ T cells, leading to the production and release of IL-3. In turn, IL-3 induces proliferation signals in LSPCs, promoting the expansion of AML cells. Direct arrows represent direct interactions, and the dotted arrow represents indirect effects. AML: Acute myeloid leukemia; LSPCs: leukemia stem/progenitor cells; IL-3: interleukin-3; EGFR: epidermal growth factor receptor; EGF: epidermal growth factor; TGF-α: transforming growth factor-alpha; AREG: amphiregulin; HB-EGF: EGF-like heparin-binding factor; BTC: betacellulin; EPR: epiregulin; SFK: src family kinases; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinase B; JAK2: Janus-activated kinase 2; JAK: Janus-activated kinase; STAT5: signal transducer and activator of transcription 5. Image created using BioRender.com.
Effects of EGFR inhibitors in AML
Despite intense research and the development of several new chemotherapeutics, the prognosis for specific subsets of acute myeloid leukemia (AML) has not improved significantly. Thus, the investigation of signaling pathways associated with the pathogenesis and progression of AML has become a source for the discovery of more effective treatments. The epidermal growth factor receptor (EGFR) belongs to the HER family of tyrosine kinase (TK) receptors and is involved in the progression of a variety of solid tumors. Although the expression of members of the HER family appears to be limited to epithelial tissues and derived neoplasms, there is evidence demonstrating their role in hematopoiesis and hematological neoplasms. In AML, preclinical studies and two anecdotal cases of response to EGFR TK inhibitors (TKI) supported the EGFR signaling pathway as a potential therapeutic target. Indeed, the presence of EGFR ligands in the bone marrow microenvironment has been shown to play pathological and regenerative/protective roles in AML. However, data reporting the expression of EGFR in AML remain controversial and the EGFR pathway inhibition in AML patients has demonstrated limited clinical significance. Further studies are required to determine the relevance of the EGFR pathway in AML biology and which patients may benefit from using EGFR TKI or other drugs that target TK receptors.
Examples of ENE measurement on hematoxylin-eosin-stained tissue samples of patients with HNSCC: (A) ENE < 2 mm with a small area of capsular disruption and a few malignant cells in the adjacent stroma (arrow); and (B) ENE > 2 mm (circle) as measured from the virtual external capsule border (C) to the farthest extend of the tumor (T).
Examples of ENE on CT: (A) macroscopic ENE of a Level 2 lymph node in a patient with HNSCC with invasion of the sternocleidomastoid muscle and subcutaneous fat tissue (arrow); and (B) less extensive (minor) ENE of a Level 2 lymph node in another patient with HNSCC with subtle infiltration of adjacent planes (arrow).
Examples of ENE on MR: (A) contrast-enhanced fat saturated T1 image; (B) T2 fat saturated image of a Level 2 lymph node in a patient with HNSCC with minor ENE with subtle enhancement and T2 hyperintensity in the tissue around the lymph node (arrows); (C) contrast-enhanced fat saturated T1; and (D) T2 fat saturated image of a Level 2/3 lymph node in a patient with HNSCC with extensive ENE all the way through the skin (circles).
The prognosis of patients with head and neck squamous cell cancer (HNSCC) decreases with the presence of extranodal extension (ENE) in lymph node metastases. Therefore, ENE was introduced in the 8th Edition TNM Classification (TNM8) for Head and Neck Cancer as a staging variable in all HPV-negative HNSCC. Patients with ENE may benefit from adjuvant or even primary chemotherapy and/or radiotherapy. There is a clear discrepancy between the definition of clinical ENE and pathological ENE. In TNM8, the radiological evaluation of ENE only plays a supportive role. Since not all patients with advanced disease will undergo a neck dissection, histologic proof of ENE will not always be available. In these cases, it would be of great help to be able to accurately determine ENE with radiological imaging. In this review, an update is given of the ability of radiological imaging to identify and grade ENE.
Duration of survival in combined SWOG and EORTC trails. Unadjusted survival curves for nephrectomy followed by interferon vs. interferon alone for patients with synchronous mRCC. O: Observation; N: nephrectomy. From Flanigan et al.[6], J Urol March 2004.
Progression-free survival of immediate vs. deferred cytoreductive nephrectomy in the SURTIME trial.
Kaplan-Meier estimates of overall survival comparing nephrectomy plus sunitinib vs. sunitinib alone in the CARMENA trial.
Cytoreductive nephrectomy has been a mainstay in treating patients with synchronous metastatic renal cell carcinoma (mRCC) for over two decades. It was supported in part by level 1 evidence that showed improved survival for patients undergoing radical nephrectomy before initiation of systemic therapy dating back almost 20 years. Since that time, the landscape of systemic therapy for mRCC has shifted mainly from IL-2 based therapy to tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor pathway, and now to immunotherapy with PD-L1 inhibitors. Given the significant advancements in systemic therapy for patients with mRCC, the role of cytoreductive nephrectomy and sequencing of treatment has been questioned. Recent randomized studies appear to disprove the theory that upfront cytoreduction improves overall survival, particularly in the TKI era, and thus treating physicians are faced with conflicting data to guide treatment decisions. The role of cytoreductive nephrectomy is in evolution, and so is the timing of surgery in selected patients. Familiarity with available evidence coupled with patient selection and targeted therapy should help to inform decision-making. Currently, an initial course of systemic therapy followed by consideration of nephrectomy in those with a favorable response may be the most prudent algorithm outside the context of a clinical trial.
