Uncommon tumors in multiple endocrine neoplasia (MEN) type 1: Do they have a relationship with the prognosis of these patients?

INTRODUCTION: The prognosis of MEN 1 patients is not only determined by pancreatic disease; it is also related to other uncommon tumors. The objective of this study is to analyze the tumors associated with MEN 1 outside the classic triad and to investigate their relationship with mortality. MATERIALS AND METHODS: One hundred and five MEN 1 patients were studied in a tertiary referral hospital (1980-2019). RESULTS: With a follow-up of 11 ± 4 years, seven patients died (8%), four as a consequence MEN syndrome. Thirty-three percent had adrenal gland tumors. One patient died of adrenal cancer. Eight percent presented with a neuroendocrine thoracic neoplasm, and one patient died. Another patient died due to cutaneous T-cell lymphoma. A further patient died because of a gastrinoma with liver metastasis. CONCLUSIONS: To conclude, 75% of MEN-related deaths were the result of an uncommon pathology, and we, therefore, recommend that these tumors should be taken into account in the screening and follow-up of these patients.

Maintenance Therapy for Cutaneous T-cell Lymphoma After Total Skin Electron Irradiation: Evidence for Improved Overall Survival With Ultraviolet Therapy.

BACKGROUND: Treatment of cutaneous T-cell lymphoma (CTCL) with total skin electron beam (TSEB) therapy has been associated with deep responses but short progression-free intervals. Maintenance therapy might prolong the response duration; however, limited data assessing the outcomes with maintenance therapy after TSEB are available. We evaluated the effect of maintenance therapy on the outcomes for patients with CTCL receiving TSEB therapy. MATERIALS AND METHODS: We conducted a single-center retrospective analysis of 101 patients with CTCL who had received TSEB therapy from 1998 to 2018 at the Winship Cancer Institute of Emory University and compared the overall survival (OS) and progression-free survival (PFS) for patients had received maintenance therapy, including retinoids, interferon, ultraviolet therapy, nitrogen mustard, and extracorporeal photopheresis compared with those who had not. RESULTS: We found that pooled maintenance therapies improved PFS (hazard ratio [HR], 0.60; P = .026) but not OS (median HR, 0.73; P = .264). The median PFS and OS was 7.2 months versus 9.6 months and 2.4 years versus 4.2 years for the no maintenance and maintenance groups, respectively. On exploratory analysis of the individual regimens, ultraviolet therapy was associated with improved OS (HR, 0.21; P = .034) and PFS (HR, 0.26; P = .002) compared with no maintenance. CONCLUSION: Among the patients with CTCL who had received TSEB therapy, maintenance therapy improved PFS for all patients, and ultraviolet-based maintenance improved both PFS and OS in a subset of patients.

Case series of cutaneous T-cell lymphomas treated with bexarotene-based therapy.

Bexarotene is useful for both early and advanced cutaneous T-cell lymphoma (CTCL), and is sometimes applied to ultraviolet-tolerant early CTCL patients as one of the first-line therapies in the real world. However, continuous administration of bexarotene is sometimes difficult because of its adverse events (AE). Development of an appropriate protocol for bexarotene that can induce a consistent response for CTCL without severe AE (SAE) is needed. We retrospectively investigated 29 Japanese cases of CTCL and evaluated the efficacy of treatment and incident ratios of all AE and SAE. Objective response rate (ORR) for the overall cohort was 65.5%. ORR of the 300 mg/m2 cohort (conventional dose) was 76.2%, while that of the 150-300 mg/body (low dose) with narrowband ultraviolet B light (NBUVB) cohort was 37.5%. Mean event-free survival was 10.0 months for all patients, 6.7 months for the bexarotene conventional-dose cohort and 19.1 months for the low-dose with NBUVB cohort. The incident ratio of total SAE for all patients was 20.7%. The incident ratio of total SAE was 23.8% for the conventional-dose cohort and 12.5% for the low-dose with NBUVB cohort. Our present study suggests that low-dose bexarotene plus NBUVB therapy is well-tolerated and could be one of the optimal therapies for advanced CTCL.

Bispecific human IL2-CCR4 immunotoxin targets human cutaneous T-cell lymphoma.

