Advancing HER2-low breast cancer management: enhancing diagnosis and treatment strategies.

BACKGROUND: Recent evidence brought by novel anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugates is leading to significant changes in HER2-negative breast cancer (BC) best practices. A new targetable category termed 'HER2-low' has been identified in tumors previously classified as 'HER2-negative'. Daily practice in pathology and medical oncology is expected to align to current recommendations, but patient access to novel anticancer drugs across geographies might be impeded due to local challenges. MATERIALS AND METHODS: An expert meeting involving ten regional pathology and oncology opinion leaders experienced in BC management in four Central and Eastern Europe (CEE) countries (Bulgaria, Croatia, Serbia, Slovenia) was held. Herein we summarized the current situation of HER2-low metastatic BC (mBC), local challenges, and action plans to prevent delays in patient access to testing and treatment based on expert opinion. RESULTS: Gaps and differences at multiple levels were identified across the four countries. These included variability in the local HER2-low epidemiology data, certification of pathology laboratories and quality control, and reimbursement conditions of testing and anticancer drugs for HER2-negative mBC. While clinical decisions were aligned to international guidelines in use, optimal access to testing and innovative treatment was restricted due to significant delays in reimbursement or limitative reimbursement conditions. CONCLUSIONS: Preventing delays in HER2-low mBC patient access to diagnosis and novel treatments is crucial to optimize outcomes. Multidisciplinary joint efforts and pro-active discussions between clinicians and decision makers are needed to improve care of HER2-low mBC patients in CEE countries.

Targeting triple-negative breast cancer: A clinical perspective.

Triple-negative breast cancer (TNBC) is a disease with often an aggressive course and a poor prognosis compared to other subtypes of breast cancer. TNBC accounts for approximately 10%-15% of all diagnosed breast cancer cases and represents a high unmet need in the field. Up to just a few years ago, chemotherapy was the only systemic treatment option for this subtype (1). To date, TNBC is considered a heterogeneous disease. One of the existing classifications is based on the analysis of mRNA expression in 587 TNBC cases, in which Lehman et al. proposed six subtypes of TNBC as follows: two basal-like (BL1 and BL2) subtypes, a mesenchymal (M) subtype, a mesenchymal stem-like (MSL) subtype, an immunomodulatory (IM) subtype, and a luminal androgen receptor (LAR) subtype (2). Later studies have demonstrated that the IM and MSL subtypes do not correlate with independent subtypes but reflect background expression by dense infiltration of tumor-infiltrating lymphocytes (TILs) or stromal cells. According to this finding, the classification of TNBC has been revised into the following four subtypes: basal 1, basal 2, LAR, and mesenchymal subtypes (3). Over the last years, several new strategies have been investigated for the treatment of patients with TNBC. Among them, immunotherapy, antibody drug conjugates, new chemotherapy agents, and targeted therapy have been and are currently being developed. The present article aims to provide an updated overview on the different treatment options that are now available or are still under investigation for patients with TNBC.

Immunotherapy in the treatment of lymphoma.

Relapsed or refractory non-Hodgkin's lymphomas, especially diffuse large B-cell lymphoma as well as relapsed or refractory Hodgkin lymphomas are hard-to-treat diseases. Patients who do not respond to initial therapy or experience relapse are treated with salvage regimens, and if eligible for aggressive therapy, treatment is continued with high-dose chemotherapy and autologous stem cell transplantation. Current therapy options can cure substantial numbers of patients, however for some it is still an uncurable disease. Numerous new drugs and cell therapies are being investigated for the treatment of relapsed or refractory lymphomas. Different types of immunotherapy options have shown promising results, and some have already become the standard of care. Here, we review immunotherapy options for the treatment of lymphoma and discuss the results, positions, practical aspects, and future directions of different drugs and cellular therapies for the treatment of this disease.

Preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer (PHranceSCa): A randomised, open-label phase II study.

