Aggressive Relapse Research Articles

Ангиомиксома полового члена: редкий клинический случай

Angiomyxoma is a rare benign tumor prone to aggressive and invasive growth and relapse. Very few case reports of tumors with this morphology have been published in the world literature. In this paper, we report a rare case of penile angiomyxoma, which illustrates that any preoperative examination does not allow physicians to suspect this tumor type. This fact makes physicians be alert for cancer and use the active surgical tactics even if a tumor is supposed to be benign.

Advances in histone deacetylase inhibitors in targeting glioblastoma stem cells.

Glioblastoma multiforme (GBM) is a lethal grade IV glioma (WHO classification) and widely prevalent primary brain tumor in adults. GBM tumors harbor cellular heterogeneity with the presence of a small subpopulation of tumor cells, described as GBM cancer stem cells (CSCs) that pose resistance to standard anticancer regimens and eventually mediate aggressive relapse or intractable progressive GBM. Existing conventional anticancer therapies for GBM do not target GBM stem cells and are mostly palliative; therefore, exploration of new strategies to target stem cells of GBM has to be prioritized for the development of effective GBM therapy. Recent developments in the understanding of GBM pathophysiology demonstrated dysregulation of epigenetic mechanisms along with the genetic changes in GBM CSCs. Altered expression/activity of key epigenetic regulators, especially histone deacetylases (HDACs) in GBM stem cells has been associated with poor prognosis; inhibiting the activity of HDACs using histone deacetylase inhibitors (HDACi) has been promising as mono-therapeutic in targeting GBM and in sensitizing GBM stem cells to an existing anticancer regimen. Here, we review the development of pan/selective HDACi as potential anticancer agents in targeting the stem cells of glioblastoma as a mono or combination therapy.

Management of patients with multiple myeloma in the era of COVID-19 pandemic: a consensus paper from the European Myeloma Network (EMN).

Patients with multiple myeloma (MM) seem to be at increased risk for more severe COVID-19 infection and associated complications due to their immunocompromised state, the older age and comorbidities. The European Myeloma Network has provided an expert consensus statement in order to guide therapeutic decisions in the era of the COVID-19 pandemic. Patient education for personal hygiene and social distancing measures, along with treatment individualization, telemedicine and continuous surveillance for early diagnosis of COVID-19 are essential. In countries or local communities where COVID-19 infection is widely spread, MM patients should have a PCR test of nasopharyngeal swab for SARS-CoV-2 before hospital admission, starting a new treatment line, cell apheresis or ASCT in order to avoid ward or community spread and infections. Oral agent-based regimens should be considered, especially for the elderly and frail patients with standard risk disease, whereas de-intensified regimens for dexamethasone, bortezomib, carfilzomib and daratumumab should be used based on patient risk and response. Treatment initiation should not be postponed for patients with end organ damage, myeloma emergencies and aggressive relapses. Autologous (and especially allogeneic) transplantation should be delayed and extended induction should be administered, especially in standard risk patients and those with adequate MM response to induction. Watchful waiting should be considered for standard risk relapsed patients with low tumor burden, and slow biochemical relapses. The conduction of clinical trials should continue with appropriate adaptations to the current circumstances. Patients with MM and symptomatic COVID-19 disease should interrupt anti-myeloma treatment until recovery. For patients with positive PCR test for SARS-CoV-2, but with no symptoms for COVID-19, a 14-day quarantine should be considered if myeloma-related events allow the delay of treatment. The need for surveillance for drug interactions due to polypharmacy is highlighted. The participation in international COVID-19 cancer registries is greatly encouraged.

Clinicopathological and Prognostic Characteristics of Malaysian Triple Negative Breast Cancer Patients Undergoing TAC Chemotherapy Regimen.