The majority of clinically diagnosed cutaneous T-cell lymphomas (CTCL) highly express the cell-surface markers CC chemokine receptor 4 (CCR4) and/or CD25. Recently, we have developed diphtheria toxin-based recombinant Ontak®-like human IL2 fusion toxin (IL2 fusion toxin) and anti-human CCR4 immunotoxin (CCR4 IT). In this study, we first compared the efficacy of the CCR4 IT vs IL2 fusion toxin for targeting human CD25+ CCR4+ CTCL. We demonstrated that CCR4 IT was more effective than IL2 fusion toxin. We further constructed an IL2-CCR4 bispecific IT. The bispecific IT was significantly more effective than either IL2 fusion toxin or CCR4 IT alone. The bispecific IT is a promising novel targeted therapeutic drug candidate for the treatment of refractory and recurrent human CD25+ and/or CCR4+ CTCL.

Brentuximab Vedotin in the Treatment of Peripheral T Cell Lymphoma and Cutaneous T Cell Lymphoma.

PURPOSE OF REVIEW: The recent development of brentuximab vedotin (BV), an antibody-drug conjugate targeting CD30-positive cells, has led to therapeutic advances in the treatment of T cell lymphomas. In this review, we discuss key studies of BV in peripheral T cell lymphoma (PTCL) and cutaneous T cell lymphoma (CTCL) and highlight important questions for further investigation. RECENT FINDINGS: Monotherapy with BV has proven to be effective and well tolerated in patients with relapsed/refractory (R/R) CD30-positive CTCL. BV has shown significant activity in R/R PTCL as well, with particularly durable responses in patients with anaplastic large cell lymphoma (ALCL). In a landmark phase III study (ECHELON-2), BV + CHP demonstrated superior progression-free and overall survival relative to CHOP as frontline therapy for patients with CD30-expressing PTCL, representing the first randomized trial demonstrating an overall survival benefit in PTCL. Though BV is overall well tolerated, peripheral neuropathy remains a clinically significant adverse effect. BV is a major therapeutic advance in the treatment of patients with R/R CTCL and of those with PTCL in both the R/R and frontline settings. Key ongoing areas of investigation include optimization of CD30 expression as a predictive biomarker as well as the role of BV in consolidation therapy.

The clinical and humanistic burden of cutaneous T-cell lymphomas and response to conventional and novel therapies: results of a systematic review.

Objectives: To summarize the impact of relapsed/refractory primary cutaneous T-cell lymphomas (CTCL) on quality of life (QoL) and the efficacy of available treatments in two systematic reviews (SRs).Methods: Searches were performed on 16 January 2018 and 23 January 2018, respectively, in Medline, Medline in process, the Cochrane database, and EconLit. Studies reporting QoL outcomes in adults with CTCL or treatment efficacy in relapsed/refractory CTCL were included.Results: Based on 15 QoL studies, CTCL symptoms/complications negatively affect patients' physical, emotional, and social functioning. Skin problems pose considerable symptom burden, while advanced disease stage is associated with poorer QoL. CTCL negatively affects caregivers, primarily through family dynamics and relationships. The clinical efficacy SR included 72 publications covering 23 therapies. Overall response rate (ORR) ranged from 14% (belinostat) to 95% (total skin electron beam therapy). ORRs >50% were reported for several therapies including brentuximab vedotin (50-78%) and bexarotene (39-86%). Over half (13 of 23 therapies) had ORRs <30%. Median progression-free survival varied between treatments (3.5-116.4 months) and was >20 months for brentuximab vedotin and alemtuzumab.Conclusion: CTCL negatively affects patients' and caregivers' QoL. A considerable proportion of patients have no response or no sustainable response to current treatments.

Radiotherapy Eradicates Malignant T Cells and Is Associated with Improved Survival in Early-Stage Mycosis Fungoides.