AIM: The aim of the study was to assess patient preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) in patients with HER2-positive early breast cancer in PHranceSCa (NCT03674112). MATERIALS AND METHODS: Patients who completed neoadjuvant P + H + chemotherapy + surgery were randomised 1:1 to three intravenous (IV) P + H cycles followed by three cycles of PH FDC SC or vice versa (crossover) and then chose subcutaneous (SC) injection or IV infusion to continue up to 18 cycles (continuation). Assessments were via patient and healthcare professional (HCP) questionnaires. RESULTS: One hundred and sixty patients were randomised (cut-off: 24 February 2020); 136 (85.0%, 95% confidence interval: 78.5-90.2%) preferred SC; 22 (13.8%) preferred IV; 2 (1.3%) had no preference. The main reasons for SC preference were reduced clinic time (n = 119) and comfort during administration (n = 73). One hundred and forty-one patients (88.1%) were very satisfied/satisfied with SC injection versus 108 (67.5%) with IV infusion; 86.9% chose PH FDC SC continuation. HCP perceptions of median patient treatment room time ranged from 33.0-50.0 min with SC and 130.0-300.0 min with IV. Most adverse events (AEs) were grade 1/2 (no 4/5s); serious AE rates were low. AE rates before and after switching were similar (cycles 1-3 IV → cycles 4-6 SC: 77.5% → 72.5%; cycles 1-3 SC → cycles 4-6 IV: 77.5% → 63.8%). CONCLUSION: Most patients strongly preferred PH FDC SC over P + H IV. PH FDC SC was generally well tolerated, with no new safety signals (even when switching), and offers a quicker alternative to IV infusion.

Survival of patients with liver metastases from colorectal cancer treated with bevacizumab and FOLFOX4.

Purpose: In patients with colorectal liver metastases (CLM) a long term survival and a probability of cure might be achieved with the surgical treatment of metastatic sites after prior application of systemic treatment. The purpose of this study was to assess the survival of patients with unresectable CLM treated with bevacizumab (bev) and FOLFOX4 (FOLFOX-bev) and to compare survival according to patient, disease and treatment characteristics. Methods: This research included 110 patients with unresectable CLM treated with FOLFOX-bev. Treatment response and resectability were estimated every 3 months. If resectability was achieved, patients were operated on and followed. Patient, disease and treatment characteristics in patients with and without hepatectomy were compared. Survival was estimated according to Kaplan-Meier method. Comparison of survival according to patient, disease and treatment characteristics was performed using log-rank test. Results: In patients with hepatectomy, treatment response was significantly more frequent (63, 63% vs 16, 66%, p<0.001). One- and three-year survival rate for the whole group was 87, 3% and 36, 1%, respectively; median overall survival (OS) was 23 months (95%CI 19, 63-28, 26). One- and three-year survival for patients with hepatectomy was 98, 48%, and 54, 76%, respectively; median OS was 35 months (95%CI 28, 83-41, 17). Three-year survival was significantly better in patients with hepatectomy (HR=3.775; 95%CI 2.150-6.627, p<0.001), older than 60 years (p=0.033), those without extrahepatic metastases (p=0.008) and those with treatment response (p=0.05). Conclusion: Significantly better survival had patients with hepatectomy, treatment response, older than 60 years and without extrahepatic metastases. FOLFOX4-bev is effective treatment for molecularly unselected patients.

CD4+ T cell phenotypes in the pathogenesis of immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts due to enhanced platelet clearance and compromised production. Traditionally, ITP was regarded a B cell mediated disorder as anti-platelet antibodies are detected in most patients. The very nature of self-antigens, evident processes of isotype switching and the affinity maturation of anti-platelet antibodies indicate that B cells in order to mount anti-platelet immune response require assistance of auto-reactive CD4+ T cells. For a long time, ITP pathogenesis has been exclusively reviewed through the prism of the disturbed balance between Th1 and Th2 subsets of CD4+ T cells, however, more recently new subsets of these cells have been described including Th17, Th9, Th22, T follicular helper and regulatory T cells. In this paper, we review the current understanding of the role and immunological mechanisms by which CD4+ T cells contribute to the pathogenesis of ITP.

Current and future targets and therapies in metastatic colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer and the second cause of cancer-related deaths worldwide. Despite early diagnosis and treatment improvement, the majority of patients will still suffer from metastatic disease (mCRC), which has a poor prognosis. Molecular diversity of CRC requires personalized targeted approach for improving patient outcomes. Antiangiogenic agents proved to be beneficial in the continuum of mCRC treatment. For efficient epidermal growth factor receptor (EGFR) directed therapy, subtle molecular selection and better strategies to overcome resistance are needed. BRAF mutant and HER-2 positive mCRC will soon be provided with approved targeted treatments and check-point inhibitors demonstrated effectiveness in microsatellite instability (MSI) - high mCRC. Moreover, numeorous promising agents are entering clinical trial arena. This review summarizes actual and possible targets and current and promising agents for mCRC treatment. With broader accessibility of liquid biopsy we could track molecular evolution of CRC and target genetic alterations as they emerge.