Triple negative breast cancer (TNBC) is associated with aggressive tumour phenotype and early tumour relapse following diagnosis. Generally, clinicopathological features such as tumour size, patient's age at diagnosis, tumour histology subtypes, grade and stage, involvement of lymph nodes, and menopausal status are commonly used for predicting disease progression, prospects of recurrence, and treatment response. Prognostic value of clinicopathological features on Malaysian TNBC patients is limited. Thus, this study is aimed at investigating the association of clinicopathological features on disease-free survival (DFS) and overall survival (OS) of Malaysian TNBC patients undergoing TAC chemotherapy. Seventy-six (76) immunohistochemistry-confirmed TNBC patients were recruited. The clinicopathological features of TNBC patients were collected and recorded. Kaplan-Meier and log-rank followed by a Cox proportional hazard regression model were performed to evaluate the TNBC patients' survival. Out of 76 TNBC patients, 25 were chemoresistant and 51 were chemoresponders to the TAC chemotherapy regimen. The overall 5-year cumulative DFS and OS of TNBC patients were 63.5% and 76.3%, respectively. Multivariate Cox analysis demonstrated that medullary and metaplastic histology subtypes and positive axillary lymph node metastasis were significant prognostic factors associated with relapse with adjusted HR: 5.76, 95% CI: 2.35, 14.08 and adjusted HR: 3.55, 95% CI: 1.44, 8.74, respectively. Moreover, TNBC patients with medullary and metaplastic histology subtypes and positive axillary lymph node metastases had a higher risk to death than patients who had infiltrating ductal carcinoma and negative axillary lymph node metastasis (adjusted HR: 8.30, 95% CI: 2.38, 28.96 and adjusted HR: 6.12, 95% CI: 1.32, 28.42, respectively). Our results demonstrate the potential use of medullary and metaplastic histology subtype and positive axillary lymph node metastasis as a potential biomarker in predicting relapse and survival of the TNBC patients. This warrants further studies on intensification of chemotherapy and also identification and development of targeted therapy to reduce relapses and improve survival of TNBC patients.

Subclonal NT5C2 mutations are associated with poor outcomes after relapse of pediatric acute lymphoblastic leukemia

AbstractActivating mutations in cytosolic 5′-nucleotidase II (NT5C2) are considered to drive relapse formation in acute lymphoblastic leukemia (ALL) by conferring purine analog resistance. To examine the clinical effects of NT5C2 mutations in relapsed ALL, we analyzed NT5C2 in 455 relapsed B-cell precursor ALL patients treated within the ALL-REZ BFM 2002 relapse trial using sequencing and sensitive allele-specific real-time polymerase chain reaction. We detected 110 NT5C2 mutations in 75 (16.5%) of 455 B-cell precursor ALL relapses. Two-thirds of relapses harbored subclonal mutations and only one-third harbored clonal mutations. Event-free survival after relapse was inferior in patients with relapses with clonal and subclonal NT5C2 mutations compared with those without (19% and 25% vs 53%, P < .001). However, subclonal, but not clonal, NT5C2 mutations were associated with reduced event-free survival in multivariable analysis (hazard ratio, 1.89; 95% confidence interval, 1.28-2.69; P = .001) and with an increased rate of nonresponse to relapse treatment (subclonal 32%, clonal 12%, wild type 9%, P < .001). Nevertheless, 27 (82%) of 33 subclonal NT5C2 mutations became undetectable at the time of nonresponse or second relapse, and in 10 (71%) of 14 patients subclonal NT5C2 mutations were undetectable already after relapse induction treatment. These results show that subclonal NT5C2 mutations define relapses associated with high risk of treatment failure in patients and at the same time emphasize that their role in outcome is complex and goes beyond mutant NT5C2 acting as a targetable driver during relapse progression. Sensitive, prospective identification of NT5C2 mutations is warranted to improve the understanding and treatment of this aggressive ALL relapse subtype.

Abstract A123: Reversal of glucocorticoid resistance in pediatric acute lymphoblastic leukemia is dependent on restoring BIM expression

