ABSTRACT
The impact of Human Immunodeficiency Virus (HIV) infection on the tumor microenvironment (TME) of classic Hodgkin lymphoma (cHL), one of the most common co-morbidities following HIV infection, is not well understood. Here, we have employed multiplexed immunofluorescence (mIF) and spatial transcriptomic analysis to dissect the impact of viral infections (EBV, HIV/EBV) on cHL TME. Compared to HIV-EBV-, HIV-EBV+ cHL TME was characterized by higher cell densities of CD8high T cells co-expressing inhibitory receptors (PD-1, TIGIT), macrophage subsets and an in situ inflammatory molecular profile associated with increased expression of TCR and BCR cell signaling pathways. Compared to HIV-EBV+, HIV+EBV+ cHL TME was characterized by significantly less CD8high T cells co-expressing PD-1 and TIGIT, a profile concomitant with significantly increased cell densities of CD155high neoplastic cells. Significant downregulation of in situ TCR-signaling and upregulation of extracellular matrix reorganization pathways were found in HIV+EBV+ cHL TME, in line with an altered topological organization of CXCL13 and heparan sulfate, an extracellular matrix glycosaminoglycan. Our data reveal the complexity of the cellular and molecular composition of cHL TME in the presence of viral infections, with possible implications for combinatorial immunotherapies. Furthermore, the data suggest specific molecular targets and pathways for further investigation that could improve our understanding of possible mechanistic links between HIV and lymphomagenesis.
ABSTRACT
Cancer-associated fibroblasts (CAFs) have emerged as a dominant non-hematopoietic cell population in the tumour microenvironment, serving diverse functions in tumour progression. However, the mechanisms via which CAFs influence the anti-tumour immunity remain poorly understood. Here, using multiple tumour models and biopsies from cancer patients, we report that α-SMA+ CAFs can form immunological synapses with Foxp3+ regulatory T cells (Tregs) in tumours. Notably, α-SMA+ CAFs can phagocytose and process tumour antigens and exhibit a tolerogenic phenotype which instructs movement arrest, activation and proliferation in Tregs in an antigen-specific manner. Moreover, α-SMA+ CAFs display double-membrane structures resembling autophagosomes in their cytoplasm. Single-cell transcriptomic data showed an enrichment in autophagy and antigen processing/presentation pathways in α-SMA-expressing CAF clusters. Conditional knockout of Atg5 in α-SMA+ CAFs promoted inflammatory re-programming in CAFs, reduced Treg cell infiltration and attenuated tumour development. Overall, our findings reveal an immunosuppressive mechanism entailing the formation of synapses between α-SMA+ CAFs and Tregs in an autophagy-dependent manner.
Subject(s)
Autophagy , Cancer-Associated Fibroblasts , Immunological Synapses , T-Lymphocytes, Regulatory , Tumor Microenvironment , T-Lymphocytes, Regulatory/immunology , Cancer-Associated Fibroblasts/metabolism , Cancer-Associated Fibroblasts/immunology , Cancer-Associated Fibroblasts/pathology , Humans , Immunological Synapses/metabolism , Immunological Synapses/immunology , Animals , Tumor Microenvironment/immunology , Mice , Autophagy/immunology , Actins/metabolism , Autophagy-Related Protein 5/genetics , Autophagy-Related Protein 5/metabolism , Neoplasms/immunology , Neoplasms/genetics , Neoplasms/pathology , Mice, Inbred C57BL , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , Female , Mice, KnockoutABSTRACT
Purpose: We conducted a phase II randomized noncomparative window of opportunity (WOO) trial to evaluate the inhibition of cellular proliferation and the modulation of immune microenvironment after treatment with olaparib alone or in combination with cisplatin or durvalumab in patients with operable head and neck squamous cell carcinoma (HNSCC). Experimental Design: Forty-one patients with HNSCC were randomized to cisplatin plus olaparib (arm A), olaparib alone (arm B), no treatment (arm C) or durvalumab plus olaparib (arm D). The primary endpoint was to evaluate the percentage of patients in each arm that achieved a reduction of at least 25% in Ki67. Secondary endpoints included objective response rate (ORR), safety, and pathologic complete response (pCR) rate. Paired baseline and resection tumor biopsies and blood samples were evaluated for prespecified biomarkers. Results: A decrease in Ki67 of at least 25% was observed in 44.8% of treated patients, as measured by quantitative immunofluorescence. The ORR among treated patients was 12.1%. pCR was observed in 2 patients. Two serious adverse events occurred in 2 patients.Programmed death ligand 1 (PD-L1) levels [combined positive score (CPS)] were significantly higher after treatment in arms A and D. Expression