Interlaboratory concordance in HER2 testing: Results of a Serbian ring-study.

PURPOSE: The purpose of this study was to assess the immunohistochemistry and chromogenic in situ hybridization (CISH) inter-laboratory consensus between national pathology laboratories in Serbia. METHODS: This study was conducted between 2013 and 2016. In 2013, HER2 results were evaluated using two sets of four different breast cancer specimens in five laboratories. A total of 20 immunohistochemistry and 20 CISH cases were tested. In 2014, there were 6 testing rounds, and a total of 24 specimens were analyzed, whereas in 2015 and 2016, seven testing rounds were conducted, with four additional cases (i.e. a total of 28 specimens). In 2014, 2015 and 2016, all institutions performed immunohistochemical analysis only. RESULTS: We found discrepan¬cies in HER2 immunohistochemical (IHC) results in all four surveys. IHC testing resulted in diagnostic discordance between participating centers in two (2/17) cases in 2013, two (2/24) in 2014, four (4/27) cases in 2015 and three cases (3/27) in 2016. The overall agreement among the centers was 79%, 85.5%, 83.5% and 89.4%, respectively. For CISH analyses, the results for 16 (84.2%) of 19 samples were consistent for all participants. Three results were found to be discordant, indicating a misdiagnosis rate of 15.8%. In all the discrepant cases, interinstitutional discordances were related to technical and evaluation issues. CONCLUSIONS: Our study highlights the difficulty encountered during HER2 testing using immunohistochemistry and CISH. This also emphasizes the need for rigorous quality control procedures for specimen preparation and analysis.

Do we really know how to overcome trastuzumab resistance in hormone sensitive metastatic breast cancer?

PURPOSE: This article focuses on how the status of hormone receptors (HR) influences the efficacy of trastuzumab in patients with metastatic HER2-positive breast cancer treated with first-line trastuzumab in combination with taxane-based chemotherapy. METHODS: A prospective study was carried out at the Clinic for Oncology, Clinical Centre in Nis, from January 2015 to until June 2018. A total of 121 patients were treated with first-line trastuzumab in combination with taxane-based chemotherapy. None of the patients from the HR-positive group received hormonotherapy after completion of chemotherapy with trastuzumab. RESULTS: Clinical benefit rate was present in 76% of the patients, including partial response (PR) in 37%, stable disease (SD) in 38%, and complete response (CR) in almost 8% of the patients. Progressive disease (PD) occurred in almost a quarter of the patients, i.e. 24%. Progression-free survival (PFS) in the entire group of patients amounted to 9 months, whereas overall survival (OS) was 30 months. PFS in the HR-negative tumor group was significantly longer (13 months) compared to 8 months in the HR-positive tumor group (p<0.0001; HR 0.49;95% CI 0.31-0.69). Furthermore, OS was significantly longer in the HR-negative tumor group (34 months), compared to 26 months in the HR-positive tumor group (p=0.0073, HR 0.57; 95% CI 0.36-0.90). CONCLUSIONS: These data indicate a different response to anti-HER2 therapy in patients with HER2+ metastatic breast cancer (MBC) according to HR status, thus emphasizing that ER most likely represents an escape pathway for the response to anti-HER2 target therapy and vice versa. Combining hormonotherapy with anti-HER2 therapy surely represents a promising strategy which could help overcome resistance to trastuzumab and other anti-HER2 agents.

Granulocyte-macrophage colony-stimulating factor as a mediator of autoimmunity in multiple sclerosis.

Autoreactive, myelin-specific, CD4+ T cells have a central role in multiple sclerosis (MS) pathogenesis; however the exact phenotype characteristics of these cells remain elusive. Recently, granulocyte-macrophage colony-stimulating factor (GM-CSF) expression has emerged as the main pathological signature of the encephalogenicity in both T and B cell compartment. In this review we have summarized the current data supporting GM-CSF relevance in MS pathophysiology, in the context of both immunomodulatory and neuroinflammatory processes; as well as the potential cellular sources of this stimulating factor, including different T and B cell subsets.

Ten years of using adjuvant trastuzumab in breast cancer in Serbia - Single institution experience.

