Effectiveness and safety of methotrexate in the treatment of mycosis fungoides: Real-world data from a multicentre study.

BACKGROUND: Methotrexate (MTX) has been a longstanding therapeutic option for mycosis fungoides (MF); however, data on its real-world effectiveness remain limited. OBJECTIVES: To evaluate treatment-related outcomes of oral MTX in patients with early- and late-stage MF. METHODS: This is a retrospective multicentre analysis involving MF subjects from five referral centres for cutaneous lymphomas in Greece. Data regarding the effectiveness and safety were analysed. RESULTS: In total, 211 MF patients were enrolled (males, 68.3%) with a median (IQR) age of diagnosis at 68.3 (56-75) years. Late-stage (IIB-IVB) disease was present in 124 patients (59.3%). MTX monotherapy was administered to 112 (53.1%) patients, with 99 receiving combination regimens with phototherapy, interferon and retinoids. MTX was used as first-line regimen in 103 (48.9%) cases. An overall response rate (ORR) of 55.5% was observed with 29.9% of patients achieving complete responses. MTX demonstrated greater effectiveness as a first-line treatment compared to subsequent use with no significant differences between monotherapy and combination therapy. The median time to best response was 3.8 months (IQR 2.3-9.9 months). Patients with erythrodermic disease (Stage III) had better ORRs compared to patients with tumour stage disease (Stage II) (61.1% vs. 44.8% respectively). The progression-free survival (PFS) varied according to stage, with a median PFS of 17.1 months for early-stage disease, 5.7 months for Stage IIB disease, 46 months for Stage III and 9.6 months for Stage IV disease (0.7-.). Serious adverse (Grade 3) events leading to treatment discontinuation occurred in 14 (6.7%) cases. All patients received oral MTX once weekly with a median weekly dose of 15 mg/week (7.5-25). CONCLUSION: Our findings support MTX as a viable treatment option for MF, particularly when used in the first-line setting, offering a favourable benefit/risk profile. Response rates are stage-dependent, with erythrodermic patients achieving superior and durable responses.

The addition of mesenchymal stem cells in a bioabsorbable scaffold does not enhance tendon healing after a repair of rotator cuff tear.

PURPOSE: The purpose of the study is to evaluate the healing potential of a full-thickness tendon defect in the rotator cuff of rabbits using a bioabsorbable scaffold impregnated with bone marrow-mesenchymal stem cells (BM-MSCs) or rotator cuff-derived mesenchymal stem cells (RC-MSCs). METHODS: Sixteen adult rabbits were subjected to a full-thickness rotator cuff deficit. Rabbits were randomly assigned to four groups of four animals. In Group 0 (control), the deficit was left untreated. In Group 1, the deficit was treated with a single synthetic scaffold alone. In Group 2, the deficit was treated with the previous scaffold loaded with allogeneic BM-MSCs. In Group 3, the deficit was treated with the previous scaffold loaded with allogenic RC-MSCs. After animal sacrifice, tissue samples were subjected to histological and immunohistochemical analysis. RESULTS: Group 1 showed the highest mean tendon maturing score (15.3 ± 0.9) postoperatively, being significantly higher, in comparison to groups 0, 2 and 3 (p = 0.01, 0.02 and 0.01, respectively). Group 1 showed the highest mean collagen I/collagen III ratio (1.4 ± 0.8) postoperatively but without any statistical significance. CONCLUSIONS: The utilization of MSCs in rotator cuff repair in a rabbit model has not been associated with an enhancement in tendon healing in 16 weeks postoperatively, in comparison to controls and bioabsorbable scaffolds. The addition of MSCs does not result in better rotator cuff healing. LEVEL OF EVIDENCE: Not applicable. This is an animal study.

A Case Report of Chronic Myelogenous Leukemia Presenting as Blastic Crisis with a T-Cell Acute Lymphoblastic Leukemia Phenotype: Awareness of a Rare Entity.