of CD163 and colony-stimulating factor 1 receptor (CSF1R) genes, markers of M2 macrophages, increased significantly posttreatment whereas the expression of CD80, a marker of M1 macrophages, decreased. Conclusion: Preoperative olaparib with cisplatin or alone or with durvalumab was safe in the preoperative setting and led to decrease in Ki67 of at least 25% in 44.8% of treated patients. Olaparib-based treatment modulates the tumor microenvironment leading to upregulation of PD-L1 and induction of protumor features of macrophages. Significance: HNSCC is characterized by defective DNA repair pathways and immunosuppressive tumor microenvironment. PARP inhibitors, which promote DNA damage and "reset" the inflammatory tumor microenvironment, can establish an effective antitumor response. This phase II WOO trial in HNSCC demonstrated the immunomodulatory effects of PARP inhibitor-induced DNA damage. In this chemo-naïve population, PARP inhibitor-based treatment, reduced tumor cell proliferation and modulated tumor microenvironment. After olaparib upregulation of PD-L1 and macrophages, suggests that combinatorial treatment might be beneficial. Synopsis: Our WOO study demonstrates that preoperative olaparib results in a reduction in Ki67, upregulation of PD-L1 CPS, and induction of protumor features of macrophages in HNSCC.
Subject(s)
Antineoplastic Agents , Head and Neck Neoplasms , Humans , Squamous Cell Carcinoma of Head and Neck/drug therapy , Cisplatin/adverse effects , B7-H1 Antigen , Poly(ADP-ribose) Polymerase Inhibitors , Ki-67 Antigen , Head and Neck Neoplasms/drug therapy , Tumor MicroenvironmentABSTRACT
Primary adrenal lymphoma (PAL) is a rare entity that presents as unilateral or bilateral rapidly growing adrenal masses, with signs and symptoms most commonly related to adrenal insufficiency due to the mass effect on the surrounding tissues. Although steroeidogenesis has not been previously described in PAL, we herein report two cases of PAL presenting as adrenal incidentalomas (AIs) that demonstrated autonomous cortisol production. A 52-year-old woman presented with lumbar pain; a computed tomography (CT) scan demonstrated a left AI measuring 8.5 × 15 × 10 cm. Similarly, an 80-year-old woman presented with lumbar pain, demonstrating in a CT scan a bilateral AI (right: 9 × 6.5 cm, left: 3.6 × 3.2 cm). Both cases underwent a full hormonal evaluation according to the algorithm for the investigation of AIs, demonstrating increased 24-h cortisol excretion, suppressed fasting adrenocorticotropic hormone (ACTH) levels, and non-suppressed serum cortisol levels in both the overnight and the low-dose dexamethasone suppression tests, indicating autonomous cortisol secretion and Cushing's syndrome. In a relatively short time, both patients developed night sweats, and their clinical picture deteriorated, while the CT scans showed increased dimensions of the masses with radiological characteristics compatible to lymphoma. Both patients underwent ultrasound-guided biopsies (FNBs), revealing infiltration of the left adrenal by diffuse large B-cell lymphoma in the first case, whereas bilateral adrenal infiltration from the same histological type was noted in the second case. Subsequently, they were treated with immunochemotherapy, but the second patient died from an infection shortly after the initiation of the treatment. To our knowledge, this is the first report of PAL presenting with Cushing's syndrome due to autonomous cortisol production, indicating that neoplastic lymphoid cells in PAL might acquire the potential for steroidogenesis; therefore, more cases of PAL should be analyzed so as to further elucidate the complex pathogenesis and the natural course of this entity.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Neoplasms , Humans , Neoplasms/therapyABSTRACT
A large number of alveolar type I and II cells from the lungs of both smokers and non-smokers was collected using 40x magnification histological images from our digital archive. These images underwent a transformation into binary images of nuclear contours, followed by the application of the box-counting method. Statistical analysis revealed a significant difference in the mean box-counting dimension values between type I cells of smokers and non-smokers. However, no significant difference was observed in the mean fractal dimensions of alveolar type II cells. This study provides preliminary evidence of the impact of cigarette smoking on the nuclear shape of alveolar type I cells. Given the high toxicity of cigarette smoke to lung cells and the interconnection between morphology and function, further study is needed to understand its impact on the nuclear shape of these cells. Future research should also explore the effects of second-hand smoke on cell shape.