Abstract Introduction: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Glucocorticoids (e.g. dexamethasone, prednisolone) form a critical component of chemotherapy regimens for pediatric ALL and initial resistance to glucocorticoid therapy is predictive of poor outcome. Acquired resistance to glucocorticoids is common at relapse and is disparate compared with other chemotherapeutic drugs used in the treatment of pediatric ALL. Glucocorticoids induce apoptosis in lymphoid cells which is mediated through the glucocorticoid receptor (GR). Resistance to glucocorticoids in pediatric ALL is associated with upregulation of the oncogene C-MYC and failure to induce the proapoptotic gene BIM. The purpose of this study was to identify small molecules that are able to reverse glucocorticoid resistance in pediatric ALL patient-derived xenografts (PDXs). Methods: A 40,000 compound high-throughput screening (HTS) campaign was carried out to identify compounds that potentiated the cytotoxicity of dexamethasone against a pediatric ALL PDX derived from a patient with aggressive and fatal relapse. Cytotoxicity assays were carried out by alamarBlue assay. Gene expression analysis was carried out using Illumina microarrays. mRNA and protein analysis was carried out by RT-PCR and immunoblotting, respectively. Results: The HTS campaign identified a novel glucocorticoid sensitiser, 2-((4,5-dihydro-1H-imidazol-2-yl)thio)-N-isopropyl-N-phenylacetamide (GCS-3). The sensitizing effect was specific to glucocorticoids, with synergy observed when GCS-3 was combined with dexamethasone or prednisolone, but not with other chemotherapeutic drugs. Synergy was observed in a range of dexamethasone-resistant and -sensitive xenografts representative of B-ALL, T-ALL, early T-cell precursor ALL and Philadelphia chromosome positive ALL. GCS-3 required a functional GR to sensitise ALL xenografts to dexamethasone. Gene expression analysis showed that GCS-3 in the presence of dexamethasone upregulated a previously published gene expression signature induced by glucocorticoid treatment of B-ALL patients (Rhein et al. Leukemia, 2007, 21:897-905). Moreover, GCS-3 in combination with dexamethasone significantly downregulated C-MYC and upregulated BIM expression in a glucocorticoid-resistant ALL xenograft. Treatment with the GR antagonist, RU486, significantly abrogated the cytotoxic effects of the GCS-3/dexamethasone combination. Although RU486 increased C-MYC expression in the dexamethasone treated cells, there was no increase in C-MYC expression in the GCS-3/dexamethasone combination. RU486 suppressed the marked induction of BIM following treatment with the GCS-3/dexamethasone combination, indicating that BIM upregulation is critical for the cytotoxicity of the GCS-3/dexamethasone combination. The GCS-3/dexamethasone combination significantly increased binding of the GR to an intronic binding site at the BIM locus which is associated with BIM transcription and glucocorticoid sensitivity in pediatric ALL. Conclusion: This study describes the potential of the novel glucocorticoid sensitizing agent, GCS-3, as a biological tool to understand glucocorticoid action and resistance. Citation Format: Richard B Lock, Cara E Toscan, Duohui Jing, Chelsea Mayoh. Reversal of glucocorticoid resistance in pediatric acute lymphoblastic leukemia is dependent on restoring BIM expression [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A123. doi:10.1158/1535-7163.TARG-19-A123

Early Salvage Treatment with Second-Generation Novel Agents at Biochemical Relapse Prolongs Overall Survival: A Real-World Single Center Experience

In Multiple Myeloma (MM) relapse can be defined according to disease aggressiveness and the presence of clinical symptoms. Aggressive relapse can occur even at biochemical level, characterized by a rapid and relevant increase of monoclonal component or LDH, or at clinical level, defined by the presence of extramedullary disease, acute renal injury or progression to secondary plasma cell leukemia. To identify the clinical outcome upon treatment with second generation novel agents (pomalidomide, carfilzomib) and monoclonal antibodies (elotuzumab, daratumumab), we collected evidence of the best timing in providing early salvage treatment to RRMM. We reviewed files of 128 R/R MM (58% males, median age 64 years, range 43-83), treated at biochemical (N=54, 42%) or clinical relapse (N=74, 58%) between January 2017 and December 2019 in our single Institution. Median number of previous lines was 2 (1-9), including autologous stem cell transplantation (ASCT) in half of cases. FISH was repeated before to start the second-generation drugs, and it was available in 53 cases: 11 carried on high-risk (del 17p, t4;14 or t14;16) and 42 standard-risk cytogenetics, without any additional marker compared to the matched sample at diagnosis. Our series included patients who received IMiD-s based treatments, alone (pomalidomide, N= 76, 59%) or in combination with proteasome inhibitors (carfilzomib, lenalidomide and dexamethasone, KRd, N= 43, 33%) or monoclonal antibodies (daratumumab-lenalidomide, N= 3 elotuzumab-lenalidomide, N 12); 16 patients (%) received Daratumumab in monotherapy, and N=16 associated to bortezomib. After a median follow-up of 19.2 months, 66 (52%) patients were alive and 33 (25%) received a further line of therapy due to progression. In multivariable analysis only the type of relapse (biochemical versus clinical) and refractory status were independent predictors of overall survival (p&lt;0.0001). Longer overall survival (OS) was associated to treatment at biochemical relapse (27.8 vs 15.2 months, p=0.0005), in relapsed patients instead of relapsed and refractory (34.1 vs 19.3 months, p=0.0004). Patients who received less than 3 lines of therapy or carrying standard-risk cytogenetics had longer OS (respectively, 33.6 vs 19.1 months, p=0.002 and 20.4 vs 11.2 months, p=0.04) without any significant difference due to previous ASCT or the type of second-generation treatment chosen. In 20/33 individuals who further progressed under novel agents treatment we found second biochemical relapse was anticipated by doubling sFLC ratio one month before. In 5 patients who developed extramedullary lesions (EMD) an increase of sFLC always preceded the diagnosis ofEMD relapse irrespective of M-spike measurement. Taken together, our findings suggest that using second generation novel agents can improve outcome even in heavily pretreated patients. Earlier treatment at biochemical asymptomatic relapse is associated with longer OS. Longitudinal monitoring of sFLC assay ratio can anticipateearly detection of aggressive and/or EMD relapse in the RRMM setting in real life. Disclosures Del Fabro: Janssen: Consultancy. Di Raimondo:Takeda: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Conticello:Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

