The role of AHI1 and CDKN1C in cutaneous T-cell lymphoma progression.

Nov 2012

Litvinov IV, Kupper TS, Sasseville D.

Source

Division of Dermatology, McGill University Health Centre, Montréal, QC, Canada.

Abstract

Cutaneous T-cell lymphoma (CTCL) is the most common lymphoma of the skin. Recent reports suggest that AHI1 is overexpressed in a subset of CTCL-derived cell lines, where it downregulates the expression of CDKN1C tumor suppressor gene. In the current work, we test the expression of these genes in 60 patients with Mycosis Fungoides and Sezary Syndrome by RT-PCR and correlate our findings with 6 years of clinical follow-up. These findings reveal that AHI1 and CDKN1C exhibit opposite expression patterns, where AHI1 is expressed in poor and intermediate prognosis patients, while CDKN1C is expressed in favourable prognosis patients. Kaplan-Meier analysis documents that downregulation of CDKN1C is associated with poor disease outcome in patients with CTCL, while upregulation of AHI1 shows a weak association with aggressive disease course.

Wiley Online

The role of molecular analysis in cutaneous lymphomas.

Dec 2012

Deonizio JM, Guitart J.

Source

Department of Dermatology, Northwestern University, Chicago, IL.

Abstract

The purpose of this review is to summarize the most important molecular techniques for the diagnosis of cutaneous lymphomas. When making a diagnosis, we are looking for the solid clinicopathological correlation. Molecular analysis includes immunophenotyping and clonality analysis, and is important for 2 principal reasons: (1) to confirm the diagnosis in cases where the clinical and/or pathological presentations are nondiagnostic, and (2) to further characterize the nature of the lymphoma. More specifically, we are trying to discern whether the lymphoma is primarily cutaneous or systemic with secondary skin involvement, and we are also attempting to subclassify the tumor. Recently, many techniques have provided a more accurate diagnosis of cutaneous lymphomas and some prognostic implications, including polymerase chain reaction, fluorescence in situ hybridization, and flow cytometry. Fluorescence in situ hybridization is not routinely used in the diagnosis of cutaneous lymphoma, but many studies have shown potential future applications in various areas. Other techniques, such as comparative genomic hybridization, are still confined to the research arena, but have added some insight into the molecular pathogenesis of cutaneous T-cell lymphoma.

PubMed

Radiographically negative, asymptomatic, sentinel lymph node positive cutaneous T-cell lymphoma in a 3-year-old male: a case report.

2012

Carson J, Bedrnicek J, Abdessalam S.

Source

Department of General Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Abstract

We present a case of a 3-year-old male originally diagnosed with a CD30+ anaplastic cutaneous T-cell lymphoma with no evidence of systemic disease after CT scan, PET scan, and bone marrow aspiration. Sentinel lymph node biopsy (SLNB) was performed as an additional step in the workup and showed microscopic disease. Current management/recommendations for cutaneous T-cell lymphoma do not include SLNB. Medical and surgical management of cutaneous malignancies is dramatically different for local versus advanced disease. Therefore adequate evaluation is necessary to properly stage patients for specific treatment. Such distinction in extent of disease suggests more extensive therapy including locoregional radiation and systemic chemotherapy versus local excision only. Two international case reports have described SLNB in cutaneous T-cell lymphoma with one demonstrating evidence of node positive microscopic disease despite a negative metastatic disease workup. This case is being presented as a novel case in a child with implications including lymphoscintigraphy and SLNB as a routine procedure for evaluation and staging of cutaneous T-cell lymphoma if the patient does not demonstrate evidence of metastatic disease on routine workup.

NIH

Advanced/aggressive CTCL: improving the efficacy of treatment.

Dec 2012

Zinzani PL.

Source

"L. e A. Seràgnoli" Institute of Hematology, University of Bologna, Bologna, Italy.

Abstract

Treatment regimens of patients with cutaneous T-cell lymphoma (CTCL) vary widely based on clinician preference and patient tolerance. Skin directed therapies are recommended for patients with early stage IA and IB MF, with combinations used in refractory cases. While no regimen has been proven to prolong survival in advanced stages, immunomodulatory regimens should be used initially to reduce the need for cytotoxic therapies. In more advanced stages of disease, treatment efforts should strive for palliation and improvement of quality of life. With many new therapies and strategies on the horizon, the future looks promising for CTCL patients.

PubMedC

Cutaneous peripheral T-cell lymphomas, unspecified/NOS and rare subtypes: a heterogeneous group of challenging cutaneous lymphomas.

Dec 2012

Kempf W, Rozati S, Kerl K, French LE, Dummer R.

Source

Department of Dermatology, University Hospital Zürich, Zürich, Switzerland - werner.kempf@access.unizh.ch.

