Should we be imaging lymph nodes at initial diagnosis of early-stage mycosis fungoides? Results from the PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) international study.

BACKGROUND: Early-stage mycosis fungoides (MF) includes involvement of dermatopathic lymph nodes (LNs) or early lymphomatous LNs. There is a lack of unanimity among current guidelines regarding the indications for initial staging imaging in early-stage presentation of MF in the absence of enlarged palpable LNs. OBJECTIVES: To investigate how often imaging is performed in patients with early-stage presentation of MF, to assess the yield of LN imaging, and to determine what disease characteristics promoted imaging. METHODS: A review of clinicopathologically confirmed newly diagnosed patients with cutaneous patch/plaque (T1/T2) MF from PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) data. RESULTS: PROCLIPI enrolled 375 patients with stage T1/T2 MF: 304 with classical MF and 71 with folliculotropic MF. Imaging was performed in 169 patients (45%): 83 with computed tomography, 18 with positron emission tomography-computed tomography and 68 with ultrasound. Only nine of these (5%) had palpable enlarged (≥ 15 mm) LNs, with an over-representation of plaques, irrespectively of the 10% body surface area cutoff that distinguishes T1 from T2. Folliculotropic MF was not more frequently imaged than classical MF. Radiologically enlarged LNs (≥ 15 mm) were detected in 30 patients (18%); only seven had clinical lymphadenopathy. On multivariate analysis, plaque presentation was the sole parameter significantly associated with radiologically enlarged LNs. Imaging of only clinically enlarged LNs upstaged 4% of patients (seven of 169) to at least IIA, whereas nonselective imaging upstaged another 14% (24 of 169). LN biopsy, performed in eight of 30 patients, identified N3 (extensive lymphomatous involvement) in two and N1 (dermatopathic changes) in six. CONCLUSIONS: Physical examination was a poor determinant of LN enlargement or involvement. Presence of plaques was associated with a significant increase in identification of enlarged or involved LNs in patients with early-stage presentation of MF, which may be important when deciding who to image. Imaging increases the detection rate of stage IIA MF, and identifies rare cases of extensive lymphomatous nodes, upstaging them to advanced-stage IVA2.

A standard set of person-centred outcomes for diabetes mellitus: results of an international and unified approach.

AIMS: To select a core list of standard outcomes for diabetes to be routinely applied internationally, including patient-reported outcomes. METHODS: We conducted a structured systematic review of outcome measures, focusing on adults with either type 1 or type 2 diabetes. This process was followed by a consensus-driven modified Delphi panel, including a multidisciplinary group of academics, health professionals and people with diabetes. External feedback to validate the set of outcome measures was sought from people with diabetes and health professionals. RESULTS: The panel identified an essential set of clinical outcomes related to diabetes control, acute events, chronic complications, health service utilisation, and survival that can be measured using routine administrative data and/or clinical records. Three instruments were recommended for annual measurement of patient-reported outcome measures: the WHO Well-Being Index for psychological well-being; the depression module of the Patient Health Questionnaire for depression; and the Problem Areas in Diabetes scale for diabetes distress. A range of factors related to demographic, diagnostic profile, lifestyle, social support and treatment of diabetes were also identified for case-mix adjustment. CONCLUSIONS: We recommend the standard set identified in this study for use in routine practice to monitor, benchmark and improve diabetes care. The inclusion of patient-reported outcomes enables people living with diabetes to report directly on their condition in a structured way.

The PROCLIPI international registry of early-stage mycosis fungoides identifies substantial diagnostic delay in most patients.