Serum Free Light Chain Assay As an Additional Tool for Defining Response and Progressive Disease in Immunoglobulin Secretory Multiple Myeloma

Serum Free Light Chain Assay As an Additional Tool for Defining Response and Progressive Disease in Immunoglobulin Secretory Multiple Myeloma

Genomic Profiling of Mantle Cell Lymphoma Suggests Poor-Risk Profile Is Present at Diagnosis and Does Not Arise By Tumor Evolution

Genomic Profiling of Mantle Cell Lymphoma Suggests Poor-Risk Profile Is Present at Diagnosis and Does Not Arise By Tumor Evolution

Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

TMIC-45. RADIATION THERAPY-INDUCED EPIGENETIC REWIRING PROMOTES GLIOMA PHENOTYPIC PLASTICITY

Abstract Therapeutic failure and relapse of glioblastoma (GBM) tumors is attributed to a fraction of chemo- and radiation-resistant glioma stem cells (GSCs). Growing evidence indicates that GSCs and tumor cells elicit phenotypic plasticity in response to radiation-therapy (RT) such as de-differentiation and acquisition of a GSC-like state, and epithelial-to- mesenchymal transition (EMT) leading to more aggressive tumors and relapse. Preliminary findings from our laboratory indicate that RT also promotes vascular transdifferentiation of glioma cells, and the transdifferentiated vascular cells are essential for tumor growth in vivo. Together, these studies suggest that RT alters the dynamic equilibrium between “stemness” and “differentiation” states of the tumor cells. Transition between different cellular states or phenotypes required global alterations in chromatin landscape and associated transcriptional changes, and this epigenetic rewiring process is observed in several stages of oncogenesis and metastatic transformation. We hypothesized that epigenetic rewiring occurs in GBM tumor cells that survive radiation-induced DNA damage altering their cell fate that leads to diverse phenotypic outcomes such as EMT, acquisition of stem-like state and vascular transdifferentiation. Preliminary findings from bulk ATAC- and RNA-sequencing of patient-derived gliomasphere lines show that RT increases chromatin accessibility, and reduces expression of several histone components and their chaperones. Gene ontology and transcription factor motif analyses of open chromatin regions showed an enrichment of factors and terms related to pluripotency, vascular specification and stem cell differentiation. Furthermore, single-cell RNA-sequencing of radiated and control tumor cells also showed an increase in vascular markers expressing-clusters, and reduction in expression of histone components post radiation supporting our hypothesis that RT causes epigenetic rewiring in glioma cells leading to diverse phenotypic outcomes including vascular transdifferentiation. Ongoing experiments are aimed at determining the precise molecular mechanism by which RT causes chromatin rewiring, and identifying candidates involved in this process for therapeutic targeting.

KMT2A rearranged acute lymphoblastic leukaemia: Unravelling the genomic complexity and heterogeneity of this high-risk disease.