PURPOSE: The purpose of this study was to determinate disease-free interval (DFI) and overall survival (OS) in HER2-positive breast cancer patients who received adjuvant trastuzumab at the University Clinic of Nis, Serbia, and to investigate the influence of clinicopathological and biological characteristics of the tumor on prognosis. The second aim was to determinate the most frequent cause for the treatment discontinuation, recurrence rate, as well as the site of most common localization of the first recurrence of disease. METHODS: This research was conducted as a retrospective study at the University Oncology Clinic, Clinical Centre in Nis. The study included 238 patients who were operated and treated for HER2-positive breast cancer between January 1st, 2007 to September 30th, 2012 and followed up until December 31st, 2016. Trastuzumab was administered concurrently with taxanes, if administered, or after the completed anthracycline-based chemotherapy. RESULTS: After a median follow up of 69 months the 5-year DFI was 65.9% and 5-year OS was 81.8% and, as expected, significantly longer in the group of patients with smaller tumors, a smaller number of positive axillary lymph nodes, as well as a lower stage of disease (p<0.0001). Patients older than 65 years had a longer DFI compared to the 45-65 and under 45 age groups of patients (p=0.01). No statistical significance was found in the length of DFI in relation to the histological tumor subtype, tumor grade, or the status of hormone receptors. Unlike DFI, a longer OS was recorded in the group of patients with lower tumor grade (p=0.03) and there was no statistically significant difference in survival regarding the age of patients (p=0.07). Recurrence occurred in approximately one third of the patients (38.23%), mostly in the form of local recurrence. Adjuvant therapy with trastuzumab was not completely carried out in 18.49% of the patients, the most common reason being the progression of disease. CONCLUSIONS: A long median follow up period of 69 months indicated that anti-HER2 monoclonal antibody trastuzumab, after anthracycline-based chemotherapy or concurrently with taxanes, is efficient and safe in treating early breast cancer.

Serbian consensus of neoadjuvant therapy for breast cancer: NeoPULSE.

Even though surgery is the primary treatment of operable breast cancer, it has been known for decades that the administration of postoperative adjuvant or preoperative neoadjuvant therapy is extremely important. Indications for neodjuvant therapy administration have been expanded over the years, and nowadays this kind of treatment represents an inevitable option in early breast cancer treatment. The NeoPULSE project, which gathered a group of experts in the field of breast cancer from five Serbian university centres, was formed with the aim to define optimal breast cancer diagnosis, indications for neoadjuvant therapy, therapeutic combinations in relation to molecular/biological parameters of breast cancer, as well as the treatment after neoadjuvant therapy. During two separate expert meetings involving surgeons, medical oncologists, radiation oncologists, a pathologist, and a "Blueprint" workshop, the project participants answered questions over the indications for neoadjuvant therapy. The first part covered local practice and referred to the existence and work of a multidisciplinary team, as well as commonly applied therapeutic regimens in the neoadjuvant setting. Experts analysed personal views regarding indications for the administration and benefits of neoadjuvant therapy, their perception on the correlation between achieving a pathological complete response (pCR) and the outcome of treatment, as well as the attitude towards controversies about this type of treatment, primarily regarding a possible change in the receptor status after therapy and therapeutic options after a suboptimal response. The analysis of the answers pointed to problems and deviations from recommendations in everyday clinical practice, based on which appropriate solutions were proposed. The establishment of such a panel and consensus is an attempt to modernize multidisciplinary teams in Serbia, achieve reaching uniform decisions of all subjects dealing with breast cancer, and therefore, at least in one segment, improve breast cancer treatment in Serbia.

Markers of proliferation and cytokeratins in the differential diagnosis of jaw cysts.

We conducted a retrospective study to analyze the histologic and immunohistochemical findings in three main types of odontogenic cyst. We studied 90 archived cystic jaw lesions: 30 dentigerous cysts, 30 keratocystic odontogenic tumors, and 30 radicular cysts. The cyst types were identified on the basis of clinical, radiologic, and histopathologic findings. Immunohistochemical analyses included staining with Ki-67, p53, epidermal growth factor receptor (EGFR), cytokeratin (CK) 8, CK14, CK17, and CK18. Cell immunopositivity was evaluated for the entire epithelium. The criteria for Ki-67 and p53 positivity were dense and/or faint nuclear staining, and cells were considered EGFR-positive if they exhibited membrane staining and/or cytoplasm staining. For the cytokeratins, cells exhibiting cytoplasm staining were considered positive. Five representative fields of each lesion were selected and identified in each of the Ki-67- and p53-stained slides. We found a statistically significant difference in the ratio of Ki-67-positive cells in the entire layer between the keratocystic odontogenic tumors and both the dentigerous cysts and the radicular cysts. A statistically significant difference was observed in the ratio of p53-positive cells between the keratocystic odontogenic tumors and the radicular cysts. Cytokeratins proved to be useful in differentiating radicular cysts from other types of cystic jaw lesions because of their CK8-positive and CK17-negative immunolabeling.