Chronic myelogenous leukemia at blast crisis with a T-cell phenotype (T-ALL CML-BC) at diagnosis, without any prior history of CML is extremely rare. After the introduction of tyrosine kinase inhibitors (TKIs), CML patients have a median survival comparable to general population and accelerated/blast crisis are rarely encountered. Most CML patients (80%) transform into acute myeloid leukemia and the rest into B-ALL. Anecdotal cases of Ph+ T-ALL, either de novo or in the context of CML-BC have been reported. Left shift in the blood, the presence of splenomegaly/extramedullary infiltration and the occurrence of BCR::ABL1 rearrangement in both the blastic population, as well as in the myeloid cell compartment are key points in differentiating de novo Ph+ T-ALL from T-ALL CML-BC. The latter is a rare entity, characterized by extramedullary disease, p210 transcript and clonal evolution. Lack of preceding CML does not rule out the diagnosis of T-ALL CML-BC. Prompt TKI treatment with ALL-directed therapy followed by allogeneic stem cell transplantation may offer long-term survival in this otherwise poor prognosis entity. In this paper, we describe a patient with T-ALL CML-BC at presentation, still alive 51 months after diagnosis and we offer a review of the literature on this rare subject. All clinical and laboratory features are provided in order to distinguish de novo Ph+ T-ALL from T-ALL CML-BC, underscoring the prognostic and therapeutic significance of such a differentiation.

The Role of mTOR in B Cell Lymphoid Malignancies: Biologic and Therapeutic Aspects.

Non-Hodgkin lymphoma's (NHL) incidence is rising over time, and B cell lymphomas comprise the majority of lymphomas. The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue 1 (Akt)/mammalian target of the rapamycin (mTOR) signaling pathway plays a critical role in a variety of cellular processes, such as cell proliferation and survival. Its role in lymphomagenesis is confirmed in many different types of B cell lymphomas. This review is mainly focused on the PI3K/v-akt/mTOR pathway-related oncogenic mechanisms in B cell NHLs with an emphasis on common B cell lymphoma types [diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL)]. Furthermore, it summarizes the literature regarding the clinical applications of the mTOR inhibitors temsirolimus and everolimus in B cell NHLs, which have been tested in a range of clinical trials enrolling patients with B cell malignancies, either as monotherapy or in combination with other agents or regimens.

Molecular analysis of NUT-positive poromas and porocarcinomas identifies novel break points of YAP1::NUTM1 fusions.

BACKGROUND: Poromas, and their malignant counterparts, porocarcinomas, harbor recurrent translocations involving YAP1-MAML2, YAP1-NUTM1, and infrequently WWTR1-NUTM1; YAP1-NUTM1 being the most common in porocarcinomas. NUT immunohistochemistry (IHC) can be used to identify NUTM1-translocated tumors. This study sought to investigate potential novel NUTM1-fusion partners among NUT IHC-positive poromas and porocarcinomas. METHODS: Thirteen NUT IHC-positive poroid tumors (four poromas and nine porocarcinomas) were identified within a multi-institutional international cohort. Next-generation sequencing (NGS) assessed for NUTM1 fusion partners. RESULTS: NGS detected a NUTM1 fusion in 12 of 13 cases: YAP1-NUTM1 (11/12 cases) and WWTR1-NUTM1 (1/12 cases). Two of the cases (2/12) with NUTM1 fusion were not called by the NGS algorithm but had at least one read-spanning YAP1-NUTM1 break point upon manual review. A NUTM1 fusion was not identified in one case; however, the sample had low RNA quality. The following fusion events were identified: YAP1 exon 4::NUTM1 exon 3 in six cases, YAP1 exon 6::NUTM1 exon 2 in one case, YAP1 exon 3::NUTM1 exon 3 in three cases, WWTR1 exon 3::NUTM1 exon 3 in one case, and YAP1 exon 8::NUTM1 exon 3 fusion in one case. CONCLUSION: While no novel NUTM1 fusion partners were identified within our cohort, 12 of 13 cases had discoverable NUTM1 fusions; YAP1-NUTM1 fusion was detected in 11 cases (92%) and WWTR1-NUTM1 in 1 case (8%). These data corroborate findings from other recent investigations and further substantiate the utility of NUT IHC in diagnosing a subset of poroid neoplasms. In addition, two of our cases harbored fusions of YAP1 exon 6 to NUTM1 exon 3 and YAP1 exon 8 to NUTM1 exon 2, which have not been reported before in poroid neoplasms and indicate novel break points of YAP1.