Results from CheckMate 743: first-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma. Overall survival in all randomised patients (A) and in patients with epithelioid tumour histology (B) and non-epithelioid tumour histology (C). The hazard ratio in part A is stratified by sex and histology. The hazard ratios in parts B and C are from unstratified Cox proportional hazard models. This figure is quoted with permission from Baas et al.[10].
A proposed framework for the evidence-based treatment of unresectable malignant pleural mesothelioma.
Selected trials in utilizing anti-VEGF agents and immunotherapies the first-line treatment of unresectable or recurrent MPM
Patients with unresectable malignant pleural mesothelioma (MPM) have historically poor outcomes and treatment, and their treatments have been limited to palliative chemotherapy. Recent efforts to improve prognosis for these patients by adding angiogenesis inhibitors to chemotherapy led to significant benefits. However, the emergence of immunotherapy combinations for the front-line treatment has upended the standard of care and has led to the first new FDA approvals for the treatment of MPM in nearly two decades. This review aims to cover the main clinical trials in unresectable MPM with VEGF inhibitors and immunotherapy which have led to paradigm shifts in current practice. Ongoing clinical trials exploring the combination of chemo and immunotherapies show a great deal of promise, and continued support for ambitious, large-scale well-designed trials remain vital for defining the future outcomes of patients diagnosed with MPM.
The incidence of esophagogastric junction (EGJ) adenocarcinoma has been increasing in Asian countries. Despite the recent advances in multidisciplinary treatments, EGJ adenocarcinoma remains aggressive with unfavorable outcomes. Regarding surgical strategy, EGJ adenocarcinoma arises between the esophagus and the stomach, and thus tumor cells spread through the lymphatic system both upward to the mediastinum and downward to the abdomen. Nevertheless, an optimal extent of lymphadenectomy remains controversial. Regarding drug therapy, the latest topic in gastric and EGJ adenocarcinoma is trastuzumab deruxtecan, which is an antibody-drug conjugate consisting of an anti-HER2 antibody. In addition, many clinical trials have recently demonstrated the efficacy of immune checkpoint inhibitors. Meanwhile, recent advances in sequencing technology have revealed that gastroesophageal adenocarcinoma could be categorized into four molecular subtypes: epstein-Barr virusassociated, high-level microsatellite instability, genomically stable, and chromosomal instability tumors. Furthermore, these subtypes show distinct clinical phenotypes and molecular alterations. We review the current surgical strategy and drug treatment such as molecular-targeted agents, immune checkpoint inhibitors, and molecular-subtype-based therapeutic strategies in EGJ adenocarcinoma. Clinical and molecular characteristics and response to immune checkpoint inhibitors differ among molecular subtypes. Treatment strategies based on molecular subtypes may be clinically beneficial for patients with EGJ adenocarcinoma.
Adaptation of niches and hematopoietic stem cells (HSC) during the transition from healthy bone marrow to myelodysplastic syndromes (MDS). Niches and HSC interdependently generate gene regulatory networks. Niche functions gradually deteriorate with aging, tissue regeneration, and other stress. Changes in niche functions enforce enrichment of HSC subpopulations that have a growth advantage compared to healthy HSC. Pre-malignant and malignant cells remodel the niches. Bi-directional alterations are soil and seed toward MDS.
Genetic and epigenetic lesions within hematopoietic cell populations drive diverse hematological malignancies. Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms affecting the hematopoietic stem cells characterized by recurrent genetic abnormalities, myelodysplasia (a pathological definition of abnormal bone marrow structure), ineffective hematopoiesis resulting in blood cytopenia, and a propensity to evolve into acute myelogenous leukemia. Although there is evidence that the accumulation of a set of genetic mutations is an essential event in MDS, there is an increased appreciation of the contribution of specific microenvironments, niches, in the pathogenesis of MDS and response to treatment. In physiologic hematopoiesis, niches are critical functional units that maintain hematopoietic stem and progenitor cells and regulate their maturation into mature blood cells. In MDS and other hematological malignancies, altered bone marrow niches can promote the survival and expansion of mutant hematopoietic clones and provide a shield from therapy. In this review, we focus on our understanding of the composition and function of hematopoietic niches and their role in the evolution of myeloid malignancies, with an emphasis on MDS.
Treatment algorithm for treatmnet naïve metastatic ccRCC. ccRCC: Clear cell renal cell carcinoma.