KMT2A rearranged (KMT2Ar) acute lymphoblastic leukaemia (ALL) is a high-risk genomic subtype, with long-term survival rates of less than 60% across all age groups. These cases present a complex clinical challenge, with a high incidence in infants, high-risk clinical features and propensity for aggressive relapse. KMT2A rearrangements are highly pathogenic leukaemic drivers, reflected by the high incidence of KMT2Ar ALL in infants, who carry few leukaemia-associated cooperative mutations. However, transgenic murine models of KMT2Ar ALL typically exhibit long latency and mature or mixed phenotype, and fail to recapitulate the aggressive disease observed clinically. Next-generation sequencing has revealed that KMT2Ar ALL also occurs in adolescents and adults, and potentially cooperative genomic lesions such as PI3K-RAS pathway variants are present in KMT2Ar patients of all ages. This review addresses the aetiology of KMT2Ar ALL, with a focus on the cell of origin and mutational landscape, and how genomic profiling of KMT2Ar ALL patients in the era of next-generation sequencing demonstrates that KMT2Ar ALL is a complex heterogenous disease. Ultimately, understanding the underlying biology of KMT2Ar ALL will be important in improving long-term outcomes for these high-risk patients.

Sub-Ventricular Zone Contact Influences Survival and Relapse Pattern in Glioblastoma

Several preclinical and retrospective data have described a relationship between glioblastomas (GB) contacting the SVZ and greater aggressiveness with decreased survival rates. We aimed to identify prognostic factors of survival and patterns of recurrence among patients with GB regarding anatomical relation between lesion and SVZ. 133 patients with GB treated between 2010 and 2016 were identified. All patients received surgical resection followed by temozolomide-based chemoradiation. 109 patients (82%) received a normofractionated radiotherapy scheme of 54-60 Gy and 24 (18%) received a hypofractionated scheme of 40,05 Gy (2,67 Gy/fr). Lesions were classified regarding their anatomical relation with SVZ using a dichotomic classification and Lim’s classification considering contact with both SVZ and cerebral cortex (Group I: SVZ+/Cortex+; Group II: SVZ +/Cortex-; Group III: SVZ -/Cortex+ and Group IV: SVZ -/Cortex-). Median follow-up, progression free survival (PFS) and overall survival (OS) were 18.6 months (95%CI 15.9-21.2), 7.5 months (95%CI 6.7 - 8.3) and 13.9 months (95%CI 10.9 - 16.9) respectively. Sixty-eight patients (51,13%) presented with anatomical contact with SVZ. Regarding Lim’s classification, the following rates were registered: SVZ+/Cortex+ (21,81%); SVZ +/Cortex- (29,32%); SVZ -/Cortex+ (33,08%) and SVZ -/Cortex- (15,79%). On univariate analysis, initial contact with SVZ was poor prognostic factor for PFS (6.1 vs. 8.7 months; p=0,006) and for OS (10.6 vs. 17.9 months; p=0,037), remaining statistically significant in multivariate analyses for PFS by both dichotomic and Lim’s classification systems. Contact with SVZ was related with higher proportion of aggressive clinical progressions (30.9% vs. 11.3%; p=0.007) and higher percentage of contralateral relapses (23.4% vs. 9.1%; p=0.048) Our results suggest that contact with SVZ might be an independent poor prognostic factor for PFS and that it is associated with reduced OS and more aggressive and contralateral relapses.

55. A case for continuing tocilizumab beyond 12 months in giant cell arteritis?

55. A case for continuing tocilizumab beyond 12 months in giant cell arteritis?

PB2189 FREE LIGHT CHAINS IN MULTIPLE MYELOMA: IS IT TIME TO EXTEND THEIR APPLICATION?