PURPOSE: Mycosis fungoides is the most common subtype of cutaneous T-cell lymphoma. Skin-directed treatments often improve but do not cure mycosis fungoides skin lesions. The purpose of this study was to (i) assess whether remission was associated with malignant T-cell clone depletion at treated sites using either low-dose radiotherapy (LDRT, 8 Gy) or topical steroids and (ii) assess whether a clone-ablative therapy, like LDRT, is associated with overall survival in patients with high-risk early-stage CTCL. EXPERIMENTAL DESIGN: Pre- and posttreatment biopsies from 20 lesional skin samples of 18 patients with mycosis fungoides who received either 8 Gy LDRT (n = 16) or topical steroids (n = 4) underwent high-throughput T-cell receptor sequencing of the TCRB gene to quantify the malignant T-cell clone. For the retrospective chart review, overall survival of 47 high-risk early-stage patients was compared between patients who did or did not receive radiation. RESULTS: LDRT eradicated the clone in 5 of 16 lesions and reduced it >90% in 11 of 16; there were no recurrences in these lesions. Patients treated with topical steroids appeared to clinically improve, but the malignant clone persisted. We found that the number of residual malignant T cells predicted lesion recurrence. A retrospective review showed that early-stage high-risk patients who received radiation as part of their treatment regimen had prolonged overall survival compared with patients who did not. CONCLUSIONS: These findings demonstrate that LDRT can eradicate malignant T cells in mycosis fungoides, provides robust disease control, and is associated with improved survival in high-risk early-stage patients.

Romidepsin treatment for relapsed or refractory peripheral and cutaneous T-cell lymphoma: Real-life data from a national multicenter observational study.

Romidepsin is a class I selective histone deacetylase (HDAC) inhibitor approved by the Food and Drug Administration (FDA) for relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), treated with at least one prior systemic therapy. Currently, there is paucity of real-life data on the efficacy and safety of romidepsin in R/R T-cell lymphoma. This national, multicenter study presents real-life data on the efficacy and safety of romidepsin in R/R T-cell lymphoma. Patients diagnosed and treated with romidepsin for R/R CTCL or PTCL between 2013 and 2018 were retrospectively reviewed. Outcomes included overall survival (OS), event-free survival (EFS), overall response rate (ORR), complete response (CR), and adverse events. Fifty-three patients with R/R PTCL (n = 42) or CTCL (n = 11) were included. Among CTCL patients, median OS was not reached, ORR was 25%, and none achieved CR. Among PTCL patients, median OS was 7.1 months, EFS was 1.9 months, ORR rate was 33%, and 12.5% achieved CR. In a univariate analysis, predictors for longer EFS include any response to therapy, number of previous lines, and PTCL subclass (with better results for angioimmunobalstic T-cell lymphoma). In a univariate and multivariate analysis for OS, treatment response was the only factor predicting OS (OR 4.48; CI 95%, 1.57-12.79; P = .005). Most grade 3 and 4 adverse events were hematological (35%). Infections were reported in 34% of patients. This real-life experience with romidepsin confirms the results of the pivotal phase II trials. PTCL subtype and the number of previous lines of therapy have an impact on EFS. In addition, patients who had good response to romidepsin benefited most in terms of both EFS and OS. Efforts should be done to identify those patients.

[Cutaneous lymphomas : Clinical presentation - diagnosis - treatment]. / Kutane Lymphome : Klinik ­ Diagnostik ­ Therapie.

Cutaneous lymphomas comprise different subgroups with distinct biological behavior. Mycosis fungoides, the most common cutaneous lymphoma, presents with patches, plaques, tumors and erythroderma. Therapeutic options depend on stage and comprise local skin-directed treatment in early stages, while later stages and Sézary syndrome require systemic therapies including bexarotene, interferon or brentuximab vedotin. While the rare CD4-positive lymphoproliferation and acral CD8-positive lymphoma present with an invariably indolent course, cutaneous peripheral T­cell lymphomas exhibit an aggressive clinical behavior. Among the subgroup of cutaneous B­cell lymphomas, primary cutaneous marginal zone lymphoma and follicle center cell lymphoma belong to indolent entities with almost unrestricted overall survival, whereas cutaneous large B­cell lymphoma presents with a significant risk of systemic dissemination and is associated with high lethality.

Overview of Cutaneous T-Cell Lymphomas.

Non-Hodgkin's lymphoma (NHL) encompasses a diverse collection of systemic and primary cutaneous lymphomas. Cutaneous T-cell lymphomas (CTCLs) represent about 13% of all NHLs, which are further subdivided into a heterogeneous group with vastly different presentations and histologic features. Diagnosis requires integration of clinical, pathologic, and molecular features. Among CTCLs, mycosis fungoides and Sézary syndrome are the most prevalent. Treatment is aimed at limiting morbidity and halting disease progression. Hematopoietic stem cell transplantation is the only therapy with curative intent.

Low Drosha protein expression in cutaneous T-cell lymphoma is associated with worse disease outcome.

