STAT3 dysregulation in mature T and NK cell lymphomas

T cell lymphomas comprise a distinct class of non-Hodgkin’s lymphomas, which include mature T and natural killer (NK) cell neoplasms. While each malignancy within this group is characterized by unique clinicopathologic features, dysregulation in the Janus tyrosine family of kinases/Signal transducer and activator of transcription (JAK/STAT) signaling pathway, specifically aberrant STAT3 activation, is a common feature among these lymphomas. The mechanisms driving dysregulation vary among T cell lymphoma subtypes and include activating mutations in upstream kinases or STAT3 itself, formation of oncogenic kinases which drive STAT3 activation, loss of negative regulators of STAT3, and the induction of a pro-tumorigenic inflammatory microenvironment. Constitutive STAT3 activation has been associated with the expression of targets able to increase pro-survival signals and provide malignant fitness. Patients with dysregulated STAT3 signaling tend to have inferior clinical outcomes, which underscores the importance of STAT3 signaling in malignant progression. Targeting of STAT3 has shown promising results in pre-clinical studies in T cell lymphoma lines, ex-vivo primary malignant patient cells, and in mouse models of disease. However, targeting this pleotropic pathway in patients has proven difficult. Here we review the recent contributions to our understanding of the role of STAT3 in T cell lymphomagenesis, mechanisms driving STAT3 activation in T cell lymphomas, and current efforts at targeting STAT3 signaling in T cell malignancies

The PROVe study: US real-world experience with chlormethine/mechlorethamine gel in combination with other therapies for patients with mycosis fungoides cutaneous T-cell lymphoma

BACKGROUND: Chlormethine/mechlorethamine gel is a skin-directed therapy for patients with mycosis fungoides cutaneous T-cell lymphoma. Currently, real-world data on chlormethine gel are lacking. OBJECTIVE: Our objective was to analyze the effect of chlormethine gel in combination with other therapies on efficacy, safety, and health-related quality of life in a real-world setting. METHODS: This prospective, observational study enrolled adult patients actively using chlormethine gel. Patients were monitored for up to 2 years during standard-of-care clinic visits. No specific visit schedules or clinical assessments, with the exception of patient-completed questionnaires, were mandated because of the expected variability in practice patterns. The primary efficacy endpoint was the proportion of patients with stage IA-IB disease receiving chlormethine + topical corticosteroids + other with ≥ 50% decrease in body surface area from baseline to 12 months. Response was assessed at each visit using by-time analysis, which investigates the trend to treatment response and allows assessment of response over time. Health-related quality of life was assessed with the Skindex-29 questionnaire. RESULTS: In total, 298 patients were monitored. At 12 months post-treatment initiation, 44.4% (chlormethine + topical corticosteroids + other) and 45.1% (patients receiving chlormethine + other treatment) of efficacy-evaluable patients were responders. By-time analysis demonstrated that peak response occurred (chlormethine + other; 66.7%) at 18 months. There was a significant correlation between responder status and lower post-baseline Skindex-29 scores. CONCLUSIONS: This real-world study confirmed that chlormethine gel is an important therapeutic option for patients with mycosis fungoides and contributes to reducing the severity of skin lesions and improving health-related quality of life

Multifocal pleomorphic dermal sarcoma and the role of inflammation and immunosuppression in a lung transplant patient: a case report

Background Pleomorphic dermal sarcoma is the cutaneous variant of undifferentiated pleomorphic sarcoma. It is a rare malignancy of unclear histogenesis; it is a diagnosis of exclusion that requires extensive use of immunohistochemistry to rule out other malignancies. Pleomorphic dermal sarcoma typically presents as a solitary tumor in sun-exposed areas and may have unpredictable clinical behavior, with some tumors associated with metastasis and death. Case presentation We present an unusual case of multifocal pleomorphic dermal sarcoma arising in the areas of alpha-1-antitrypsin deficiency panniculitis in a lung transplant patient. Our patient was a 58-year-old white woman whose initial presentation was consistent with alpha-1-antitrypsin deficiency panniculitis. She then developed extensive multifocal, bleeding, and ulcerated nodules in the areas of the panniculitis. A skin biopsy was consistent with a diagnosis of pleomorphic dermal sarcoma. Her immunosuppressive regimen was decreased, and she was treated with liposomal doxorubicin 40 mg/m2 every 3 weeks with some initial improvement in the size of her tumors. However, soon after beginning therapy, she developed pneumonia and septic shock and ultimately died from multi-organ failure. Conclusions We hypothesize that chronic, multifocal inflammation in the skin in the setting of immunosuppression led to simultaneous, malignant transformation in numerous skin lesions. We discuss the challenges of diagnosing pleomorphic dermal sarcoma, therapeutic options, and stress the need for multidisciplinary management of these cases

Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium

ABSTRACT Background Advanced-stage mycosis fungoides (MF)/Sezary 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

Data from: An integrated data resource for genomic analysis of cutaneous T-cell lymphoma

Recently, several groups have conducted sequencing studies of cutaneous T-cell lymphoma (CTCL) in order to identify disease driving mutations. An integrated genomic dataset that combines multiple cohorts may facilitate more comprehensive studies of disease pathways and genomic classification of CTCL, but currently no such resource is available. In this study we compiled and analyzed one such dataset that included matched genomic mutations and copy number alterations of 139 CTCL cases. Using this dataset, we studied mutual exclusivity of mutations in the most frequently mutated pathways and survival curves depending on mutation load and other parameters. We found that mutations in the NFkB pathway genes PLCG1, CARD11 and TNFRSF1B were mutually exclusive. Mutations in the NFkB pathway genes and those in p53 were also mutually exclusive. No significant difference in overall survival was seen between SS cases with or without mutations in p53 or the NFkB pathway genes. There was a difference in overall survival between SS cases with the most and the fewest mutations in the genome. These results suggest the possibility of classifying CTCL by underlying pathogenic pathways and the potential for selective targeting of CTCL by patient-specific mutations in order to personalize CTCL therapies