BACKGROUND: Survival in mycosis fungoides (MF) is varied and may be poor. The PROCLIPI (PROspective Cutaneous Lymphoma International Prognostic Index) study is a web-based data collection system for early-stage MF with legal data-sharing agreements permitting international collaboration in a rare cancer with complex pathology. Clinicopathological data must be 100% complete and in-built intelligence in the database system ensures accurate staging. OBJECTIVES: To develop a prognostic index for MF. METHODS: Predefined datasets for clinical, haematological, radiological, immunohistochemical, genotypic, treatment and quality of life are collected at first diagnosis of MF and annually to test against survival. Biobanked tissue samples are recorded within a Federated Biobank for translational studies. RESULTS: In total, 430 patients were enrolled from 29 centres in 15 countries spanning five continents. Altogether, 348 were confirmed as having early-stage MF at central review. The majority had classical MF (81·6%) with a CD4 phenotype (88·2%). Folliculotropic MF was diagnosed in 17·8%. Most presented with stage I (IA: 49·4%; IB: 42·8%), but 7·8% presented with enlarged lymph nodes (stage IIA). A diagnostic delay between first symptom development and initial diagnosis was frequent [85·6%; median delay 36 months (interquartile range 12-90)]. This highlights the difficulties in accurate diagnosis, which includes lack of a singular diagnostic test for MF. CONCLUSIONS: This confirmed early-stage MF cohort is being followed-up to identify prognostic factors, which may allow better management and improve survival by identifying patients at risk of disease progression. This study design is a useful model for collaboration in other rare diseases, especially where pathological diagnosis can be complex.

'It's a traumatic illness, traumatic to witness': a qualitative study of the experiences of bereaved family caregivers of patients with cutaneous T-cell lymphoma.

BACKGROUND: Cutaneous T-cell lymphomas (CTCL) are rare cancers, which can be difficult to diagnose, are incurable and adversely affect quality of life, particularly in advanced disease. Families often provide care, but little is known about their experiences or needs while caring for their relative with advanced disease or in bereavement. OBJECTIVES: To explore the experiences of bereaved family caregivers of patients with CTCL. METHODS: Single, semi-structured qualitative interviews were conducted with bereaved family caregivers of patients with CTCL recruited via a supra-regional CTCL clinic. Transcribed interviews were analysed thematically, focusing on advanced disease, the approach of death and bereavement. RESULTS: Fifteen carers of 11 deceased patients participated. Experiences clustered under four themes: (1) complexity of care and medical intervention; (2) caregiver roles in advanced CTCL; (3) person-centred vs. organization-centred care in advanced CTCL and (4) knowing and not knowing: reflections on dying, death and bereavement. Caregivers often had vivid recollections of the challenges of caring for their relative with advanced CTCL and some took on quasi-professional roles as a result. Advanced disease made high demands on both organizational flexibility and family resources. For many caregivers, seeing disease progression was a prolonged and profoundly traumatic experience. The extent to which they were prepared for their relative's death and supported in bereavement was highly variable. Sub-themes within each theme provide more detail about caregiver experiences. CONCLUSIONS: Family caregivers should be considered part of the wider healthcare team, acknowledging their multiple roles and the challenges they encounter in looking after their relative with CTCL as the disease progresses. Their experiences highlight the importance of organizational flexibility and of good communication between healthcare providers in advanced CTCL.

Multiple cutaneous, oropharyngeal and pulmonary nodules.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis defined by heterogeneous multiorgan involvement. Due to the rarity of this disease strong evidence-based therapies have yet to be established and prognosis has previously been considered to be poor, with more than half of patients dying within 3 years of initial presentation. We describe an 86-year-old woman with a 34-year history of extensive cutaneous and internal nodules with typical pathological and immunophenotypical (CD68(+) /CD1a(-) ) features of ECD without evidence of the BRAF V600E mutation. The cosmetic appearance of cutaneous nodules and hoarse voice caused by vocal cord nodules has been managed surgically. More aggressive therapies reported for ECD were trialled for this patient, such as radiotherapy and interferon-α, with no response. This case demonstrates a relatively good prognosis in ECD that has been managed conservatively.

'We're all carrying a burden that we're not sharing': a qualitative study of the impact of cutaneous T-cell lymphoma on the family.