IL-17 signalling in astrocytes promotes glutamate excitotoxicity: Indications for the link between inflammatory and neurodegenerative events in multiple sclerosis.

OBJECTIVE: Th-17 cells have been exclusively referred to inflammatory events in multiple sclerosis (MS), while their importance in the development of glutamate excitotoxicity and the consequent neurodegeneration has been a completely unexplored concept. Accordingly, the objective of our study was to assess IL-17A effect on astrocyte ability to metabolize and release glutamate, considering that astrocytes had the central role in glutamate homeostasis. METHODS: By using primary rat astrocyte cultures, astrocyte ability to uptake glutamate was estimated by the alterations of glutamate transporters (GLAST and GLT-1) expression, whereas changes in glutamine synthetase expression were used to estimate the ability to metabolize glutamate. Gene expression was determined by real time polymerase chain reaction (rtPCR). IL-17A effect on astrocyte ability to produce glutamate was investigated directly, by measuring the level of released glutamate using high performance liquid chromatography (HPLC). RESULTS: Lower concentrations of IL-17A reduced the expressions of both glutamate transporters and glutamine synthetase; however, this effect was lost when IL-17A was applied in a higher dose. IL-17A did not significantly modify glutamate release from astrocyte in basal conditions, but following Ca2+ stimulation, as well as Ca2+ removal from the culture medium, IL-17A stimulated glutamate release in dose-dependent manner. CONCLUSION: Together, these results support that IL-17A could promote glutamate excitotoxicity by decreasing astrocyte ability to uptake and convert glutamate to non-toxic glutamine, but also by stimulating Ca2+ dependent glutamate release. Such interactions between IL-17A and glutamate excitotoxicity implicate the potential link between inflammation and neurodegeneration during MS pathogenesis, and identify astrocytes as a potential target in achieving neuroprotective effects in MS.

Stressful life events and breast cancer risk: a hospital-based case-control study.

PURPOSE: Elucidation of the factors contributing to the incidence of breast cancer is of crucial importance for the development of preventive or therapeutic strategies targeting the disease. Research on stress and breast cancer has been documented by various studies published over the years. In view of breast cancer importance as the most commonly occurring malignancy in females in Serbia, this study was undertaken to examine the association between stressful life events and breast cancer risk. METHODS: The present hospital-based case-control study comprised 120 new breast cancer cases and 120 hospital controls matched with respect to age (± 2 years). This study used the Paykel Life Events Scale to obtain information about stressful life events in the years before diagnosis. The SPSS statistical package was used and odds ratios (OR) and 95% confidence intervals (95% CI) were calculated from multivariate conditional logistic regression model. RESULTS: Multiple conditional logistic regression analysis revealed six independent predictors of breast cancer risk: experience of severe and moderate threats (first 25 life events from the scale) (OR=3.15, 95% CI=2.01-4.93), son's military service (OR=6.09, 95% CI=4.17-12.37), death of close family member (OR=7.98, 95% CI=2.18-9.14), moderate financial difficulties (OR=3.26, 95%CI=1.24-8.56), maternal death in childhood (OR=3.46, 95% CI=1.21-9.92) and serious financial difficulties (OR=3.55, 95% CI=1.20-10.52). CONCLUSION: Stress exposure has been proposed to contribute to the etiology of breast cancer. There is a need for understanding the differing physiological effects of types or times of stress exposure.

Deleterious versus protective autoimmunity in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder of central nervous system, in which myelin specific CD4(+) T cells have a central role in orchestrating pathological events involved in disease pathogenesis. There is compelling evidence that Th1, Th9 and Th17 cells, separately or in cooperation, could mediate deleterious autoimmune response in MS. However, the phenotype differences between Th cell subpopulations initially employed in MS pathogenesis are mainly reflected in the different patterns of inflammation introduction, which results in the development of characteristic pathological features (blood-brain barrier disruption, demyelination and neurodegeneration), clinically presented with MS symptoms. Although, autoimmunity was traditionally seen as deleterious, some studies indicated that autoimmunity mediated by Th2 cells and T regulatory cells could be protective by nature. The concept of protective autoimmunity in MS pathogenesis is still poorly understood, but could be of great importance in better understanding of MS immunology and therefore, creating better therapeutic strategies.