Background:Free Light Chain (FLC) assay is used for multiple myeloma screening, prediction of risk progression and response assessment as indicated by IMWG guidelines, particularly to define stringent complete response (sCR). The assay is also recommended in cases of unmeasurable (non‐secretory, NS) or low values of M‐protein (oligo‐secretory, OS).Aims:Here we describe the value of FLC assay in predicting extramedullary relapse in four MM patients.MethodsDuring the course of therapy, FLC was monitored routinely on a monthly basis.Results:An OS MM IgG κ patient (first case) started in May 2017 4th line KRd therapy, due to new lytic lesions, with negative BM biopsy. During the course of therapy, sIFE remained negative, while sFLC continued to rise (May 2017–March 2018: sFLC κ 175 vs 340 mg/L, rFLC 4.2 vs 19.9). In March 2018 a right femur mass appeared and histology, confirmed EMD relapse. Patient underwent surgical removal and rFLC returned within normal range (1.3).Considering that it was the only site of disease, KRD regimen was restarted in June 2018 for four more cycles. Unfortunately, in November 2018 the knee mass reappeared, and, once again, sFLC was altered (FLC κ 124 mg/L, ratio 25), with negative sIFE. Biopsy of the mass confirmed EMD relapse, BM biopsy remained negative.A patient with IgG κ MM (second case) started in May 2017 2nd line KRd therapy for disease progression, confirmed by BM biopsy. A partial response was obtained quickly, but since March 2018 a progressive rise of rFLC was noticed (March–September 2018: rFLC 0.67 vs 1.67), and it anticipated of 5 months the increase of MP (August 2018). In June 2018 patient complained vague gastrointestinal symptoms and in September a CT scan revealed hepatic nodularities, confirmed by biopsy as hepatic EMD.A LC MM λ patient (third case) started in March 2017 KRd as 2nd line treatment for disease progression (MP 0.7 g/dL, sFLC λ 2000 mg/dL, rFLC 171), with positive BM biopsy. Patient obtained CR after the first cycle, but during the treatment in June 2018 sFLC started increasing and in July alteration of liver and bilirubin tests was noticed, without any clinical sign, always with negative sIFE. In October 2018 sIFE became positive and in November MP reappeared (0.37 g/dL) while both the sFLC (June–November 2018: sFLC λ 53 vs 207 mg/dL; rFLC 6 vs 68) and the liver tests continued to rise. A solid hepatic mass was revealed and biopsy confirmed an EMD relapse.A MM IgA λ patient (fourth case) diagnosed with biopsy of soft paravertebral tissues, was treated with 1st line VMP treatment in September 2018. During the treatment the patient complained sight loss and a CT scan showed the presence of a right ocular mass. The MP was reduced while sFLC increased (September–October 2018: MP 2.4 vs 0.2 g/dL; sFLC λ 158 vs 263 mg/dL; rFLC 5.7 vs 29.4). Biopsy confirmed an aggressive EMD relapse and the patient started 2nd line KRD treatment in October 2018. A complete remission was obtained with ocular mass regression, negative sIFE and improvement of FLC.Unfortunately, in January 2019 during the fourth cycle, a cutaneous lesion appeared on the right tibia, confirmed as EMD relapse. While both the sIFE and BM biopsy remained negative, a slight increase of sFLC was noticed, although always within range.Summary/Conclusion:In all four cases an increase of FLC always preceded the diagnosis of EMD relapse irrespective of MP measurement. We therefore recommend serial use of sFLC assay, particularly in heavily pretreated patients for early detection of aggressive and/or EMD relapse.

New Insights into the Implication of Epigenetic Alterations in the EMT of Triple Negative Breast Cancer.

Breast cancer is the most common cancer and leading cause of cancer death among women worldwide, encompassing a wide heterogeneity of subtypes with different clinical features. During the last two decades, the use of targeted therapies has emerged in clinical research in order to increase treatment efficiency, improve prognosis and reduce recurrence. However, the triple negative breast cancer (TNBC) subtype remains a clinical challenge, with poor prognosis since no therapeutic targets have been identified. This aggressive breast cancer entity lacks expression of oestrogen receptor (ER) and progesterone receptor (PR), and it does not overexpress human epidermal growth factor receptor 2 (HER2). The major reason for TNBC poor prognosis is early therapeutic escape from conventional treatments, leading to aggressive metastatic relapse. Metastases occur after an epithelial-mesenchymal transition EMT of epithelial cells, allowing them to break free from the primary tumour site and to colonize distant organs. Cancer-associated EMT consists not only of acquired migration and invasion ability, but involves complex and comprehensive reprogramming, including changes in metabolism, expression levels and epigenetic. Recently, many studies have considered epigenetic alterations as the primary initiator of cancer development and metastasis. This review builds a picture of the epigenetic modifications implicated in the EMT of breast cancer. It focuses on TNBC and allows comparisons with other subtypes. It emphasizes the role of the main epigenetic modifications lncRNAs, miRNAs, histone and DNA- modifications in tumour invasion and appearance of metastases. These epigenetic alterations can be considered biomarkers representing potential diagnostic and prognostic factors in order to define a global metastatic signature for TNBC.

Recent advances in the first-line treatment of follicular non-Hodgkin lymphoma.

Follicular lymphoma (FL) is the most common type of indolent B-cell lymphoma. Twenty years ago, FL was considered an indolent lymphoma with a long survival time but without a high rate of complete remission with chemotherapies. The use of rituximab has improved the response and survival of patients with this lymphoma. More recently, development of biological knowledge and use of targeted drugs have offered new perspectives, including improvement of response rates and survival with chemo-free treatment strategies. In 2019, patients have a 10-year overall survival probability of over 70%. Histological transformation to more aggressive lymphoma and treatment relapses remain a medical challenge, especially for patients relapsing within two years. This article will review the recent advances in the treatment of FL. As the use of new drugs is directly related to the development of biological aspects, we will first summarize recent advances in biological aspects of FL.

