No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
Systemic Therapy of Cutaneous T-Cell Lymphomas (Mycosis Fungoides and the Sezary Syndrome)
... It was first synthesized in 1935 and in the same year for the first time it was applied to tumors in laboratory animals [1][2][3]. Finally, in 1946, after clinical trials, pharmacologists predicted that it could be used to treat prostate cancer, Hodgkin's disease, lymphomas andleukemia, etc. [4,5]. This anticancer drug binds to DNA and crosslinking two strands to prevent cell duplication. ...
... To understand the thermodynamic stability of our complexes, we also investigated the thermodynamic parameters such as the change in enthalpy (ΔH), Gibbs free energy (ΔG) and entropy (ΔS) by using equation (4)(5)(6) and the values are tabulated in Table 2. The positive values of ΔH and ΔG represent the reaction process is an endothermic and non-spontaneous whereas the negative values of ΔH and ΔG indicate the reaction is an exothermic and spontaneous process [66]. ...
The chlormethine (CM) drug adsorption on C24, B12C6N6 and B12N12 nanocages has been investigated by using density functional theory at B3LYP/6-31G(d,p) method. Also, the adsorption energy (EAd) investigation of the CM adsorbed complexes has been done by using wB97XD functional to understand the non-local dispersion interactions. Our study reveals that C24 and B12C6N6 nanocages are unfavorable (very low value of EAd) for CM drug adsorption but B12N12 is a promising adsorbent for this drug as EAd of CM/B12N12 complex is -101.70 kJ/mol (-84.77 BSSE corrected) at B3LYP method and -139.70 kJ/mol (-123.43 BSSE corrected) at wB97XD method. NBO and Mulliken charge analysis predicts that large charge transfer occurs from CM to B12N12 about 0.324|e| and 0.259|e| respectively. Also, the spontaneous and favorable interaction between CM drug and B12N12 nanocage is also confirmed by the investigation of solvation Gibbs free energy and quantum theory of atoms in molecules analysis.
... It was first synthesized in 1935 and works as a binding element to DNA, can establish cross-linkage between two constituents and prevent cell replication [1,2]. It is used for the treatment of prostate cancer, lymphoid malignancies such as Hodgkin's disease, lymphosarcoma, chronic myelocytic leukemia, polycythemia vera, bronchogenic carcinoma [3][4][5]. Also, the topical formulation of this drug is very effective in skin diseases and mycosis fungoides-type cutaneous T cell lymphoma [3,4]. This drug is a key element for the synthesis of pethidine which is used to relieve the pain during childbirth [6]. ...
The application of nanomaterials as drug delivery vehicles for a vast number of anticancer drugs to reduce their severe adverse effects by transporting them into the targeted tumour cell region is currently a widely investigated novel biomedical application of various nanomaterials. In this research work, we have investigated the performance of the pristine B12N12 nanocage (BN) and several other transition metal (TM) functionalized BN nanostructures as a drug delivery vehicle for Chlormethaine (CM) anticancer drug using DFT B3LYP/6-31G (d, p) level of theory. Among our investigated nanostructures, we have found Ni-BN as the most prominent nanostructure to form a drug delivery complex to transport CM drug by exhibiting the most stable adsorption of CM drug in both gas (−39.04 kcal/mol) and water (−30.93 kcal/mol) medium with an increase in the dipole moment from 3.57 (8.37) Debye to a maximum of 7.88 (12.11) Debye in the gas (water) medium. The interaction of CM drug with the nanostructures is also confirmed from the frontier molecular orbitals and QTAIM analysis. The NBO, MEP, and fractional charge transfer analysis reveals a significant charge transfer from CM drug molecules to the nanostructures. Finally, with the confirmation of stable adsorption of CM drug on each investigated nanostructures with negative values for the stabilization energies ranging −0.117 to −0.247 eV, the complexes were also found to be stable on the water medium with negative values for the solvation energies which is favorable for the CM drug delivery applications
Advances in the biology of lymphoid cells have greatly improved the classification and understanding of the pathogenesis of primary cutaneous lymphomas. Classification is based on clinical, pathological, immunopathological, molecular and cytogenetic findings and recognises that the site of origin of extranodal lymphomas and tumour morphology determines clinical behaviour, which in turn has a critical influence on prognosis and therapeutic approach. Mycosis fungoides and its variants are the most common primary cutaneous T‐cell lymphoma subset, but other subsets with clearly identifiable clinicopathological features and varying prognoses have also been described. A critical observation has been the realisation that lymphomas with a similar pathology arising in different organs have different prognoses and distinct pathogenesis: nodal CD30+ anaplastic large‐cell lymphomas are usually anaplastic lymphoma kinase (ALK) positive but ALK‐negative variants are associated with a poor prognosis, whereas primary cutaneous CD30+ anaplastic large‐cell lymphomas are invariably ALK negative and have a good prognosis. The majority of primary cutaneous B‐cell lymphomas also have an excellent prognosis, and primary cutaneous follicle centre lymphomas are pathogenetically distinct from nodal follicular lymphomas. Furthermore, it is appreciated that cutaneous and systemic T‐cell lymphomas are usually derived from specific tissue‐resident T‐cell subsets.