BACKGROUND: Cutaneous T-cell lymphoma (CTCL) is a rare, progressive cancer that can be life limiting and highly disfiguring. Patients with CTCL experience poor quality of life; however, there is little published about the experiences of their families. OBJECTIVES: To describe the impact of CTCL on family members and how they cope and adjust, to inform support services. METHODS: Semistructured qualitative interviews were conducted with adult informal caregivers of patients with CTCL recruited via a supraregional CTCL clinic. Interviews explored the history of each patient's illness, the impact of CTCL on the patient and the family, and views about family support. Data were analysed thematically using the Family Adjustment and Adaptation Response model as an interpretative framework. RESULTS: Fourteen caregivers were interviewed (11 spouses, one friend, two daughters; 10 women, four men; all white British; aged 39-85 years). Three key themes emerged: (i) demands of CTCL (the disease, caregiving, financial impact, physical and emotional intimacy); (ii) family capabilities (family support, information, healthcare provider support, other coping strategies); and (iii) adjustment and adaptation (acceptance, changes in patient-caregiver relationship and family dynamics). CTCL was central in many aspects of caregivers' lives, particularly relationships, communication and intimacy. CONCLUSIONS: Our findings demonstrate the multiple demands that CTCL places on caregivers, the capabilities and resources they draw upon to cope, and the significant impact of CTCL on the family. To support families and patients, easily accessible services are needed that include the family in the unit of care, provide support and information, and understand the process of family adjustment and adaptation.

'We had to change to single beds because I itch in the night': a qualitative study of the experiences, attitudes and approaches to coping of patients with cutaneous T-cell lymphoma.

BACKGROUND: Primary cutaneous T-cell lymphoma (CTCL) is a rare but prevalent condition which can have a significant impact on many aspects of quality of life. However, there is little evidence of patients' lived experience of CTCL. OBJECTIVES: To understand in greater depth patients' experiences of living and coping with CTCL, and to inform the development of models of care for this population in line with U.K. METHODS: Semi-structured interviews were conducted with a purposive sample of patients with CTCL who attended an inner-city teaching hospital. Participants were purposively selected according to their disease stage, age, sex and ethnicity. RESULTS: Nineteen patients with CTCL (stages IB-IVB), aged between 41 and 83 years, participated in a single interview. This included 10 men; 15 people identified themselves as white British. Interviews lasted a median of 55 (range 28-170) min. Two main themes emerged: issues regarding diagnosis, particularly a perceived delay in diagnosis, and the impact of CTCL (subthemes related to physical well-being, practical concerns and psychological and social well-being and coping). CONCLUSIONS: Findings from this study illuminate the diverse effects of CTCL on patients' lives. The universal experience of delays in diagnosis was striking and a concern to patients. The disease, particularly its physical symptoms, had a significant impact on patients' lives, including employment, leisure and relationships. Despite the symptom burden and its impact, participants described effective coping strategies such as drawing on social support, maintaining normal lives and becoming well informed about CTCL. Proactive holistic assessment and management of the range of patient concerns is needed in providing care for patients with CTCL and their family and friends.

Cutaneous Richter syndrome: a better place to transform?

The development of high-grade lymphoma in patients with chronic lymphocytic leukaemia is known as Richter syndrome (RS) and is associated with a grave prognosis, with a mean survival of 8 months despite treatment. Cutaneous RS has been described in a handful of cases and may be associated with a better outcome than the more common extracutaneous variants. We review the literature with particular emphasis on pathogenesis, treatment and survival of RS. We postulate that the absence of B symptoms and a normal lactate dehydrogenase level, presumably reflecting localized or limited disease, and a lower tumour burden, may explain the apparently better survival in some patients with cutaneous RS than with extracutaneous variants.

What are the supportive and palliative care needs of patients with cutaneous T-cell lymphoma and their caregivers? A systematic review of the evidence.