High dose chemotherapy with stem cell support in the treatment of testicular cancer.

Testicular germ cell cancer (TGCC) is rare form of malignant disease that occurs mostly in young man between age 15 and 40. The worldwide incidence of TGCC is 1.5 per 100000 man with the highest rates in North Europe. After discovery of cisplatin cure rates of TGCC are very favorable between 90%-95% and unlike most solid tumors, cure rate for metastatic TGCC is around 80%. Metastatic TGCC is usually treated with 3-4 cycles of bleomycin, etoposide, cisplatinum chemotherapy with or without retroperitoneal surgery and cure rates with this approach are between 41% in poor risk group and 92% in good risk group of patients. Cure rates are lower in relapsed and refractory patients and many of them will die from the disease if not cured with first line chemotherapy. High dose chemotherapy (HDCT) approach was used for the first time during the 1980s. Progress in hematology allowed the possibility to keep autologous haematopoietic stem cells alive ex-vivo at very low temperatures and use them to repopulate the bone marrow after sub-lethal dose of intesive myeloablative chemotherapy. Despite the fact that there is no positive randomized study to prove HDCT concept, cure rates in relapsed TGCC are higher after high dose therapy then in historical controls in studies with conventional treatment. Here we review clinical studies in HDCT for TGCC, possibilities of mobilising sufficient number of stem cells and future directions in the treatment of this disease.

Young age and pathological features predict breast cancer outcome - report from a dual Institution experience in Serbia.

PURPOSE: The aim of this study was to investigate the influence of clinicopathological and biological characteristics on prognosis, disease free survival (DFS) and overall survival (OS), of very young patients (≤35 years of age) with breast cancer. METHODS: We retrospectively collected information of 150 women diagnosed with breast cancer, aged ≤35 years, who were operated and treated at two University Hospitals in Serbia between January 2009 and February 2011. RESULTS: After a median follow up of 44 months patients ≤30 had shorter DFS and OS compared to patients aged 31-35 years (p=0.004 and p=0.037, respectively). The differences in DFS and OS were significant with decreased survival associated with higher tumor grade (p=0.005 and p=0.0001, respectively). Tumor size and number of positive nodes were predictors of outcome with decreased survival associated with higher tumor size (p=0.0019 for DFS and p<0.0001 for OS) and increasing number of nodes (p<0.0001 for both). HER 2 receptor did not seem to have a prognostic influence while patients with hormonal receptors (HRs) positive tumors had a better DFS (p=0.034) and OS (p=0.046) than those with HRs negative tumors. In univariate survival analysis, a significant difference in DFS (p=0.0003) and OS (p=0.0003) was found between patients with vs without lymphovascular invasion (LVI). CONCLUSION: Diagnosis of breast cancer at very young age (<30) was associated with increased risk of death and shorter DFS than women aged 31-35. Negative impact on survival was seen in patients with presence of LVI, negative HRs and higher grade and stage at the time of presentation.

Mantle cell lymphoma-current literature overview.

Mantle cell lymphoma (MCL) is a distinct subtype of lymphoma identified as a particular entity in the early 1990s. The prognosis of MCL is generally poor, and is considered one of the worst among all B-cell lymphomas. In general, conventional chemotherapy is only palliative and the median duration of remissions is only 1-2 years. With the exception of allogeneic hematopoietic stem cell transplantation (allo-SCT), current treatment approaches are not curative and the corresponding survival curve is characterized by a relatively steep and continuous decline, with a median survival of about 4 years and <15% long-term survivors. Only a small proportion of patients may be exempted from this disappointing picture, because they have an indolent course of the disease and could be handled with watch and wait strategy. Optimal first-line therapy in MCL is not established yet. Very intensive regimens, including autologous (auto-SCT) and allo-SCT, seem to be required to improve the outcome. Allogeneic stem cell transplantation is the only therapy that can achieve a plateau in the survival curve, but, however, it is not applicable in most of the cases due to the patients' older age when the disease mostly occurs. Molecular knowledge of MCL has progressed and therefore a large number of molecular targeted therapies have been introduced in relapsed and refractory disease.