Primary cutaneous lymphomas are extranodal non‐Hodgkin lymphomas and consist of different variants defined by specific clinicopathological and immunophenotypic features. Primary cutaneous T‐cell lymphomas are the most common subset and are derived from resident memory T cells, whereas primary cutaneous B‐cell lymphomas are more closely related to their nodal counterparts with derivation from B cells at different stages of differentiation. Whilst the underlying pathogenesis of cutaneous lymphomas remains unclear, there is emerging evidence for a heterogenous pattern of somatic mutations and epigenetic events. Although the prognosis for many indolent primary cutaneous lymphoma variants remains excellent, the treatment of some rare variants and advanced stages of mycosis fungoides and Sezary syndrome represents an unmet medical need in view of high levels of chemotherapy resistance and limited durable responses. A variety of novel biological agents have been recently approved but long‐term remissions are rare. There is still an urgent need to clarify the underlying molecular pathogenesis and identify more effective targeted therapies for mycosis fungoides and Sézary syndrome.
The efficacy of pure and aluminum (Al)-doped boron nitride nanocarriers (B12N12 and AlB11N12) in adsorbing Chlormethine (CM), an anti-cancer drug, was comparatively dissected by means of the density functional theory method. The CM···B12N12 and ···AlB11N12 complexes were studied within two configurations, A and B, in which the adsorption process occurred via N··· and Cl···B/Al interactions, respectively. The electrostatic potential affirmations confirmed the opulent ability of the studied nanocarriers to engage in delivering CM via two prominent electrophilic sites (B and Al). Furthermore, the adsorption process within the CM···AlB11N12 complexes was noticed to be more favorable compared to that within the CM···B12N12 analog and showed interaction and adsorption energy values up to –59.68 and −52.40 kcal/mol, respectively, for configuration A. Symmetry-adapted perturbation theory results indicated that electrostatic forces were dominant in the adsorption process. Notably, the adsorption of CM over B12N12 and AlB11N12 nanocarriers exhibited predominant changes in their electronic properties. An elemental alteration was also revealed for the softness and hardness of B12N12 and AlB11N12 nanocarriers before and following the CM adsorption. Spontaneity and exothermic nature were obviously observed for the studied complexes and confirmed by the negative values of thermodynamic parameters. In line with energetic manifestation, Gibbs free energy and enthalpy change were drastically increased by the Al doping process, with values raised to –37.15 and –50.14 kcal/mol, respectively, for configuration A of the CM···AlB11N12 complex. Conspicuous enhancement was noticed for the adsorption process in the water phase more than that in the gas phase and confirmed by the negative values of the solvation energy up to −53.50 kcal/mol for configuration A of the CM···AlB11N12 complex. The obtained outcomes would be the linchpin for the future utilization of boron nitride as a nanocarrier.
Overview
Mycosis fungoides (MF) and its leukemic variant, Sézary syndrome (SS), are the most common cutaneous T‐cell lymphomas. MF/SS originates in the skin and presentation may vary from limited patches to erythroderma and/or widespread cutaneous tumors. Although patients with limited patch‐plaque disease generally have an indolent course with favorable prognosis and survival similar to age‐matched control populations, patients who present with cutaneous tumors or extracutaneous disease have a relentless progressive course of disease. Treatments for patients with limited disease are primarily skin‐directed and include various topical therapies including steroids, chemotherapy (nitrogen mustard), retinoids (bexarotene), immunomodulators (imiquimod), radiation therapy, and phototherapy. When the disease is advanced, skin‐directed therapies are still often needed, but systemic treatment becomes essential. Conventional chemotherapy (single agent or combination) is frequently not effective. However, nonchemotherapeutic systemic agents such as retinoids, extracorporeal photopheresis, histone deacetylase inhibitors, the interferons, mogamulizumab, brentuximab vedotin, alemtuzumab, and checkpoint inhibitors may achieve responses. Durable responses are not normally observed and patients will typically require multiple sequential therapies with different mechanisms of action to maintain adequate disease control. Allogeneic hematopoietic cell transplant can be curative in select cases.