JAK2V617F positive polycythemia vera with paroxysmal nocturnal hemoglobinuria and visceral thromboses: a case report and review of the literature.

BACKGROUND: Polycythemia vera (PV) is characterized by red cell mass expansion in the peripheral blood and can be complicated with thrombosis, bleeding, evolution to acute myeloid leukemia (AML) or a fibrotic phase. Paroxysmal nocturnal hemoglobinuria (PNH) in an acquired clonal haematopoietic stem cell disorder associated with chronic intravascular hemolysis, venous thrombosis, defective hematopoiesis, frequent episodes of infection and, rarely, leukemic transformation. Herein, we report an interesting case of a patient with coexistence of PNH clones and a JAK2V617F positive PV, with unusual thromboses without hemolysis. CASE PRESENTATION: A 51-year-old woman presented with increased levels of hematocrit, multiple liver, spleen, and left kidney infarctions and ascites; further investigation revealed a JAK2V617F-positive polycythemia vera and the presence of a significant PNH population (more than 90% CD55- CD59- cells among both granulocytes and red blood cells). Interestingly, the patient has experienced severe thrombotic events without any signs or symptoms of hemolysis. CONCLUSIONS: This case raises questions over uncharted aspects of the PNH etiopathogenesis and its potential association with myeloproliferative neoplasms (MPN) and highlights the difficulty of diagnosing and managing patients with more than one potentially thrombophilic conditions, especially with established and severe thromboses.

Novel CTNND2-TERT fusion in a spindle cell liposarcoma.

Soft tissue tumors can be categorized molecularly into two categories: tumors which are known to have recurrent molecular alterations and tumors which do not have consistent recurrent molecular alterations or translocations. These "nontranslocation" associated sarcomas are clinically more aggressive than their more stable counterparts. However, recent advances in RNA sequencing have discovered recurrent novel fusions within the latter group, namely TERT-TRIO fusions. Furthermore, a recent report discovered this fusion in a spindle cell liposarcoma. Our case describes a novel fusion of CTNND2, a neighbor gene of TRIO, and TERT in a spindle cell liposarcoma, and provides further evidence that spindle cell liposarcoma should be a distinct entity from dedifferentiated liposarcoma.

Clinical Reasoning: Progressive Peripheral Neuropathy in a 66-Year-Old Woman With Sezary Syndrome.

Evaluating patients with neuropathy is common, especially in elderly patients with comorbidities. Neuropathy can often be a manifestation of systemic diseases, cancer, or drug-induced toxicity; thus, the differential diagnosis is challenging. The mechanism of nerve damage can vary significantly, affecting the patient's therapeutic management. We describe a 66-year-old woman who presented with subacute and progressively worsening motor weakness of the lower extremities with bilateral numbness and tingling after a recent respiratory tract infection. Her medical history included diabetes mellitus and Sezary syndrome in the context of cutaneous T-cell lymphoma. This case emphasizes the significance of a detailed evaluation and considering clinical signs and electrophysiologic findings in patients with neuropathy and a history of hematologic malignancy. Early recognition and management can be crucial in shaping the clinical course of the disease.

Acute hemorrhagic leukoencephalitis following the first dose of BNT162b2 vaccine against SARS-CoV-2: A case report.