BACKGROUND: Dysregulation of microRNAs (miRNAs) key regulators may contribute to the pathogenesis of malignancies. miRNA machinery genes such Dicer and Drosha have been reported to be biomarkers in different cancer types. OBJECTIVES: We aimed to evaluate Drosha and Dicer protein expression in cutaneous T-cell lymphoma (CTCL). METHODS: We performed Drosha and Dicer immunohistochemistry in 45 patients with mycosis fungoides and subtypes. Drosha and Dicer expression scores were correlated with clinical parameters including disease-specific death (DSD), stage of disease and different laboratory data. Uni- and multivariate statistics were performed. RESULTS: On univariate analysis, elevated serum LDH and low Drosha expression were significantly associated with advanced stage (P = 0.032 and 0.0062, respectively) and lymphoma-specific death (LSD; P = 0.017 and P = 0.005, respectively). Moreover, elevated circulating CD4+/CD26- lymphocytes were significantly associated with advanced stage (P = 0.032) and DSD (P = 0.0098). On multivariate analysis, low Drosha expression remained in the logistic regression model as significant independent predictor for advanced disease stages [P = 0.013; odds ratio: 5 (confidence interval) CI 1.3-19.3]. Moreover, low Drosha expression (P = 0.026) and elevated LDH (P = 0.025) remained as significant independent predictors for DSD with odds ratios of 13.5 (CI 1.3-134.4 and 8.7 CI 1.3-57.2, respectively). CONCLUSIONS: Low Drosha expression is an independent predictor for advanced stage as well as LSD in CTCL patients indicating a tumour suppressor gene function of Drosha in this disorder.

Prognostic Significance of Serum Copper in Patients With Cutaneous T-cell Lymphoma.

BACKGROUND: Serum copper has been reported to be increased in various cancers, including lymphoma. The purpose of the present study was to investigate the clinical and prognostic importance of serum copper levels in patients with cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: Serum copper was measured in 60 men and 38 women with mycosis fungoides (MF) and 14 men and 3 women with erythrodermic CTCL (6 with Sézary syndrome) consecutively evaluated from July 1980 to June 1985. RESULTS: A greater than normal copper level was present in nearly 20% of patients and was associated with an increased risk of disease progression and shortened disease-specific survival for patients with patch or plaque phase MF, but not for those with tumor phase MF or erythrodermic CTCL. In contrast, the serum lactate dehydrogenase level and neutrophil/lymphocyte ratio were not significantly associated with prognosis in our patient cohort. CONCLUSION: The reason for the association between the high serum copper levels and adverse prognosis is unknown. We hypothesized that interleukin-6 is secreted primarily by non-neoplastic cells at MF skin sites, leading to release of copper by the liver. Local production of interleukin-6 at the lesion sites might conceivably also promote neoplastic cell progression by stimulation of the STAT3 pathway. Further studies on the relationship between activated tumor-associated macrophages, serum copper levels, interleukin-6, or C-reactive protein and prognosis might be informative.

Association of insurance status with survival in patients with cutaneous T-cell lymphoma.

The effect of insurance status on overall survival (OS) of patients with cutaneous T-cell lymphoma (CTCL) is unclear. We identified 11,861 patients from the US National Cancer Data Base diagnosed with CTCL from 2004-2014, of which 6088 had private insurance, 756 had Medicaid, 4536 had Medicare, and 481 are uninsured. Privately insured patients were more likely to present at an early stage (p < .001). On multivariate Cox regression analysis, privately insured patients had significantly longer OS than patients with Medicaid (HR: 1.936, 95% CI: 1.680-2.230, p < .001), Medicare (HR: 1.342, 95% CI: 1.222-1.474, p < .001), or no insurance (HR 1.849, 95% CI: 1.539-2.222, p < .001). The survival advantage of privately insured patients persisted on relative survival and propensity score-matched analyses. In conclusion, privately insured patients were more likely to present at an early stage, and had longer OS than patients who were Medicaid-, Medicare-, or not insured.

Increased HMGB1 levels in lesional skin and sera in patients with cutaneous T-cell lymphoma.