In the present research, the adsorption and release of chlormethine (CM) drug on the B24O24 nanocage have been reported in the water media and gas phase at GGA/PBE/DNP computational level. The interaction between B24O24 nanocage and CM drug shows that adsorptions of the chlormethine on B24O24 nanocage for the most stable complexes are - 1.47 to - 1.36 eV in the gas phase and water media, respectively. The CM adsorption caused a notable change in the band gap (Eg) and work function (Φ) of the B24O24 nanocage in the studied complexes. The binding of chlormethine to B24O24 also significantly increased the polarity of the drug carrier, which is a desirable property for drug delivery in biological environments. CM drugs can be released from the nanocage in the presence of an external electric field along the X-axis direction. The present study results show that the B24O24 nanocage is a possible carrier for delivering chlormethine drugs.
Development of resistance to currently available standard therapies in advanced prostate cancer (PCa) emphasizes the need for novel therapeutic options. Here, we report the synthesis of new hybrid molecules consisting of 2-chloroethylthio and 1,4-naphthoquinone pharmacophores and describe their activity in PCa. In screening analyses, the introduction of one 2-chloroethylthio group improved the anticancer properties of 1,4-naphthoquinones, whereas the introduction of a second 2-chloroethylthio moiety rather decreased activity. Two most promising of the synthesized compounds, 30 and 32, were highly active in different human PCa cell lines harboring varying resistance profiles at nanomolar concentrations. The generated data suggest that the compounds are capable of mitochondria targeting, cytotoxic ROS induction, and DNA damage, which resulted in apoptosis presumably executed in a caspase-dependent manner. The substances synergized with the clinically approved PARP inhibitor olaparib and resensitized AR-V7-expressing PCa cells to antiandrogen enzalutamide, as well as to a combination of enzalutamide and an AKT inhibitor. This was at least in part exerted via down-regulation of AR-V7 expression and inhibition of AR signaling. Mild antagonism was observed in combination with platinum- or taxane-based chemotherapy, which was putatively related to treatment-induced activation of p38, JNK1/2, ERK1/2, MEK1/2, and AKT, functioning as potential pro-survival factors. Thus, the synthesized (2-chloroethylthio)-1,4-naphthoquinone derivatives exhibit promising anticancer properties in vitro, suggesting their further development as potential therapeutics for the treatment of castration-resistant PCa.
Simple Summary
In the last few years, the field of cutaneous T-cell lymphomas has experienced major advances. In the context of an active translational and clinical research field, next-generation sequencing data have boosted our understanding of the main molecular mechanisms that govern the biology of these entities, thus enabling the development of novel tools for diagnosis and specific therapy. Here, we focus on mycosis fungoides and Sézary syndrome; we review essential aspects of their pathophysiology, provide a rational mechanistic interpretation of the genomic data, and discuss the current and upcoming therapies, including the potential crosstalk between genomic alterations and the microenvironment, offering opportunities for targeted therapies.
Abstract
Primary cutaneous T-cell lymphomas (CTCLs) constitute a heterogeneous group of diseases that affect the skin. Mycosis fungoides (MF) and Sézary syndrome (SS) account for the majority of these lesions and have recently been the focus of extensive translational research. This review describes and discusses the main pathobiological manifestations of MF/SS, the molecular and clinical features currently used for diagnosis and staging, and the different therapies already approved or under development. Furthermore, we highlight and discuss the main findings illuminating key molecular mechanisms that can act as drivers for the development and progression of MF/SS. These seem to make up an orchestrated constellation of genomic and environmental alterations generated around deregulated T-cell receptor (TCR)/phospholipase C, gamma 1, (PLCG1) and Janus kinase/ signal transducer and activator of transcription (JAK/STAT) activities that do indeed provide us with novel opportunities for diagnosis and therapy.
Since the publication of the Japanese “Guidelines for the management of cutaneous lymphomas” in 2011, the World Health Organization (WHO) classification of hematolymphoid neoplasms and the WHO–European Organisation for Research and Treatment of Cancer classification for primary cutaneous lymphomas were updated and a number of novel systemic drugs for cutaneous T‐cell lymphoma had been approved in Japan. In 2020, we revised the Japanese guidelines for the management of cutaneous lymphomas with consideration of the recent advances in the understanding of the pathophysiology and classification of cutaneous lymphomas together with the update of treatment strategies reflecting the advent of novel drugs. In addition to a brief explanation of epidemiology, diagnosis, staging system, prognosis and management of each subtype of cutaneous lymphomas, the recommendations for nine clinical questions regarding treatment options that can vary even among experts are also described. A systematic review process and determination of recommendations in answer to each clinical question have been performed in accordance with the Grading of Recommendations, Assessment, Development and Evaluation scheme by a multidisciplinary expert panel consisting of dermatologists, a hematologist and a radiation oncologist. In this article, we present the outlines of the revised Japanese “Guidelines for the management of cutaneous lymphomas”.