Abstract

Cutaneous peripheral T-cell lymphoma, unspecified/not otherwise specified (PTL NOS) represents a phenotypically and prognostically heterogenous group of cutaneous T-cell lymphomas (CTCL) that do not fit into any of well defined defined CTCL subtypes. In the WHO-EORTC classification as well as the WHO classification, three entities have been delineated as provisional rare subtypes of PTL based on their characteristic clinico-pathological, immunophenotypic and prognostic features and have been separated out from PTL, NOS: Primary cutaneous CD4-positive small/medium T-cell lymphoma(CD4+ SMTL), primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma (CD8+ AECTCL), and primarycutaneous gamma/delta T-cell lymphoma (CGD-TCL). CD4+ SMTL manifests in most patients with a solitary nodule in the head and neck area and nodular infiltrates of CD4+ small to medium-sized lymphocytes with nuclear pleomorphism. The prognosis of this lymphoproliferation is excellent in patients with a solitary lesion, but may be impaired in patients with multifocal disease. Rapidly evolving erosive or necrotic plaques and nodules with an epidermotropic infiltrate of CD8+ atypical lymphocytes are the hallmark of CD8+ AECTCL, which exhibits a poor prognosis. CGD-TCL displays a broad spectrum of clinical and histological manifestations with expression of the T-cell receptor gamma/delta chain as the common denominator and diagnostic marker. As most of other forms of PTL, CGD-TCL carries a poor prognosis. Despite the rarity of PTL NOS, clinicians as well as dermatopathologists and pathologists should be familiar with these rare CTC, especially since most of these lymphomas exhibit an unfavourable prognosis. Immediate intense treatment with multiagent chemotherapy and hematopoietic stem cell transplantation is indicated in patients with PTL NOS. This review focuses on the clinicopathological aspects, the diagnostic criteria and the classification of the rare subtypes of PTL and PTL NOS.

PubMed

MDx/CDx Focus: Phase III Adcetris Trial in Hodgkin Lymphoma; FDA Priority Review for Roche's T-DM1

MDx/CDx Focus: Phase III Adcetris Trial in Hodgkin Lymphoma; FDA Priority Review for Roche's T-DM1

November 07, 2012

Millennium, Seattle Genetics Launch Phase III Adcetris Trial in Hodgkin Lymphoma

Millennium and Seattle Genetics earlier this month initiated a Phase III trial to investigate the efficacy and safety of Adcetris, a drug being developed for the treatment of advanced Hodgkin lymphoma.

Adcetris targets the cell membrane protein CD30, which is expressed in Hodgkin lymphoma. The trial, being conducted under a special protocol agreement with the US Food and Drug Administration, will study Adcetris (brentuximab vedotin) in combination with chemotherapy as a first-line treatment for previously untreated Hodgkin lymphoma patients.

“This is a key step in our efforts to explore the potential of this targeted therapy as part of a front-line treatment regimen,” Karen Ferrante, chief medical officer of Millennium, a subsidiary of Takeda Pharmaceuticals' oncology division, said in a statement.

This trial is part of Millennium and Seattle's ongoing program to identify patient populations with CD30-expressing malignancies that might benefit from Adcetris treatment.

Earlier this year, Millennium and Seattle Genetics launched a Phase III study evaluating Adcetris in previously treated patients with CD30-expressing cutaneous T-cell lymphoma. In this study, the partners are also evaluating a companion test to identify patients with CD30-expressing malignancies. Millennium and Seattle Genetics have inked a deal with Ventana Medical Systems to develop the molecular companion diagnostic test accompanying Adcetris (PGx Reporter 5/9/2012).

Seattle Genetics Chief Medical Officer Thomas Reynolds noted in a statement that there is an unmet medical need for new treatments for Hodgkin lymphoma. This Phase III trial might lead to the development of a new front-line treatment for Hodgkin lymphoma patients, but it also may yield data that the companies can submit to the FDA to garner accelerated approval for Adcetris in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma patients.

The randomized, open-label study will compare Adcetris plus combination chemotherapy (adriamycin, vinblastine, dacarbazine) versus just chemotherapy (adriamycin, bleomycin, vinblastine, dacarbazine) in more than 1,000 patients with advanced, classical Hodgkin lymphoma. Researchers will investigate whether the Adcetris plus chemo regimen improves progression-free survival in patients compared to only chemo based on the Revised Response Criteria for malignant lymphoma. Other endpoints that will be studied include overall survival, complete remission, and safety.

Pharmacogenomics Reporter

HDAC inhibitor-based therapies: Can we interpret the code?

Oct 2012

New M, Olzscha H, La Thangue NB.

Source

Department of Oncology, Laboratory of Cancer Biology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford OX3 7DQ, UK.