ABSTRACT
Glomerulonephritis is a common cause of chronic kidney disease, which has emerged as a major cause of end-stage renal disease. Autoimmune diseases, such as Systemic Lupus Erythematosus (SLE) and ANCA-associated vasculitis (AAV) are often associated with proliferative glomerulonephritis. Transforming growth factor-ß1 (TGF-ß1) is a cytokine with pleiotropic effects in chronic renal diseases, based on in vivo and in vitro studies. The Smad-dependent signalling pathway plays an important role in the regulation of renal fibrosis (excessive production of extracellular matrix [ECM]) and inflammation. However, clinical trials targeting TGF-ß1 have presented disappointing results, suggesting that the downstream signalling is quite complex. The diversity of the effects may associate with the interactions between TGF-ß1 signalling and other downstream signalling, as well as the different cellular responses, which TGF-ß1 promotes. Recently, macrophage chemoattract and epigenetic effects have also been identified as new mechanisms, wherefore TGF-ß1/Smad signalling mediates renal injury. This review provides an overview of the role of TGF-ß1/Smad signalling pathway from in vivo and in vitro studies in the pathogenesis of glomerulonephritis and particularly in proliferative glomerulonephritis, which is associated with autoimmune diseases.
ABSTRACT
Lymphoma is known to be a systemic lymphoproliferative malignancy, which is divided into two subtypes: Hodgkin lymphoma and non-Hodgkin lymphoma. Non-Hodgkin lymphoma originates from nodal and extranodal sites. In the staging of non-Hodgkin lymphoma, the liver is implicated in 40% of cases; however, primary liver non-Hodgkin lymphoma represents <1% of all non-Hodgkin lymphoma cases. Because of its rarity, it is not usually considered in the differential diagnosis of patients that present with jaundice. Since the first case of primary non-Hodgkin lymphoma of the extra-hepatic bile ducts was presented, only 42 similar cases have been reported in the English literature. The present case report describes a rare case of non-Hodgkin lymphoma of the common hepatic duct, which presented with obstructive jaundice and represented a complex differential diagnostic issue.
ABSTRACT
Colon cancer is the third most common malignancy and the fifth most frequent cause of death from neoplastic disease worldwide. At the time of diagnosis, more than 20% of patients already have metastatic disease. In the last 20 years, the natural course of the disease has changed due to major changes in the management of metastatic disease such as the advent of novel surgical and local therapy approaches as well as the introduction of novel chemotherapy drugs and targeted agents such as anti-epidermal growth factor receptor, anti-BRAF and antiangiogenics. Angiogenesis is a complex biological process of new vessel formation from existing ones and is an integral component of tumor progression supporting cancer cells to grow, proliferate and metastasize. Many molecules are involved in this proangiogenic process, such as vascular endothelial growth factor and its receptors on endothelial cells. A well-standardized methodology that is applied to assess angiogenesis in the tumor microenvironment is microvascular density by using immunohistochemistry with antibodies against endothelial CD31, CD34 and CD105 antigens. Even smaller molecules, such as the microRNAs, which are small non-coding RNAs, are being studied for their usefulness as surrogate biomarkers of angiogenesis and prognosis. In this review, we will discuss recent advances regarding the investigation of angiogenesis, the crosstalk between elements of the immune microenvironment and angiogenesis and how a disorganized tumor vessel network affects the trafficking of CD8+ T cells in the tumor bed. Furthermore, we will present recent data from clinical trials that combine antiangiogenic therapies with immune checkpoint inhibitors in colorectal cancer.