BACKGROUND: Primary cutaneous T-cell lymphoma (CTCL) is progressive, can cause significant symptoms, and impacts on quality of life. Therefore supportive and palliative care might have a role in the care of patients and families. OBJECTIVES: To identify and appraise the available peer-reviewed evidence on the supportive and palliative care needs of patients and their caregivers. METHODS: A systematic review of the literature was conducted. Extracted data from eligible papers were collated in themes relating to supportive and palliative care needs and outcomes for patients, informal caregivers, health professionals and reported service models. RESULTS: Eighteen retained papers reported a symptom or quality-of-life measure. Five reported only these measures, 13 reported outcomes in relation to an intervention. Systemic therapy targeted at disease remission was the most commonly reported intervention (12/13). No quality-of-life tool was consistently used. Pruritus was frequently reported as an outcome (n = 9) often using the visual analogue scale, VAS itch. Psychosocial, spiritual and caregiver needs were reported infrequently or not at all. CONCLUSIONS: No measure is routinely used to measure supportive and palliative care outcomes in CTCL. Physical needs, particularly pruritus, were reported commonly; however, qualitative evidence of experience is limited. Caregivers' needs are rarely explored. To compare outcomes from clinical studies, a single multidimensional tool used in routine practice would be useful. Further work is needed to explore a model of service that meets the specific physical, psychosocial and spiritual needs of this group of patients and their carers.

Prognostic factors, prognostic indices and staging in mycosis fungoides and Sézary syndrome: where are we now?

Mycosis fungoides is the most prevalent form of primary cutaneous T-cell lymphoma. Patients frequently present with early-stage disease typically associated with a favourable prognosis and survival of 10-35 years, but over 25% may progress to advanced disease with a median survival < 4 years, and just 13 months in those with nodal involvement. Sézary syndrome presents in advanced disease with erythroderma, blood involvement and lymphadenopathy. The Bunn and Lamberg staging system (1979) includes stages IA-IIA (early-stage disease) and IIB-IVB (advanced-stage disease) and provides prognostic information, but some patients with tumour-stage disease (IIB) have a worse prognosis than those with erythrodermic-stage (III). Conversely, patients with plaque-stage (IB) folliculotropic mycosis fungoides may have a worse outcome than those with tumour-stage (IIB). The more recent staging system of the European Organisation for the Research and Treatment of Cancer/International Society for Cutaneous Lymphoma has been designed to reflect tumour burden at different sites. However, this staging system has not been validated prospectively for prognosis. Furthermore, this staging system does not include a detailed measurement of skin tumour burden, as indicated by the modified skin weighted severity assessment tool. This assessment measures body surface area of disease and is weighted to record patch, plaque and tumour to produce a numerical value from 0·5 to 400 and is an established endpoint for clinical studies. Nor does this staging include clinicopathological features associated with a poor prognosis such as folliculotropism. Here we review the clinical, haematological, pathological and genotypic parameters outside the staging system, which may affect survival in mycosis fungoides and Sézary syndrome. Most studies are retrospective and single centre. The identification of poor prognostic factors may be used to develop a prognostic index to use alongside staging, which may be of benefit in mycosis fungoides/Sézary syndrome to identify patients with a potentially poor prognosis.

Long term outcomes of nonmyeloablative allogeneic stem cell transplantation with TSEB TLI and ATG for Mycosis Fungoides and Sezary Syndrome.

Advanced stage (IIB-IVB) Mycosis Fungoides (MF) and Sezary Syndrome (SS) have a poor prognosis with median survival <5 years. We report long-term outcomes of a non-myeloablative allogeneic stem cell transplantation regimen consisting of total skin electron beam therapy, total lymphoid irradiation and antithymocyte globulin. Our prospective cohort consisted of 41 patients with a higher proportion of MF (34MF, 7SS). Acute GVHD Grade 2 to 4 was seen in 31.7% and chronic GVHD Grade 2 to 4 in 24%. The cumulative incidence of non-relapse mortality was 9.8% at 1 year and 12.6% at 2 years. At Day +90 post-transplant 66% of patients had a complete response (CR). With a median post-transplant follow up of 5.27 years, the 5-year overall survival rate was 37.7% (MF 36.7%, SS 57.1%). The 5-year cumulative incidence of progressive disease or relapse was 52.7% in all patients but only 20.8% in those with CR at transplant compared to 70.6% in those not in CR at transplant (p = 0.006). Long term survival is possible in advanced MF and SS with non-myeloablative transplantation and outcomes are improved in patients with CR at transplant.