Cytotoxic agents are a class of drug that are used to treat severe and/or refractory skin disease. Examples methotrexat, azathioprine, mycophenolate mofeti, topical 5-fluoruracil, thioguanine, hydroxyurea, cyclophosphamide and chlorambucil, with melphalan. These drugs have numerous toxicities and the therapeutic advantage afforded by these medications must be balanced against the consequences of use. In a general sense, the side effects of these medicines may include carcinogenesis, teratogenesis, and myelosuppression, and familiarity with dosing regimens, common toxicities, and proper laboratory monitoring schedules is necessary for successful use.
Sézary syndrome is a leukemic form of epidermotropic cutaneous T-cell lymphoma related to the malignant proliferation of clonal CD4+ T cells. Extracorporeal photochemotherapy may induce a transient improvement of the clinical signs, but its efficiency is discussed. To investigate the frequency of the T-cell clone in the peripheral blood of patients with Sézary syndrome and to monitor its evolution in patients treated using extracorporeal photopheresis or chemotherapy, we used the immunoscope technique. In one patient, we observed a decrease of the relative frequency of the clone from 15.6% to 0%, paralleling a complete remission of the clinical disease and a disappearance of the circulating Sézary cells. In the other cases, the evolution of the relative frequency paralleled the initial improvement of the clinical status and the absence of long-term efficiency in patients treated with extracorporeal photopheresis or chemotherapy. We observed a quick-acting direct cytotoxicity of the association 8MOP + UVA on the T-cell clone. The immunoscope technique appears to be an efficient tool to appreciate the amount of tumoral cells and to monitor the evolution of the clonal component in the Sézary syndrome.
Mycosis fungoides and Sézary syndrome are the most common types of primary cutaneous T cell lymphomas. The clinical presentation of mycosis fungoides is generally indolent, whereas Sézary syndrome represents a more aggressive disease variant. Stage at diagnosis is the most important determinant of long-term survival outcome. Although most patients present with early-stage disease, those who develop progressive disease or have an advanced stage represent a therapeutic challenge because of a lack of effective therapies. Allogeneic hematopoietic cell transplantation (allo-HCT) has been used as a potentially curative treatment modality with encouraging long-term outcomes. However, a lack of randomized controlled data remains, and the published literature is limited to mostly retrospective studies. We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE, and Cochrane reviews on September 13, 2018. We extracted data on clinical outcomes related to benefits (overall [OS] and progression-free [PFS] survival) and harms (relapse and nonrelapse mortality [NRM]) independently by 2 authors. Our search strategy identified 289 references. Five studies (266 patients) were included in this systematic review and meta-analysis. Reduced-intensity and nonmyeloablative regimens were more commonly prescribed (76%). Mobilized peripheral blood stem cells were the preferred graft source (78%). The pooled OS and PFS rates were 59% (95% confidence interval [CI], 50% to 69%) and 36% (95% CI, 27% to 45%), respectively. Pooled relapse rate was 47% (95% CI, 41% to 53%) and pooled NRM rate 19% (95% CI, 13% to 27%). Results of this systematic review and meta-analysis show that allo-HCT yields encouraging OS and PFS rates; however; relapse remains a significant cause of allo-HCT failure. Novel strategies to further improve outcomes should focus on offering allo-HCT before the development of resistant disease and reducing relapse by incorporating post-transplant maintenance therapies.
Nitrogen mustards, a family of DNA alkylating agents, marked the start of cancer pharmacotherapy. While traditionally characterized by their dose-limiting toxic effects, nitrogen mustards have been the subject of intense research efforts, which have led to safer and more effective agents. Even though the alkylating prodrug mustards were first developed decades ago, active research on ways to improve their selectivity and cytotoxic efficacy are a currently active topic of research. This review addresses the historical development of the nitrogen mustards, outlining the mechanism of action, and discussing the improvements on their therapeutic profile made through rational structure modifications. A special emphasis is made on discussing the nitrogen mustard prodrug category, with cyclophosphamide (CPA) serving as the main highlight. Selected insights on the latest developments on nitrogen mustards are then provided, limiting such information to agents that preserve the original nitrogen mustard mechanism as their primary mode of action. Additionally, future trends that might follow in the quest to optimize these invaluable chemotherapeutic medications are succinctly suggested.
Background& Objective: Nitrogen mustard derivatives form one of the major class of the anti-cancer agents according to the USFDA approved drugs. These are polyfunctional alkylating agents which are distinguished by a unique mechanism of adduct formation with the DNA that involves a cross-linking between guanine N-7 of one strand of DNA with the other. The generated cross-linking is irreversible and leads to cell apoptosis. Thus, there is an upsurge in the interest to explore this class of anticancer alkylating agents.