ABSTRACT
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the respiratory system can progress to a multisystemic disease with aberrant inflammatory response. Cellular senescence promotes chronic inflammation, named senescence-associated secretory phenotype (SASP). We investigated whether coronavirus disease 2019 (COVID-19) is associated with cellular senescence and SASP. METHODS: Autopsy lung tissue samples from 11 COVID-19 patients and 43 age-matched non-COVID-19 controls with similar comorbidities were analysed by immunohistochemistry for SARS-CoV-2, markers of senescence and key SASP cytokines. Virally induced senescence was functionally recapitulated in vitro, by infecting epithelial Vero-E6 cells and a three-dimensional alveosphere system of alveolar type 2 (AT2) cells with SARS-CoV-2 strains isolated from COVID-19 patients. RESULTS: SARS-CoV-2 was detected by immunocytochemistry and electron microscopy predominantly in AT2 cells. Infected AT2 cells expressed angiotensin-converting enzyme 2 and exhibited increased senescence (p16INK4A and SenTraGor positivity) and interleukin (IL)-1ß and IL-6 expression. In vitro, infection of Vero-E6 cells with SARS-CoV-2 induced senescence (SenTraGor), DNA damage (γ-H2AX) and increased cytokine (IL-1ß, IL-6, CXCL8) and apolipoprotein B mRNA-editing (APOBEC) enzyme expression. Next-generation sequencing analysis of progenies obtained from infected/senescent Vero-E6 cells demonstrated APOBEC-mediated SARS-CoV-2 mutations. Dissemination of the SARS-CoV-2-infection and senescence was confirmed in extrapulmonary sites (kidney and liver) of a COVID-19 patient. CONCLUSIONS: We demonstrate that in severe COVID-19, AT2 cells infected by SARS-CoV-2 exhibit senescence and a proinflammatory phenotype. In vitro, SARS-CoV-2 infection induces senescence and inflammation. Importantly, infected senescent cells may act as a source of SARS-CoV-2 mutagenesis mediated by APOBEC enzymes. Therefore, SARS-CoV-2-induced senescence may be an important molecular mechanism of severe COVID-19, disease persistence and mutagenesis.
Subject(s)
COVID-19 , SARS-CoV-2 , Cellular Senescence , Cytokines/metabolism , Humans , Inflammation , Interleukin-6 , Lung/metabolism , Mutagenesis , PhenotypeABSTRACT
The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsiveness to PD-1 blockade remain partly unknown. In human ovarian cancer, we show that tumor-specific CD8+ TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, which restrains their functions. Intraepithelial PD-1+CD8+ TIL can be, however, polyfunctional. PD-1+ TIL indeed exhibit a continuum of exhaustion states, with variable levels of CD28 costimulation, which is provided by antigen-presenting cells (APC) in intraepithelial tumor myeloid niches. CD28 costimulation is associated with improved effector fitness of exhausted CD8+ TIL and is required for their activation upon PD-1 blockade, which also requires tumor myeloid APC. Exhausted TIL lacking proper CD28 costimulation in situ fail to respond to PD-1 blockade, and their response may be rescued by local CTLA-4 blockade and tumor APC stimulation via CD40L.