Acute hemorrhagic leukoencephalitis (AHLE), is a rare inflammatory demyelinating disorder, variant of acute disseminated encephalomyelitis. The diagnosis of AHLE remains challenging due to the rarity of the disease and the lack of a reliable biomarker. We report here a case of a 73-year-old male patient with a progressive, low-grade febrile confusional syndrome 20 days after receiving the first dose of BNT162b2 vaccine against SARS-CoV-2. Evidence indicative of the underlying condition by an extensive panel of imaging (brain magnetic resonance imaging, computed tomography and digital subtraction angiography), laboratory (complete blood count, biochemistry, coagulation, tests for autoimmune or infectious disorders, tumor markers, hormonal levels, cerebrospinal fluid analysis) and electrodiagnostic tests were scarce, and mainly non-specific. Sequential neuroimaging revealed the appearance of extensive T2 lesions (signs of gliosis) along with multiple hemorrhagic lesions at various cortical sites. The patient was treated with corticosteroids, discontinued due to severe adverse effects, and subsequently with sessions of plasmapheresis and monthly intravenous administration of cyclophosphamide. Considering the rapid aggravation of the patient's neurological status, the MRI findings of cortical lesions and the lack of response to any treatment, a biopsy of a frontal lobe lesion was conducted, confirming the presence of confluent, inflammatory-edematous lesions with scattered areas of necrosis and hemorrhage, and ultimately areas of demyelination, thus confirming the diagnosis of AHLE. After more than 5 months of hospitalization the patient was transferred in a primary care facility and remained in a permanent vegetative state until his death, more than 2 years later.

A Patient with Synchronous Gallbladder and Bone Plasmacytoma.

Multiple myeloma (MM) is the most common primary bone-originating tumor, whereas extramedullary plasmacytoma (EMP) is a plasma cell tumor that arises outside the bone and is most commonly found in the head and neck area. Gastrointestinal and particularly gallbladder involvement is exceedingly rare, and symptoms, if any are present, are usually similar to those seen with cholelithiasis. Treatment options usually include surgical resection and/or chemotherapy. In this report, we present a rare case of a clinically unexpected plasmablastic extramedullary plasmacytoma that was found on abdominal ultrasound (US) and magnetic resonance imaging (MRI) in a 61-year-old asymptomatic patient and led him to undergo cholecystectomy. A fluorodeoxyglucose positron emission computed tomography (FDG PET-CT) that was performed due to the onset of left thigh pain also demonstrated concurrent bone plasmacytoma. The patient is currently receiving chemotherapy and is also being prepared for autologous stem cell transplantation. In this context, we further present the diagnostic, therapeutic and prognostic challenges of EMPs. Lastly, we point out the distinct features of the plasmablastic subtype and analyze its differences compared to other histologic subtypes in achieving a successful diagnosis and management.

Glioma Cells Expressing High Levels of ALDH5A1 Exhibit Enhanced Migration Transcriptional Signature in Patient Tumors.

Accumulating data shows that altered metabolic activity contributes to glioma development. Recently, modulation of SSADH (succinic semialdehyde dehydrogenase) expression, implicated in the catabolism of GABA neurotransmitter, was shown to impact glioma cell properties, such as proliferation, self-renewal and tumorigenicity. The purpose of this study was to investigate the clinical significance of SSADH expression in human gliomas. Using public single-cell RNA-sequencing data from glioma surgical resections, we initially grouped cancer cells according to ALDH5A1 (Aldehyde dehydrogenase 5 family member A1) expression, which encodes SSADH. Gene ontology enrichment analysis of genes differentially expressed between cancer cells expressing high or low levels of ALDH5A1, highlighted enrichment in genes implicated in cell morphogenesis and motility. In glioblastoma cell lines, ALDH5A1 knockdown inhibited cell proliferation, induced apoptosis and reduced their migratory potential. This was accompanied by a reduction in the mRNA levels of the adherens junction molecule ADAM-15 and deregulation in the expression of EMT biomarkers, with increased CDH1 and decreased vimentin mRNA levels. Evaluation of SSADH expression in a cohort of 95 gliomas using immunohistochemistry showed that SSADH expression was significantly elevated in cancer tissues compared to normal brain tissues, without any significant correlation with clinicopathological characteristics. In summary, our data show that SSADH is upregulated in glioma tissues irrespective of the histological grade and its expression sustains glioma cell motility.