Roles of SETD2 in Leukemia-Transcription, DNA-Damage, and Beyond.

The non-redundant histone methyltransferase SETD2 (SET domain containing 2; KMT3A) is responsible for tri-methylation of lysine 36 on histone H3 (H3K36me3). Presence of the H3K36me3 histone mark across the genome has been correlated with transcriptional activation and elongation, but also with the regulation of DNA mismatch repair, homologous recombination and alternative splicing. The role of SETD2 and the H3K36me3 histone mark in cancer is controversial. SETD2 is lost or mutated in various cancers, supporting a tumor suppressive role of the protein. Alterations in the SETD2 gene are also present in leukemia patients, where they are associated with aggressive disease and relapse. In line, heterozygous SETD2 loss caused chemotherapy resistance in leukemia cell lines and mouse models. In contrast, other studies indicate that SETD2 is critically required for the proliferation of leukemia cells. Thus, although studies of SETD2-dependent processes in cancer have contributed to a better understanding of the SETD2–H3K36me3 axis, many open questions remain regarding its specific role in leukemia. Here, we review the current literature about critical functions of SETD2 in the context of hematopoietic malignancies.

Pathological profiles and clinical management challenges of breast cancer emerging in young women in Indonesia: a hospital-based study

BackgroundBreast cancer diagnosed at a young age is often associated with aggressive biology, advanced stage, and unfavorable prognosis. The median age of breast cancer diagnosis in Indonesia is younger (48 vs. 68 years-old in Europe) with a relatively higher proportion of patients younger than 40 years old. Although prognosis and outcome of young breast cancer are well studied in developed nations, research evaluating biological characteristics, delivered treatment, and clinical outcomes is very limited in Indonesia.MethodsWe analyzed all breast cancer patients who underwent surgery at Dr. Sardjito Hospital, Indonesia, in 2012–2017. Details of pathology profiles, treatment administrated, and outcomes, as well as reproductive factors among patients younger than 40 years old, were collected and analyzed. Kaplan-Meier curve was used to assess conditional survival based on baseline characteristics.ResultsFrom the total of 1259 breast cancer patients (median age 51 years), 144 (11.4%) were younger than 40 years old (median age 37 years). Of these young patients, 19 (13.2%) were bilateral and 92 (64%) were diagnosed in advanced stages (stages IIIA-C and IV). Median tumor diameter was 5.5 cm and nodal infiltration was present in 73%. Distant metastasis was found in 16% at the time of diagnosis. Moderate and poor differentiation of tumor were 20.8 and 78.5%, respectively, and lymphovascular invasion was found in 90.3%. Around 40% were hormone receptor-positive, 30.6% human epidermal growth factor receptor 2 positive, and 38.2% triple negative. Patients underwent radical surgery in 121 cases (84%) and breast conserving surgery in 7 cases (4.9%). Adjuvant chemotherapy was administrated in 68% and hormonal therapy in 34%. Progression-free survival was significantly shorter in patients with advanced stage, skin and chest wall involvement (T4), positive lymph node infiltration, positive hormonal receptor, and triple negative subtype (log-rank Mantel-Cox tests, p < 0.05).ConclusionWe found a high frequency of young breast cancer with biologically more aggressive tumors, late diagnosis, frequent relapse, and poor prognosis. Further actions to improve clinical management and meet psychosocial needs in young breast cancer patients are warranted.

Peripheral Ossifying Fibroma: A Case Report and Review of Literature

Peripheral ossifying fibroma (POF) is an infrequently occurring, slowly progressing, innocuous, nodular overgrowth of the gingiva, which belongs to the category of the “reactive lesions of the gingiva.” There are several such overgrowths with similar clinical manifestations, but diverse etiology and histopathological features, thus presenting a challenge for the clinician. Thorough clinical examination, radiographic and histopathological features help to establish the diagnosis which is key to the successful management of such lesions. This article describes a case of POF in a 43-year-old male patient. The clinical, radiographic, histologic features, aggressive treatment strategies, relapse and close follow-up of POF are discussed in detail.&#x0D;