Subject(s)
Antigen-Presenting Cells/metabolism , CD28 Antigens/metabolism , Immune Checkpoint Inhibitors/therapeutic use , Myeloid Cells/metabolism , Neoplasms/drug therapy , Stem Cell Niche/genetics , Humans , Immune Checkpoint Inhibitors/pharmacology , Neoplasms/immunologyABSTRACT
INTRODUCTION: Transforming growth factor-ß1 (TGF-ß1) is a multifunctional cytokine, with diverse roles in fibrosis and inflammation, which acts through Smad signaling in renal pathology. We intended to investigate the expression of TGF-ß/Smad signaling in glomerulonephritis (GN) and to assess its role as risk factor for progression to chronic kidney disease (CKD). METHODS: We evaluated the immunohistochemical expression of TGF-ß1, phosphorylated Smad3 (pSmad3), and Smad7 semiquantitatively and quantitatively using computerized image analysis program in different compartments of 50 renal biopsies with GN, and the results were statistically analyzed with clinicopathological parameters. We also examined the associations among their expressions, the impact of their co-expression, and their role in progression to CKD. RESULTS: TGF-ß1 expression correlated positively with segmental glomerulosclerosis (p= 0.025) and creatinine level at diagnosis (p = 0.002), while pSmad3 expression with interstitial inflammation (p = 0.024). In glomerulus, concomitant expressions of high Smad7 and medium pSmad3 were observed to be correlated with renal inflammation, such as cellular crescent (p = 0.011), intense interstitial inflammation (p = 0.029), and lower serum complement (C) 3 (p = 0.028) and C4 (p = 0.029). We also reported a significant association between pSmad3 expression in glomerular endothelial cells of proliferative GN (p = 0.045) and in podocytes of nonproliferative GN (p = 0.005). Finally, on multivariate Cox-regression analysis, TGF-ß1 expression (hazard ratio = 6.078; 95% confidence interval: 1.168-31.627; p = 0.032) was emerged as independent predictor for CKD. DISCUSSION/CONCLUSION: TGF-ß1/Smad signaling is upregulated with specific characteristics in different forms of GN. TGF-ß1 expression is indicated as independent risk factor for progression to CKD, while specific co-expression pattern of pSmad3 and Smad7 in glomerulus is correlated with renal inflammation.
Subject(s)
Renal Insufficiency, Chronic/etiology , Smad3 Protein/physiology , Smad7 Protein/physiology , Transforming Growth Factor beta1/physiology , Adult , Aged , Disease Progression , Female , Humans , Male , Middle Aged , Retrospective Studies , Signal TransductionABSTRACT
In this study, we investigate mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency (HRD). BRCA1 loss is found to lead to transcriptional reprogramming in tumor cells and cell-intrinsic inflammation involving type I interferon (IFN) and stimulator of IFN genes (STING). BRCA1-mutated (BRCA1mut) tumors are thus T cell inflamed at baseline. Genetic deletion or methylation of DNA-sensing/IFN genes or CCL5 chemokine is identified as a potential mechanism to attenuate T cell inflammation. Alternatively, in BRCA1mut cancers retaining inflammation, STING upregulates VEGF-A, mediating immune resistance and tumor progression. Tumor-intrinsic STING elimination reduces neoangiogenesis, increases CD8+ T cell infiltration, and reverts therapeutic resistance to dual immune checkpoint blockade (ICB). VEGF-A blockade phenocopies genetic STING loss and synergizes with ICB and/or poly(ADP-ribose) polymerase (PARP) inhibitors to control the outgrowth of Trp53-/-Brca1-/- but not Brca1+/+ ovarian tumors in vivo, offering rational combinatorial therapies for HRD cancers.