Methods:
From an exhaustive list of reviews, research articles, patents, books, patient information leaflets, and the orange book the contents related to nitrogen mustard anti-cancer agents have been reviewed. We have attempted to present the synthesis schemes in a simplified manner along with the elaborated mechanism of action of the drugs and their side effects.
Results:
This review provides a platform for understanding all the aspects of such drugs right from the synthesis to their mechanism of action and side effects and lists the approved Abbreviated New Drug Applications (ANDA)among the alkylating anticancer agents in the current market.
Conclusion:
The present review will help to envisage the scientific community to access the literature information in this domain, in order to gain insights about the nitrogen mustard alkylating agents for further ANDA development. It will help the scientific and research community to continue their pursuit for the design of newer and novel heterocyclic alkylating agents of this class in near future.
Novel systemic therapies are generally prescribed to patients with advanced-stage disease or those with early-stage disease refractory to skin-directed therapies. In general, systemic chemotherapy should be reserved for patients who fail to respond to biological agents. Such biological agents include interferon alfa, bexarotene, histone deacetylase inhibitors (vorinostat, romidepsin), brentuximab vedotin and mogamulizumab. Extracorporeal photopheresis is particularly effective for patients with Sézary Syndrome. Allogeneic transplantation is becoming increasing used for younger patients. Novel agents in advanced development include the monoclonal antibody IPH4102,duvelisib,and the new modified formulation of denileukin diftitox. The choice of agents for patients is typically a balance of patient factors (age, co-morbidities, geographic location), relative efficacy and toxicity.
Introduction: Folliculotropic mycosis fungoides (FMF) is a cutaneous T cell lymphoma that is recognized as a distinct variant of mycosis fungoides (MF) due to its unique clinicopathologic features and its more aggressive disease course as compared to classic MF. Recent studies distinguished an indolent (early stage FMF) and a more aggressive (advanced stage FMF) subgroup, that require a different therapeutic approach.
Areas covered: This review provides an overview of the evolving concepts and recent developments in FMF and summarizes various treatment options for early and advanced stages of FMF including skin-directed therapies, immunomodulating agents, HDAC inhibitors, targeted anti-CD30 therapy and the role of chemotherapy and haematological stem cell transplantation.
Expert opinion: Recently defined prognostic subgroups show that early stage FMF patients have an indolent disease course and may benefit very well from skin-directed therapies, also used in early stage classic MF. Advanced skin limited FMF patients benefit most from radiotherapy based treatment modalities. Systemic chemotherapy is reserved for patients with extracutaneous dissemination or progressive disease that cannot be controlled with skin-directed or immunomodulating therapies.
Background:
Advanced-stage mycosis fungoides (MF)/Sézary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival.
Patients and methods:
This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese).
Results:
Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks.
Conclusion:
This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach.
Der M. Hodgkin
ist eine seltene Erkrankung, die Häufigkeit beträgt etwa 0,7 % aller bösartigen Erkrankungen und die Todesrate liegt bei etwa 0,3 % aller Todesfälle durch Malignome. Die Morbidität liegt bei etwa 3,1 pro 100.000 Einwohner, Männer sind etwas häufiger betroffen als Frauen (1,1:1), die Altersverteilung weist 2 Gipfel auf, zwischen 25 und 35 Jahren und zwischen 60 und 75 Jahren.
Primary cutaneous T-cell lymphomasTreatment of mycosis fungoides and Sézary syndromeCD30+ cutaneous lymphoproliferative disordersSecondary cutaneous lymphomasPrimary cutaneous B-cell lymphomasSecondary cutaneous B-cell lymphomasPseudolymphomasLeukaemia cutisCutaneous Hodgkin's diseaseLennert's lymphoma
Overview
Mycosis fungoides/Sézary syndrome (MF/SS) is the most common cutaneous T‐cell lymphoma. It originates in the skin and its presentation may range from very limited patch disease to wide‐spread cutaneous tumors. When there is peripheral blood involvement, usually in conjunction with erythroderma, it is known as the SS. Although patients with limited patch disease have a very long natural history, respond to a variety of topical therapies, and even enjoy a survival similar to age‐matched control populations, patients who present with cutaneous tumors or extracutaneous disease have a relentless progressive course of disease. Treatments for patients with limited disease are primarily topical and include topical chemotherapy (nitrogen mustard), radiation therapy, and phototherapy. When the disease is advanced, topical therapies are still often needed, but systemic treatment becomes essential. Conventional chemotherapy (single agent or combination) is often not effective. However, systemic biologics such as histone deacetylase inhibitors, the interferons, photopheresis, alemtuzumab, and brentuximab vedotin may achieve responses. Most recently, hematopoietic cell transplant, especially with nonablative conditioning regimens, has shown promising results in a cohort of patients with advanced MF or SS.