Phase II study of gemcitabine and bexarotene (GEMBEX) in the treatment of cutaneous T-cell lymphoma.

BACKGROUND: Both gemcitabine and bexarotene are established single agents for the treatment of cutaneous T-cell lymphoma (CTCL). We investigated the feasibility and efficacy of combining these drugs in a single-arm phase II study. METHODS: Cutaneous T-cell lymphoma patients who had failed standard skin-directed therapy and at least one prior systemic therapy were given four cycles of gemcitabine and concurrent bexarotene for 12 weeks. Responders were continued on bexarotene maintenance until disease progression or unacceptable toxicity. RESULTS: The median age was 65 years, stage IB (n=5), stage IIA (n=2), stage IIB (n=8), stage III (n=8) and stage IVA (n=12), 17 patients were erythrodermic, 17 patients were B1, and 10 patients were both erythrodermic and B1. Thirty (86%) patients completed four cycles of gemcitabine. In all, 80.0% of patients demonstrated a reduction in modified Severity-Weighted Assessment Tool (mSWAT) score although the objective disease response rate at 12 weeks was 31% (partial response (PR) 31%) and at 24 weeks 14% (PR 14%, stable disease (SD) 23%, progressive disease (PD) 54%, not evaluable 9%). Median progression-free survival was 5.3 months and median overall survival was 21.2 months. CONCLUSION: The overall response rate of the combination did not reach the specified target to proceed further and is lower than that previously reported for gemcitabine as a single agent.

BRAF mutation testing algorithm for vemurafenib treatment in melanoma: recommendations from an expert panel.

The incidence of melanoma has increased rapidly over the past 30 years, and the disease is now the sixth most common cancer among men and women in the U.K. Many patients are diagnosed with or develop metastatic disease, and survival is substantially reduced in these patients. Mutations in the BRAF gene have been identified as key drivers of melanoma cells and are found in around 50% of cutaneous melanomas. Vemurafenib (Zelboraf(®) ; Roche Molecular Systems Inc., Pleasanton, CA, U.S.A.) is the first licensed inhibitor of mutated BRAF, and offers a new first-line option for patients with unresectable or metastatic melanoma who harbour BRAF mutations. Vemurafenib was developed in conjunction with a companion diagnostic, the cobas(®) 4800 BRAF V600 Mutation Test. The purpose of this paper is to make evidence-based recommendations to facilitate the implementation of BRAF mutation testing and targeted therapy in patients with metastatic melanoma in the U.K. The recommendations are the result of a meeting of an expert panel and have been reviewed by melanoma specialists and representatives of the National Cancer Research Network Clinical Study Group on behalf of the wider melanoma community. This article is intended to be a starting point for practical advice and recommendations, which will no doubt be updated as we gain further experience in personalizing therapy for patients with melanoma.

U.K. consensus statement on safe clinical prescribing of bexarotene for patients with cutaneous T-cell lymphoma.