BACKGROUND: High mobility group box-1 (HMGB1) is a ubiquitously expressed non-histone nuclear protein which acts as a danger signal when released from cells. HMGB1, which is associated with inflammation, angiogenesis, and T helper (Th)2 polarization, contributes to the development of various inflammatory diseases and malignancies. However, it remains to be determined whether HMGB1 is involved in cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To investigate the role of HMGB1 in CTCL. MATERIALS & METHODS: Serum HMGB1 levels were measured in patients with CTCL and healthy controls using an enzyme-linked immunosorbent assay. HMGB1 messenger RNA (mRNA) expression in CTCL and normal skin was examined by quantitative reverse transcription polymerase chain reaction and immunohistochemistry. Moreover, we analysed correlations between the levels of HMGB1 and other cytokines and chemokines, laboratory data, disease activity, and prognosis. RESULTS: HMGB1 levels were significantly higher in sera of CTCL patients than those of normal controls and correlated with serum levels of soluble interleukin-2 receptor, lactate dehydrogenase, thymus and activation-regulated chemokine, and the number of eosinophils in peripheral blood. Serum HMGB1 levels also reflected disease activity and prognosis for each patient with CTCL. HMGB1 mRNA levels in CTCL lesional skin were significantly elevated and correlated with IL-4, IL-10, IL-19, and angiogenin mRNA levels. Immunohistochemical staining revealed that HMGB1 was expressed not only in the nucleus but also in the cytoplasm of various cells in CTCL lesional skin. CONCLUSION: These results suggest that enhanced HMGB1 expression may contribute to the progression of CTCL through Th2 polarization and promotion of angiogenesis.

Evaluation of the Cutaneous Lymphoma International Prognostic Index in patients with early stage mycosis fungoides

Abstract: Background: Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma. TNMB system is the staging method used in MF, and it not only guides therapeutic management, but represents the main prognostic factor. In order to improve the prognostic evaluation, the Cutaneous Lymphoma International Prognostic Index (CLIPi) was proposed. Objective: To evaluate the performance of CLIPi score for prognostic analysis in patients with early stage MF. Methods: This is a retrospective cross-sectional observational study, with exploratory analysis. The outcome variables were disease progression and related death. Results: One hundred and two patients were stratified according to CLIPi score, being the majority classified as low risk. Patients with intermediate or high risk presented disease progression more frequently than those with low risk (PR: 1.2 / p = 0.004 / 95%CI: 1.0 - 1.6). The same did not occur with the variable related death. In addition, survival rates were not consistent with risk stratification. Study Limitations: Small sample and its retrospective analysis. Conclusions: Since CLIPi score was proposed, four other studies that we could consult showed conflicting results, similar to the present study. Further studies are necessary for a recommendation of its use.

Cobomarsen, an oligonucleotide inhibitor of miR-155, co-ordinately regulates multiple survival pathways to reduce cellular proliferation and survival in cutaneous T-cell lymphoma.

miR-155, a microRNA associated with poor prognosis in lymphoma and leukaemia, has been implicated in the progression of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). In this study, we developed and tested cobomarsen (MRG-106), a locked nucleic acid-modified oligonucleotide inhibitor of miR-155. In MF and human lymphotropic virus type 1 (HTLV-1+) CTCL cell lines in vitro, inhibition of miR-155 with cobomarsen de-repressed direct miR-155 targets, decreased expression of multiple gene pathways associated with cell survival, reduced survival signalling, decreased cell proliferation and activated apoptosis. We identified a set of genes that are significantly regulated by cobomarsen, including direct and downstream targets of miR-155. Using clinical biopsies from MF patients, we demonstrated that expression of these pharmacodynamic biomarkers is dysregulated in MF and associated with miR-155 expression level and MF lesion severity. Further, we demonstrated that miR-155 simultaneously regulates multiple parallel survival pathways (including JAK/STAT, MAPK/ERK and PI3K/AKT) previously associated with the pathogenesis of MF, and that these survival pathways are inhibited by cobomarsen in vitro. A first-in-human phase 1 clinical trial of cobomarsen in patients with CTCL is currently underway, in which the panel of proposed biomarkers will be leveraged to assess pharmacodynamic response to cobomarsen therapy.

Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial.

BACKGROUND: Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma. METHODS: In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB-II vs III-IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805. FINDINGS: Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7-10·3] in the mogamulizumab group vs 3·1 months [2·9-4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41-0·69; stratified log-rank p<0·0001). Grade 3-4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related. INTERPRETATION: Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma. FUNDING: Kyowa Kirin.