Etwa 20% aller malignen Geschwülste des Menschen sind an der Haut lokalisiert. Mehr als 90% dieser Patienten sind älter als 50 Jahre. Die Entwicklung der Hautkrebse zeigt deutlich den Einfluß exogener Faktoren. An erster Stelle steht die Lichtexposition, weitere ätiologische Faktoren sind chemische und entzündliche karzinogene Reize (Arsen, Teer, Röntgenstrahlen, Narben). Diese chronischen Reize bewirken Hautveränderungen, die über das Stadium einer länger bestehenden Präkanzerose schließlich zum Hautkarzinom entarten.
Introduction:
CTCL are rare neoplasms. Optimal care requires integrated use of diagnostic and treatment modalities spanning multiple specialties. Current instruments for patient risk stratification and disease measurement across all anatomical compartments are suboptimal. A common treatment dichotomy between early (Dermatology) and advanced stage (Hematology-Oncology) has hindered accrual of long term outcome data. Thus, important facts about natural history, such as frequency and determinants of stage progression, and the impact of specific treatment modalities on these endpoints, are not known. Areas covered: One of the most important decisions in the management of CTCL is when to start systemic therapy and what agents to use. This review provides background information to understand why systemic therapy is needed and what goals are currently achievable. Expert commentary: Risk-adapted approaches, based on better knowledge of host and tumor biology, and more accurate disease measurement tools are needed to optimize the use of specific systemic therapies.
Der Arzt ist nicht nur Erbringer von apparativen und operativen Leistungen, sondern auch Vertrauensperson und psychologischer Begleiter des Patienten. Gespräche mit onkologischen Patienten über Dignität, Therapiemöglichkeiten und Prognose der Erkrankung bereiten vor allem jüngeren Kollegen Probleme, da sie oft weder über das erforderliche Fachwissen noch über genügend Erfahrung in Patientenführung verfügen. Die Aufklärung sollte weitgehend individuell dem Persönlichkeitsprofil des Patienten angepasst werden und in der Regel dem Grundsatz „Die Wahrheit, aber nicht die Realität vermitteln“ folgen. So hat zum Beispiel ein Patient mit Melanommetastasen das Recht, über Ausmaß der Erkrankung und Therapieoptionen genau informiert zu werden (zum Beispiel „Es finden sich einzelne neue Herde in der Lunge. Die Computertomographie lässt vermuten, dass zumindest einer von ihnen vom ursprünglichen Melanom stammen kann. Insgesamt muss man die Lage als sehr ernst bezeichnen. Wir müssen einige diagnostische und therapeutische Möglichkeiten besprechen. Im Übrigen möchte ich Sie auch den Kollegen von der Thoraxchirurgie vorstellen … “). Da der individuelle Verlauf einer Erkrankung nie exakt vorausberechenbar ist, wäre es absolut kontraproduktiv, demotivierend und zudem sachlich falsch, den Patienten mit Prognosezahlen zu konfrontieren („Sie haben noch sechs Monate zu leben!“), die einer Statistik entstammen und die enorme Variationsbreite der individuellen Entwicklung nicht wiedergeben.
Up to 30% of acute lymphoblastic leukaemias (ALLs) and 10%–20% of non-Hodgkin’s lymphomas (NHLs) are of T cell lineage (Collins 1982). In many respects, much less is known of the T cell leukaemias and lymphomas then the B cell malignancies, and it is only recently that they have been studied in the detail previously accorded the B cell neoplasms. The classification of T cell malignancies is even more controversial than the classification of B cell malignancies. No more than a few authors have attempted to provide a comprehensive classification of this subject (Catovsky et al. 1982a; Collins 1982; Kadin et al. 1983; Leong 1984). As with the B cell neoplasms, it is not always possible to make a distinction between lymphoma and leukaemia. In fact, the overlap is even more pronounced in the T cell malignancies and the use of the term “lymphoma/leukaemia” is often more appropriate.