Non-random geographic distribution of patients with cutaneous T-cell lymphoma in the Greater Pittsburgh Area

Background: Environmental hazards may play a role in the etiology of cutaneous T-cell lymphoma (CTCL). Some studies have found an increased incidence of CTCL among workers in chemical science, transportation, and manufacturing industries, but other studies have not. This discrepancy may be attributable to population migration, complicating accurate assessment of lifetime exposures. The Pittsburgh population has very low migration rates and most CTCL patients seen at the University of Pittsburgh Medical Center (UPMC) Cutaneous Lymphoma Center are life-long local residents. The Greater Pittsburgh Area used to be an industrial hub. There are residential communities positioned within close proximity to inactive industrial sites that continue to contain pollutants.Objective: To determine whether CTCL patients’ residences cluster within specific Pittsburgh regions, in particular, those with high levels of environmental pollutants.Methods: Our study included patients diagnosed with CTCL at the UPMC Cutaneous Lymphoma Center between 2000 and 2012. We mapped the longitudinal and latitudinal coordinates of patients’ residences at diagnosis, superfund sites, toxic release inventory sites, particular matter levels, and dermatologists’ offices using ArcMap 10.1. We then performed a SaTScan analysis using zip codes to assess for geographic clustering of patients’ residences in the Pittsburgh metropolitan statistical area. We assessed for a correlation between case distribution and both environmental hazards sites and dermatologist density in the area.Results: We identified 274 patients with CTCL in the Greater Pittsburgh area. We identified a statistically significant geographic cluster (p<.001) in zip code 15213, which is the most densely populated neighborhood in Pittsburgh and the site of the region’s only CTCL clinic.  We observed no relationship between the locations of superfund sites, toxic release inventory sites, or particular matter levels and CTCL case distribution.Conclusion: Our findings do not support an association between exposure to environmental toxins and CTCL. CTCL cases clustered in areas with the highest population density, which also happen to include a regional CTCL center. To evaluate a possibility of urban pollutants playing a role in etiology of CTCL, dermatologist density and access to care need to be addressed as potential confounders in the future studies

Non-random geographic distribution of patients with cutaneous T-cell lymphoma in the Greater Pittsburgh Area

Background: Environmental hazards may play a role in the etiology of cutaneous T-cell lymphoma (CTCL). Some studies have found an increased incidence of CTCL among workers in chemical science, transportation, and manufacturing industries, but other studies have not. This discrepancy may be attributable to population migration, complicating accurate assessment of lifetime exposures. The Pittsburgh population has very low migration rates and most CTCL patients seen at the University of Pittsburgh Medical Center (UPMC) Cutaneous Lymphoma Center are life-long local residents. The Greater Pittsburgh Area used to be an industrial hub. There are residential communities positioned within close proximity to inactive industrial sites that continue to contain pollutants.Objective: To determine whether CTCL patients’ residences cluster within specific Pittsburgh regions, in particular, those with high levels of environmental pollutants.Methods: Our study included patients diagnosed with CTCL at the UPMC Cutaneous Lymphoma Center between 2000 and 2012. We mapped the longitudinal and latitudinal coordinates of patients’ residences at diagnosis, superfund sites, toxic release inventory sites, particular matter levels, and dermatologists’ offices using ArcMap 10.1. We then performed a SaTScan analysis using zip codes to assess for geographic clustering of patients’ residences in the Pittsburgh metropolitan statistical area. We assessed for a correlation between case distribution and both environmental hazards sites and dermatologist density in the area.Results: We identified 274 patients with CTCL in the Greater Pittsburgh area. We identified a statistically significant geographic cluster (p<.001) in zip code 15213, which is the most densely populated neighborhood in Pittsburgh and the site of the region’s only CTCL clinic.  We observed no relationship between the locations of superfund sites, toxic release inventory sites, or particular matter levels and CTCL case distribution.Conclusion: Our findings do not support an association between exposure to environmental toxins and CTCL. CTCL cases clustered in areas with the highest population density, which also happen to include a regional CTCL center. To evaluate a possibility of urban pollutants playing a role in etiology of CTCL, dermatologist density and access to care need to be addressed as potential confounders in the future studies

Racial and ethnic disparities in the perception of respect from physicians among skin cancer patients in the United StatesCapsule Summary

Background: Racial and ethnic minority groups are at increased risk of poor skin cancer outcomes. Successful patient-physician communication is linked to better health outcomes, but it is unknown whether disparities in perceived care exist among skin cancer patients. Objective: To investigate whether there are racial and ethnic disparities in the perception of physicians showing respect, listening, and explaining during clinical encounters. Methods: A cross-sectional study was conducted using data from participants with a self-reported skin cancer history from the 2008 to 2017 and 2019 Medical Expenditure Panel Survey. Race and ethnicity were self-identified. Results: Of 5570 participants, 5263 were non-Hispanic White and 307 were racial and ethnic minority individuals. Racial and ethnic minority participants were less likely to report that their doctors show them respect, listen to, and explain to them than non-Hispanic White participants, even when adjusting for age, sex, insurance type, health status, and survey year. Among racial and ethnic minority participants, perceptions of physicians listening and explaining were strongly associated with perceived respect. Limitations: Lack of disaggregated racial and ethnic subgroup analysis. Conclusions: Our findings suggest racial and ethnic disparities in perceived care among skin cancer patients. Future research is warranted to determine whether such perceptions contribute to disparities in skin cancer care and/or outcomes