Subject(s)
BRCA1 Protein/deficiency , Inflammation/pathology , Membrane Proteins/metabolism , Ovarian Neoplasms/immunology , Ovarian Neoplasms/pathology , Animals , BRCA1 Protein/metabolism , Cell Line, Tumor , Chemokine CCL5/metabolism , Chromatin/metabolism , DNA/metabolism , DNA Damage , Epigenesis, Genetic , Female , Gene Silencing , Humans , Immune Checkpoint Inhibitors/pharmacology , Inflammation/complications , Inflammation/immunology , Interferons/metabolism , Mice, Inbred C57BL , Neoplasm Grading , Neovascularization, Pathologic/pathology , Ovarian Neoplasms/complications , Ovarian Neoplasms/genetics , Protein Serine-Threonine Kinases/metabolism , T-Lymphocytes/immunology , Transcription, Genetic , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Metastatic involvement of the thyroid occurs rarely, by either hematogenous spread or direct extension from adjacent organs. The most frequent metastatic tumors are clear cell, renal cell, lung, breast, and squamous cell carcinoma. The occurrence of osteosarcoma and papillary thyroid carcinoma in the same patient is rare, with only a few reported cases in the literature. On the other hand, only one case of osteosarcoma thyroid metastasis has so far been reported. We herewith present another case with metastatic osteosarcoma and multifocal papillary thyroid carcinoma presenting as a collision tumor and review the relevant literature.
ABSTRACT
Extramedullary plasmacytoma (EMP) represents a distinct yet rare entity among the plasma cell neoplasms. Given its rarity, no therapeutic consensus has been met. We report the case of a 57-year-old man with a one-year history of nasal congestion and occasional dyspnoea. Imaging showed a hypermetabolic mass in the right nasopharynx extending backward towards the adjacent oropharynx, infiltrating the epiglottis. As incisional biopsy showed histologic and immunophenotypic features consistent with plasma cell neoplasm, whereas the possibility of a marginal zone lymphoma with plasmacytic differentiation was included in the differential diagnosis. A final diagnosis of EMP was reached by using flow cytometry (FC) of a cell suspension from the neoplastic tissue. The patient received local radiotherapy (RT) which resulted to complete remission. In conclusion, flow cytometry might serve as an auxiliary method in cases where immunohistochemistry cannot differentiate between a plasma cell dyscrasia and a B-non-Hodgkin lymphoma. In cases of an established diagnosis of solitary nasopharyngeal EMP RT represents an excellent treatment modality offering prolonged disease-free survival.
Subject(s)
Plasmacytoma , Flow Cytometry , Humans , Immunohistochemistry , Male , Middle Aged , Nasopharynx/pathology , Plasmacytoma/diagnosis , Plasmacytoma/radiotherapyABSTRACT
BACKGROUND: The combination of JAK/STAT and HDAC inhibitors exerted beneficial effects in haematological malignancies, presenting promising therapeutic CTCL targets. We aim to investigate the efficacy of JAK1/2i ruxolitinib in combination with HDACi resminostat in CTCL in vitro. MATERIAL & METHODS: Non-toxic concentrations of ruxolitinib and/or resminostat were administered to MyLa (MF) and SeAx (SS) cells for 24h. Cytotoxicity, cell proliferation and apoptosis were estimated through MTT, BrdU/7AAD and Annexin V/PI assay. Multi-pathway analysis was performed to investigate the effect of JAK1/2i and/or HDACi on JAK/STAT, Akt/mTOR and MAPK signalling pathways. RESULTS: Both drugs and their combination were cytotoxic in MyLa (p<0.05) and in SeAx cell line (p<0.001), inhibited proliferation of MyLa (p<0.001) and SeAx (p<0.001) at 24h, compared to untreated cells. Moreover, combined drug treatment induced apoptosis after 24h (p<0.001) in MyLa, and SeAx (p<0.001). The combination of drugs had a strong synergistic effect with a CI<1. Importantly, the drugs' combination inhibited phosphorylation of STAT3 (p<0.001), Akt (p<0.05), ERK1/2 (p<0.001) and JNK (p<0.001) in MyLa, while it reduced activation of Akt (p<0.05) and JNK (p<0.001) in SeAx. CONCLUSION: The JAKi/HDACi combination exhibited substantial anti-tumor effects in CTCL cell lines, and may represent a promising novel therapeutic modality for CTCL patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Lymphoma, T-Cell, Cutaneous/drug therapy , MAP Kinase Signaling System/drug effects , Neoplasm Proteins/metabolism , Cell Line, Tumor , Drug Synergism , Humans , Hydroxamic Acids/agonists , Hydroxamic Acids/pharmacology , Lymphoma, T-Cell, Cutaneous/metabolism , Lymphoma, T-Cell, Cutaneous/pathology , Nitriles , Pyrazoles/agonists , Pyrazoles/pharmacology , Pyrimidines , Sulfonamides/agonists , Sulfonamides/pharmacologyABSTRACT