Sowohl die orale Photochemotherapie (PUVA) als auch die systemische Therapie mit Interferonen haben sich in der Behandlung kutaner T-Zell-Lymphome als erfolgreich erwiesen. Zur Verbesserung der Behandlungsergebnisse wurde daraufhin die Kombination dieser beiden Therapieformen untersucht, die sich in ersten nicht kontrollierten Studien ebenfalls als sehr wirksam zeigte. Um die Wertigkeit der Interferongabe zusätzlich zu einer PUVA-Therapie vergleichend zu untersuchen, wurde 1996 ein multizentrisches prospektives randomisiertes Therapieoptimierungsprotokoll PUVA versus Interferon α2a plus PUVA bei Patienten mit kutanen T-Zell-Lymphomen der Stadien IA bis IIA begonnen. Eine erste Zwischenanalyse zeigt bei einer höheren Rate kompletter Remissionen im IFN+PUVA-Arm (63,6 versus 55,9%) eine kürzerer Abheilungszeit mit deutlich geringerer UVA-Dosis (47)5 versus 163,9 J/cm2). Vorbehaltlich der Endauswertung ergibt sich somit ein Vorteil durch die Kombination Interferon α2a mit PUVA bei Patienten mit kutanen T-Zell-Lymphomen im Stadium IA bis IIA.
Cutaneous lymphomas (CL) comprise a heterogeneous group of diseases that are characterized by a clonal accumulation of lymphocytes in the skin. Cutaneous lymphoproliferative disorders can present in the skin alone, in the skin and extracutaneous sites, or as extracutaneous disease with secondary skin involvement. In a strict sense, they are lymphoproliferative disorders primarily manifesting in the skin and being confined to the skin for ever or at least for many years [1]. Malignant lymphomas can originate from cells at any level of differentiation between stem cells and the peripheral differentiated B- or T-lymphocytes. There is growing evidence that a clonal disease may have different clinical and histologic features, depending not only on the time-point in the disease process, but also probably on the state of activation [2]. In many cases the histopathologic evaluation of biopsies maybe extended to include immunophenotyping (immunologic analysis of cellular antigen expression using antibodies) or immunogenotyping (molecular analysis of antigen receptor genes).
Unter den kutanen T-Zell-Lymphomen (CTCL) versteht man eine Gruppe verschiedener Non-Hodgkin-Lymphome, die sich primär an der Haut manifestieren und deren Infiltrate zum Großteil aus malignen T-Lymphozyten bestehen. Die häufigste klinische CTCL-Variante ist die sogenannte Mycosis fungoides (MF). Die MF gehört zu den niedrigmalignen Non-Hodgkin-Lymphomen, deren klinischer Verlauf durch eine langsame Progression von einem frühen Plaquestadium über ein Tumorstadium bis hin zur Lymphknoten- und Organbeteiligung gekennzeichnet ist. Häufig überlappen sich jedoch die klinischen Stadien, oder es kommt zum Überspringen einzelner Stadien. Das Sézary-Syndrom (SS) ist eine Sonderform der MF mit generalisiertem Hautbefall im Sinne einer Ery-throdermie und einer Leukozytose mit malignen Lymphozyten. Weitere typische klinische Zeichen sind Befall der Handflächen und Fußsohlen mit palmoplantarer Hyperkeratose und tumoröse Infiltrate des Gesichtes (Facies leonina). MF und SS sind histopathologisch durch infiltrierende und/oder zirkulierende kleine T-Lymphozyten mit zerebriformen Zellkernen gekennzeichnet, die typischerweise den T-Helferphänotyp aufweisen (CD3+, CD4+, CD8+)
.
Die Mycosis fungoides (MF) und ihre leukämische Variante, das Sézary-Syndrom (SS), sind die häufigsten kutanen Lymphome. In der adaptierten Kiel-Klassifikation für kutane Lymphome entsprechen sie den kleinzelligen, peripheren T-Zell-Lymphomen mit niedrigem Malignitätsgrad [5, 7]. Die Erkrankungen sind relativ selten. Die Inzidenz dürfte bei etwa 4 Fällen pro 100 000 Einwohner pro Jahr liegen [41].
Die peripheren T-Zell-Leukämien/-Lymphone umfassen eine Vielzahl histologisch definierter Subentitaäten, wie T-PLL/T-CLL,LGL-leukämie,Mycosis fungoides/Sézary-Syndrom, pleomorphe T-Zell-Lymphome oder das angioimmunoblastische Lymphom (AILD) (Kiel- und R.E.A.L.-Klassifikation) (Tabelle 1).
The skin is an immunoregulatory organ that hosts various types of immunoregulatory cells, both professional ones (such as lymphocytes and dendritic cells) and nonprofessional ones (such as keratinocytes, endothelial cells, and others), which may become actively involved under certain pathophysiologic circumstances in immunoregulatory events. These cells are either resting in or traveling through the skin depending on a network of chemotactic, adhesion, promoting, or blocking factors in a permanently interactive feedback context.
Zytokine sind Mediatorstoffe von niedrigem Molekulargewicht, die von verschiedenen Zellen produziert werden und unter physiologischen und pathologischen Bedingungen von großer Bedeutung sind.