An Unusual Presentation of Diffuse Large B-Cell Lymphoma.

Hyperlactemia is a rare and potentially fatal complication of hematologic malignancies, as well as an oncological emergency, which requires a fast diagnosis and early therapeutic management, as these interventions may alter disease prognosis. Herein, we present a case of secondary liver-biopsy-confirmed diffuse large B-cell lymphoma (DLBCL), presented with elevated liver enzymes and lactic acidosis, without depicted hepatic lesions, hepatosplenomegaly, or enlarged lymph nodes on computed tomography. This case confirms the poor prognosis of cases with delayed diagnostic intervention and highlights the importance of early clinical suspicion, liver biopsy, and prompt treatment initiation.

Epithelioid Hemangioma of Bone: A Rare Vascular Neoplasm. A Case Report and Literature Review.

Epithelioid hemangioma (EH) of bone is a rare benign, albeit locally aggressive vascular neoplasm. It is usually solitary and involves the metaphysis or diaphysis of long tubular bones, especially in the lower extremities. Rarely it may present as multifocal lesions. The differential diagnosis includes malignant vascular bone tumors such as epithelioid hemangioendothelioma and epithelioid angiosarcoma. Clinical presentation and radiographic and histological findings are not specific and diagnosis is based mostly on immunohistochemical and molecular studies. There is no consensus regarding the optimal treatment. Curettage and bone grafting or en bloc resection are the current treatment options, however local recurrence have been reported. We present a case of multifocal EH of the distal tibia, distal fibula and hindfoot in a 38 year-old male managed with curettage, radiofrequency ablation and cement osteoplasty. The imaging features, histological findings and treatment options of this rare vascular tumor are discussed.

Lymphogranuloma Venereum Mimicking Lymphoma on FDG PET/CT.

ABSTRACT: A 42-year-old man presented with painless, left inguinal lymphadenopathy, which was suspicious of malignant lymphoma. Multiple left-sided foci of markedly increased metabolic activity were observed on PET/CT (SUVmax up to 22.3), located at the inguinal, iliac, and para-aortic lymph nodes along with small-sized right inguinal lymphadenopathy. Laboratory tests revealed increased inflammation markers and neutrophilic leukocytosis. Pathological examination from dissected inguinal lymph node was consistent with granulomatous disease. Infection by chlamydia trachomatis was made serologically establishing the diagnosis of lymphogranuloma venereum.

Diagnostic challenges in a diffuse large B-cell lymphoma of the maxilla presenting as exposed necrotic bone.

Lymphoma is the second most common malignancy in the head and neck area, affecting both nodal and extranodal sites, including oral soft and hard tissues, usually in the form of non-Hodgkin's lymphoma (NHL). However, lymphomas of the jaws, including diffuse large B-cell lymphoma (DLBCL), the most common type of NHL, are very rare and may cause significant diagnostic challenges resembling common jaw pathologies, such as periapical lesions, osteomyelitis and osteonecrosis. The aim of this paper is to present a rare case of DLBCL in an 84-years-old diabetic male patient on methylprednisolone treatment for autoimmune hemolytic anemia. The lesion appeared clinically as exposed necrotic bone of the maxilla with surrounding soft tissue ulceration and radiographically as an extensive osteolytic lesion with ill-defined borders. Despite the resemblance of the lesion with osteonecrosis or osteomyelitis that could be theoretically related to diabetes and/or systemic use of corticosteroids, histopathologic examination, necessitating a repeat biopsy in order to acquire sufficient tissue, revealed the final diagnosis of lymphoma. The need for increased clinical awareness and vigilance of this possible diagnostic conundrum is emphasized. Key words:Diffuse large B-cell lymphoma, exposed bone, oral, malignancy, maxilla, jaw osteonecrosis, differential diagnosis.