Approximately one-third of extranodal non-Hodgkin lymphomas involve the gastrointestinal (GI) tract, with the vast majority being diagnosed in the stomach, duodenum, or proximal small intestine. A few entities, especially diffuse large B-cell lymphoma and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, represent the majority of cases. In addition, there are diseases specific to or characteristic of the GI tract, and any type of systemic lymphoma can present in or disseminate to these organs. The recent advances in the genetic and molecular characterisation of lymphoid neoplasms have translated into notable changes in the classification of primary GI T-cell neoplasms and the recommended diagnostic approach to aggressive B-cell tumours. In many instances, diagnoses rely on morphology and immunophenotype, but there is an increasing need to incorporate molecular genetic markers. Moreover, it is also important to take into consideration the endoscopic and clinical presentations. This review gives an update on the most recent developments in the pathology and molecular pathology of upper GI lymphoproliferative diseases.
Subject(s)
Gastrointestinal Neoplasms/diagnosis , Lymphoma/diagnosis , Upper Gastrointestinal Tract/pathology , Diagnosis, Differential , Gastrointestinal Neoplasms/metabolism , Gastrointestinal Neoplasms/pathology , Humans , Immunophenotyping , Lymphoma/metabolism , Lymphoma/pathology , Upper Gastrointestinal Tract/metabolismABSTRACT
BACKGROUND: Erdheim-Chester Disease (ECD) is a clonal non-Langerhans histiocytosis, classified as a macrophage-dendritic cell neoplasm in the 2016 WHO classification. The exact cell of origin of ECD is unknown, although some limited evidence suggests that it arises from myeloid progenitors. CASE PRESENTATION: A 43-year-old patient, diagnosed with BRAF V600E mutated ECD, developed NPM1+/FLT3+ acute myeloid leukemia (AML) with wild-type BRAF, 15 months after the initial ECD diagnosis. The patient received intensive chemotherapy plus midostaurin, followed by midostaurin maintenance. Six months into maintenance, the patient remains in complete remission with low-level measurable residual disease, whereas ECD shows a sustained partial metabolic response. Molecular karyotype at several distinct timepoints, namely ECD diagnosis, AML diagnosis, and following treatment of AML, highlighted a molecular signature, indicative of a persistent, underlying clonal hematopoiesis. CONCLUSION: This case report suggests that ECD and AML might represent an expansion of two distinct clones in a background of clonal hematopoiesis, indicating their shared origin. Moreover, molecular karyotype might serve as a strong, inexpensive tool for revealing clonal hematopoiesis in cases of negative targeted next-generation sequencing. Finally, the moderate response of ECD to midostaurin suggests that kinase inhibition might have a potential role in ECD treatment.
ABSTRACT
Preclinical data suggest that head and neck squamous cell carcinoma (HNSCC) is a profoundly immunosuppressive disease, characterized by abnormal secretion of proinflammatory cytokines and dysfunction of immune effector cells. Based on landmark phase III trials, two anti-Programmed Cell Death-1 (PD-1) antibodies, pembrolizumab and nivolumab have been approved for HNSCC by FDA and EMEA in the recurrent/metastatic setting; in addition, pembrolizumab has recently received FDA and EMEA approval as first line treatment. In clinical practice, only a minority of patients with HNSCC derive benefit from immunotherapy and the need for the discovery of novel biomarkers to optimize treatment strategies is becoming increasingly more relevant. Although currently only PD-L1 is widely used as a predictive biomarker for response to immune checkpoint inhibitors in HNSCC, there are many ongoing trials focusing on the identification of new biomarkers. This review will summarize current data on emerging biomarkers for response to immunotherapy in HNSCC.