Die bösartigen Geschwulstkrankheiten lymphatischer Gewebe (maligne Lymphome) werden in zwei Hauptgruppen eingeteilt, die sich histopathologisch und in ihrem biologischen Verhalten vielfach unterscheiden, nämlich einerseits Morbus Hodgkin (Lymphogranulomatose), und andererseits ein ganzes Spektrum unterschiedlicher Entitäten, für welches sich in neuerer Zeit der Terminus Non-Hodgkin-Lymphome (NHL) eingebürgert hat. Der vorliegende Beitrag befaßt sich hauptsächlich mit den NHL des Erwachsenenalters.
Primary cutaneous lymphomas (PCL) are a heterogeneous group of non-Hodgkin’s lymphomas that characteristically present on the skin. By definition, extracutaneous involvement at the moment of diagnosis must be absent.
PCL are rare diseases. Annual incidence is around 0.4–1/100.000. About two-thirds have T-cell origin and the rest, B-cell origin. Given that PCL can be easily reached, skin-directed treatments (alone or in combination with systemic agents) are frequently used (phototherapy, photochemotherapy, radiotherapy, topical treatments or intralesional infusion of several drugs). Skin-directed therapies are out of the scope of this chapter and will be treated elsewhere.
The choice of treatment will depend on the type of PCL and the stage of the disease. Some of our cases will need systemic approach from the beguinning. Others will not be treated systemically almost never.
Non-Hodgkin Lymphome (NHL) umfassen eine Gruppe von Erkrankungen, die durch eine monoklonale Proliferation von B- oder T-Lymphozyten (oder ihrer Vorl?uferzellen) hervorgerufen sind. Ihr neoplastisches Wachstum erfolgt im lymphatischen System (?nodal?) und/oder au?erhalb desselben (?extranodal?). Die einzelnen Lymphomentit?ten k?nnen als Reifungsstorung (?frozen states?) in der Entwicklung normaler B- oder TLymphozyten aufgefa?t werden. In der vorliegenden ?bersicht beziehen wir uns in erster Linie auf die Kiel-Klassifikation, die neben zytologischen vor allem auch funktionelle Gesichtspunkte ber?cksichtigt (?bersicht bei [221, 222, 354]). Daneben wird die Working Formulation (WF) [280] angef?hrt, die sich vor allem nach den von Lukes und Collins erarbeiteten histomorphologischen Kriterien orientiert (z. B. ?cleaved cells? als morphologisches Kriterium vieler Keimzentrumszellen). Sie ber?cksichtigt auch das Wachstumsverhalten (follikul?r, diffus). Dies stellt wie zuerst Rappaport und seine Gruppe zeigten [269, 311] ein besonders wichtiges Prognosekriterium dar.
Primary cutaneous T cell lymphoma is a rare malignant disease, and the most common clinicopathological subtypes are mycosis fungoides and Sézary syndrome. Disease management is based largely on uncontrolled studies. Current treatments, particularly in the later stages of disease, often provide only short-lived responses, and there is an urgent need for more effective therapies in all stages of the disease. The recent publication of a consensus statement outlining clinical end points and response criteria will promote standardization in future clinical trials
Background
What are the effects of topical therapy in mycosis fungoides?What are the effects of phototherapy in MF/SS?What are the effects of immunotherapy in MF/SS?What are the effects of systemic retinoids in MF/SS?What are the effects of antibody and toxin therapies in MF/SS?What are the effects of radiotherapy in MF/SS?What are the effects of single agent chemotherapy in MF/SS?What are the effects of multiagent chemotherapy regimens in MF/SS?Conclusions
Although cutaneous lymphomas arising in skin are rare, they can be the cause of significant morbidity and mortality. The most common of the cutaneous T-cell lymphomas (CTCLs) are mycosis fungoides (MF) and its leukemic variant, Sézary syndrome (SS), followed by the CD30+ lymphoproliferative disorders. CTCLs are separated by T-cell markers and by clinical presentations and response to therapy. Early MF is treated with skin-directed therapies whereas refractory lesions need combination of skin therapy and biological response modifiers. Advanced MF responds to monotherapy with targeted therapies or chemotherapies, whereas Sezary patients often do well on photopheresis with skin therapy and biological response modifiers. In spite of new approved therapies for T-cell lymphomas of the skin, they remain challenging and uncurable at the current time.
Traditional chemotherapies, interleukins, phosphorylase inhibitors, and proteasome inhibitors are important therapies available to patients with cutaneous T-cell lymphoma (CTCL). Traditional chemotherapies, both in combination and as single agents, are commonly used in relapsed, refractory CTCLs that behave in an aggressive manner. Interleukins, phosphorylase inhibitors, and proteasome inhibitors are less commonly used but data support a role in patients with more refractory disease.
ResearchGate has not been able to resolve any references for this publication.