The therapeutic landscape for advanced clear cell renal cell carcinoma (ccRCC) is rapidly evolving with improved knowledge of the biology of disease leading to the incorporation of a variety of antiangiogenic agents and immunotherapies. In this review, we discuss historical, current, and emerging first line treatment options for patients with advanced ccRCC. These include data with single agent vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs): sunitinib, pazopanib and cabozantinib as well as the recently reported results for the combination of lenvatinib and everolimus (mTOR inhibitor). We also discuss results of the nivolumab anti-programmed cell death (PD-1)/ipilimumab (anti-cytotoxic T lymphocyte-associated antigen 4) combination as well as emerging front-line data with nivolumab and pembrolizumab (anti-PD-1) monotherapy. Finally, we review data supporting recent approvals of TKI and anti-PD-1 or anti-PD-Ligand 1 (PD-L1) combinations (e.g., axitinib/pembrolizumab, axitinib/avelumab and cabozantinib/nivolumab) and initial outcomes of lenvatinib (multi-kinase inhibitor) and pembrolizumab. With many individual and combination treatment options and the lack of head-to-head comparisons, treatment selection will depend on the goals of therapy (endpoints) and the identification and validation of clinical and tumor-based predictive biomarkers that are linked to the desired treatment endpoints.
Murine multicolour banding (mcb) was applied on chromosomes of the KLN 205 cell line. This figure depicts the summary of 20 chromosome-specific FISH experiments as typical pseudo-colour banding. Derivative chromosomes consisting of different chromosomes are highlighted by frames and shown twice in this summarising karyogram.
aCGH results and copy number variations detected in the KLN 205 cell line are summarised here with respect to a diploid-basic karyotype. Gains are shown as green bars, losses are shown as red bars and breaks are registered as arrows. (A) The imbalances found in the cell line depicted along a murine chromosome set. (B) The results translated and projected along the human chromosome set.
Aim: Murine tumour cell lines have been used in thousands of studies. Strikingly, it is rather the rule than exception for most of them that not much is known about their genetic characteristics. The squamous cell carcinoma (SCC) cell line KLN 205 is such an example. KLN 205 cells have not been studied yet for karyotype or acquired copy number variations (CNVs), but they have been used as models for (metastatic) lung cancer, lung-SCC, non-small cell lung cancer, tongue cancer and subcutaneous SCC. Here, it was characterised cytogenomically for the first time. Methods: The cell line KLN 205 was characterised comprehensively by molecular cytogenetics using multicolour banding as well as molecular karyotyping. Based on these results, a map of the imbalances and breakpoints determined in the murine genome was translated to the human genome. Results: Here, it could be shown that this > 40-year-old cell line has a stable, approximately tetraploid karyotype comprising 77-82 chromosomes. However, there are few structural chromosomal aberrations: only six derivatives involving chromosomes 2, 3, 5, 9, 10 and/or 19 could be found. According to the literature, SCCs derived from different human tissues, as well as lung SCC and non-small cell lung cancer, display overall similar CNV patterns. Conclusion: Thus, according to the genetic profile found here, KLN 205 can be applied as a general model for human SCC; it is also suited as a model for lung cancer in general. Further molecular genetic characterisation of KLN 205 cell line may find more lung- and/or SCC-specific alterations.
Recent advances in the treatment of metastatic renal cell carcinoma expose a gap in the treatment of less advanced, localized disease. Tyrosine kinase inhibitors, which revolutionized the treatment of metastatic disease, have not provided a similar survival benefit in the adjuvant setting and currently only sunitinib is approved by the Food and Drug Administration for adjuvant treatment in patients with high-risk of recurrence based on S-TRAC disease-free survival data. The advent of immune checkpoint inhibitors has offered a fresh hope in the field of adjuvant treatment after encouraging results are seen with combination of immune checkpoint inhibitors as well as with targeted therapy in the metastatic setting. Several studies are investigating these combinations in the adjuvant setting, and it is hoped that they will bring about a better outcome for a largely unmet need in kidney cancer treatment.
Comparison between the heads of the PFS curves from Checkmate 214, Keynote 426, Checkmate 9ER, and CLEAR. Possible interpretation is reported within the text (modified from[1-4]).
We aim to describe the most recent advances in the upfront treatment of metastatic renal cell carcinoma, and to provide criteria - though often subjective - which could be used for treatment selection, by means of a critical review of the results of novel trials of immune-based combinations, coupled with personal considerations and experiences. To date, 5 immune-based combinations have been tested within large phase III trials; four of them yielded a significant overall survival benefit (Ipilimumab + Nivolumab, Pembrolizumab + Axitinib, Nivolumab + Cabozantinib and Pembrolizumab + Lenvatinib), while the combination of Avelumab + Axitinib, although reaching study primary endpoint, determined just a significant progression-free survival benefit. In terms of safety, the excess of adverse events is overall counterbalanced to the higher activity of the combinations. Overall, all the discussed immune-based combinations were ultimately approved by different regulatory authorities, and are indeed included in the most important international guidelines. Waiting for longer follow-ups and more mature trial data, as well as for real-world experiences, in the absence of validated biomarkers, our 1st line treatment choice cannot but rely on methodologically incorrect treatment comparisons, personal preferences, and experience.
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Mauricio Baptista
  • University of São Paulo
Leticia Labriola
  • University of São Paulo
Daria Raquel Queiroz De Almeida
  • University of São Paulo
Mohamed S. Aziz
  • The American University of the Caribbean School of Medicine
Stanley J. Oiseth
  • The American University of the Caribbean School of Medicine