Abstract

Abnormal epigenetic control is a common early event in tumour progression, and aberrant acetylation in particular has been implicated in tumourigenesis. One of the most promising approaches towards drugs that modulate epigenetic processes has been seen in the development of inhibitors of histone deacetylases (HDACs). HDACs regulate the acetylation of histones in nucleosomes, which mediates changes in chromatin conformation, leading to regulation of gene expression. HDACs also regulate the acetylation status of a variety of other non-histone substrates, including key tumour suppressor proteins and oncogenes. Histone deacetylase inhibitors (HDIs) are potent anti-proliferative agents which modulate acetylation by targeting histone deacetylases. Interest is increasing in HDI-based therapies and so far, two HDIs, vorinostat (SAHA) and romidepsin (FK228), have been approved for treating cutaneous T-cell lymphoma (CTCL). Others are undergoing clinical trials. Treatment with HDIs prompts tumour cells to undergo apoptosis, and cell-based studies have shown a number of other outcomes to result from HDI treatment, including cell-cycle arrest, cell differentiation, anti-angiogenesis and autophagy. However, our understanding of the key pathways through which HDAC inhibitors affect tumour cell growth remains incomplete, which has hampered progress in identifying malignancies other than CTCL which are likely to respond to HDI treatment.

PubMed

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma: Transformation from indolent to aggressive phase in association with CCR7-positive conversion.

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma: Transformation from indolent to aggressive phase in association with CCR7-positive conversion.

Oct 2012

Kasuya A, Hirakawa S, Tokura Y.

Source

Hamamatsu University School of Medicine Hamamatsu, Shizuoka, Japan.

Abstract

We report a case of primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma that transformed from the indolent phase to the aggressive phase. In the aggressive phase, the patient developed numerous subcutaneous lesions on the trunk, limbs, and face. The involvement of muscle, right testis, and pharynx were also found. We immunohistochemically analyzed the expression of chemokine receptors, before and after the transformation of aggressive epidermotropic CD8+ T-cell lymphoma. The transformation was accompanied by positive conversion of CCR7. CCR7 is crucial in lymphatic cell migration and chemotaxis to lymph nodes. Therefore, its expression is likely associated with the disseminated behavior of T-cell lymphoma.

PubMed

Mycosis fungoides palmaris et plantaris.

Nov 2012

[Article in German]

Pfaff S, Megahed M.

Source

Klinik für Dermatologie und Allergologie, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Deutschland, spfaff@ukaachen.de.

Abstract

Mycosis fungoides (MF) is a low-grade cutaneous T-cell lymphoma characterized by skin-homing CD4- positive helper T cells. Mycosis fungoides palmaris et plantaris is an uncommon variant primarily involving the palms and soles. An 80-year old man presented with hyperkeratotic erythematous palmoplantar changes. Clinical and histopathologic criteria led to the diagnosis mycosis fungoides palmaris et plantaris. Tumor staging using sonography of the abdomen and lymph nodes, chest x-ray and blood examination is recommended, because extracutaneous manifestations may be present.

Springerlink

PML-IRIS IN A PATIENT TREATED WITH BRENTUXIMAB.

Oct 2012

von Geldern G, Pardo CA, Calabresi PA, Newsome SD.

Source

From the Departments of Neurology (G.v.G., C.A.P., P.A.C., S.D.N.) and Pathology (C.A.P.), The Johns Hopkins Hospital, Baltimore, MD.

Abstract

A 38-year-old woman was diagnosed with cutaneous anaplastic T-cell lymphoma that proved refractory to methotrexate, bexarotene, denileukin diftitox, interferon γ-1b, interferon α-2b, vorinostat, and pralatrexate. She was therefore started on the newly approved monoclonal anti-CD30 antibody brentuximab vedotin. Treatment with brentuximab 1.8 mg/kg IV every 3 weeks quickly led to disappearance of her cutaneous tumors. The day after her second brentuximab infusion she developed word-finding difficulties and unsteady gait. Due to further neurologic deterioration, she was admitted to an outside hospital. Brain MRI revealed multifocal enhancing white matter lesions throughout bilateral cerebral hemispheres and posterior fossa (figure, A-C). Brain biopsy was performed 15 days after her last brentuximab dose to rule out metastases and she was diagnosed with progressive multifocal leukoencephalopathy (PML) (figure, J). The patient was discharged home with hospice care. Upon discharge, she was started on prednisone 50 mg daily to help treat her eczema. Her family brought her to our clinic for a second opinion.

Neurology

Painful and rapidly growing exophytic lesion of the vestibular upper lip

Nov  2012

[Article in German]

Trempler C, Maurer P, Wysluch A.

Source

Abteilung für Mund-, Kiefer- und Gesichtschirurgie, Klinikum Bremerhaven-Reinkenheide gGmbh, Postbrookstr. 103, 27574, Bremerhaven, Deutschland, christina.trempler@klinkum-bremerhaven.de.

Abstract

A 49-year-old healthy woman presented with a painful exophytic-growing mucous lesion on her upper lip that had been primarily noted for 2 weeks. The biopsy showed histological changes of a dense infiltration of lymphoid cell elements. The immunohistological examination presented the diagnosis of primary cutaneous CD30-positive large cell T-cell lymphoma. In the diagnosis of oral lesions cutaneous CD30-positive large cell T-cell lymphoma constitutes a rare but important differential diagnosis.

Springerlink