Symptomatic ovarian involvement as the initial presentation of primary mediastinal large b-cell lymphoma.

Primary mediastinal large B- cell lymphoma (PMLBCL) is a mature aggressive B-cell lymphoma which affects mainly young and middle-aged women. The majority of patients present with bulky mediastinal lymphadenopathy. Extranodal involvement is a rare phenomenon at disease presentation. Herein, we describe a case of a young female with PMLBCL presenting with symptomatic, bulky ovarian involvement. The 23-year old patient presented at the Emergency Department with abdominal pain. The chest X-ray film revealed a mediastinal mass and CT scan revealed a large pelvic mass, possibly involving the ovaries. Due to the development of signs of acute abdomen, she was urgently transferred to the operation room where surgical resection of the right ovary and the adjacent mass was performed. The histological examination of the resected material revealed proliferation of PMLBCL cells. This is the first report in the scientific literature describing symptomatic ovarian mass as the initial mode of presentation of PMLBCL.

Laying the groundwork for the Biobank of Rare Malignant Neoplasms at the service of the Hellenic Network of Precision Medicine on Cancer.

Biobanks constitute an integral part of precision medicine. They provide a repository of biospecimens that may be used to elucidate the pathophysiology, support diagnoses, and guide the treatment of diseases. The pilot biobank of rare malignant neoplasms has been established in the context of the Hellenic Network of Precision Medicine on Cancer and aims to enhance future clinical and/or research studies in Greece by collecting, processing, and storing rare malignant neoplasm samples with associated data. The biobank currently comprises 553 samples; 384 samples of hematopoietic and lymphoid tissue malignancies, 72 samples of pediatric brain tumors and 97 samples of malignant skin neoplasms. In this article, sample collections and their individual significance in clinical research are described in detail along with computational methods developed specifically for this project. A concise review of the Greek biobanking landscape is also delineated, in addition to recommended technologies, methodologies and protocols that were integrated during the creation of the biobank. This project is expected to re­enforce current clinical and research studies, introduce advances in clinical and genetic research and potentially aid in future targeted drug discovery. It is our belief that the future of medical research is entwined with accessible, effective, and ethical biobanking and that our project will facilitate research planning in the '­omic' era by contributing high­quality samples along with their associated data.

Targeting post-translational histone modifying enzymes in glioblastoma.

Glioblastoma (GBM) is the most common primary brain tumor in adults, and the most lethal form of glioma, characterized by variable histopathology, aggressiveness and poor clinical outcome and prognosis. GBMs constitute a challenge for oncologists because of their molecular heterogeneity, extensive invasion, and tendency to relapse. Glioma cells demonstrate a variety of deregulated genomic pathways and extensive interplay with epigenetic alterations. Epigenetic modifications have emerged as essential players in GBM research, with biomarker potential for tumor classification and prognosis and for drug targeting. Histone posttranslational modifications (PTMs) are crucial regulators of chromatin architecture and gene expression, playing a pivotal role in malignant transformation, tumor development and progression. Alteration in the expression of genes coding for lysine and arginine methyltransferases (G9a, SUV39H1 and SETDB1) and acetyltransferases and deacetylases (KAT6A, SIRT2, SIRT7, HDAC4, 6, 9) contribute to GBM pathogenesis. In addition, proteins of the sumoylation pathway are upregulated in GBM cell lines, including E1 (SAE1), E2 (Ubc9) components, and a SUMO-specific protease (SENP1). Preclinical and clinical studies are currently in progress targeting epigenetic enzymes in gliomas, including a new generation of histone deacetylase (HDAC), protein arginine methyltransferase (PRMT) and bromodomain (BRD) inhibitors. Herein, we provide an update on recent advances in glioma epigenetic research, focusing on the role of histone modifications and the use of epigenetic therapy as a valid treatment option for glioblastoma.