BACKGROUND: Bexarotene is a synthetic retinoid from the subclass of retinoids called rexinoids which selectively activate retinoid X receptors. It has activity in cutaneous T-cell lymphoma (CTCL) and has been approved by the European Medicines Agency since 1999 for treatment of the skin manifestations of advanced-stage (IIB-IVB) CTCL in adult patients refractory to at least one systemic treatment. In vivo bexarotene produces primary hypothyroidism which may be managed with thyroxine replacement. It also affects lipid metabolism, typically resulting in raised triglycerides, which requires prophylactic lipid-modification therapy. Effects on neutrophils, glucose and liver function may also occur. These side-effects are dose dependent and may be controlled with corrective therapy or dose adjustments. OBJECTIVES: To produce a U.K. statement outlining a bexarotene dosing schedule and monitoring protocol to enable bexarotene prescribers to deliver bexarotene safely for optimal effect. METHODS: Leaders from U.K. supraregional centres produced this consensus statement after a series of meetings and a review of the literature. RESULTS: The statement outlines a bexarotene dosing schedule and monitoring protocol. This gives instructions on monitoring and treating thyroid, lipid, liver, blood count, creatine kinase, glucose and amylase abnormalities. The statement also includes algorithms for a bexarotene protocol and lipid management, which may be used in the clinical setting. CONCLUSION: Clinical prescribing of bexarotene for patients with CTCL requires careful monitoring to allow safe administration of bexarotene at the optimal dose.

An ultrasound needle insertion guide in a porcine phantom model.

We compared nerve blockade with and without the Infiniti(TM) needle guide in an ultrasound in-plane porcine simulation. We recruited 30 anaesthetists with varying blockade experience. Using the guide, the needle tip was more visible (for a median (IQR [range]) of 67 (56-100]) % of the time; and invisible for 2 (1-4 [0-19]) s) than when the guide was not used (respectively 23 (13-43 [0-80]) % and 25 (9-52 [1-198]) s; both p < 0.001). The corresponding block times were 8 (6-10 [3-28]) s and 32 (15-67 [5-225]) s, respectively; p < 0.001. The needle guide reduced the block time and the time that the needle was invisible, irrespective of anaesthetist experience.

Efficacy and safety of bexarotene combined with psoralen-ultraviolet A (PUVA) compared with PUVA treatment alone in stage IB-IIA mycosis fungoides: final results from the EORTC Cutaneous Lymphoma Task Force phase III randomized clinical trial (NCT00056056).

BACKGROUND: Psoralen plus ultraviolet A (PUVA) is the standard treatment for early stages of mycosis fungoides. There have been no adequate randomized controlled trials with sufficient power comparing this modality with other therapies. OBJECTIVE: To assess disease response and to compare the response rates of patients treated with PUVA alone or PUVA and bexarotene. METHODS: EORTC 21011 (NCT 00056056) was a randomized phase III study comparing combined bexarotene (Targretin(®) ) and PUVA vs. PUVA alone in patients with stage IB and IIA mycosis fungoides (MF). The primary endpoint was the overall response rate [complete clinical response (CCR) plus partial response (PR)]. RESULTS: The study was prematurely closed due to low accrual after 93 of 145 required patients (65%) were randomized. Of the 93 randomized patients, 87 started treatment, 41 received PUVA and 46 received PUVA + bexarotene. Total UVA doses received were 107 J cm(-2) (range 1·4-489·9) in the PUVA arm vs. 101·7 J cm(-2) (0·2-529·9) in the combination arm. The safety profile was acceptable with few grade 3-4 toxicities observed in either arm. More drop-outs due to toxicity were observed in the combination arm compared with the PUVA-alone arm. The best overall response (CCR + PR) rate was 71% for PUVA alone and 77% for the combination arm (P = 0·57). The median duration of response was 9·7 months for PUVA vs. 5·8 months for the combination arm (P = 0·33). CCR was seen in 25 patients of whom 10 received PUVA alone (CCR 22%) and 15 received combination therapy (CCR 31%) (P = 0·45). CCR was sustained in 25% of patients regardless of therapy. There was a trend towards fewer PUVA sessions needed to achieve CCR in the combination arm (median 22) compared with the PUVA arm (median 27·5) (P = 0·11). Similarly, a trend towards lower UVA dose required to achieve CCR in the combination arm (median 55·8 J cm(-2) ) compared with the PUVA arm alone (median 117·5 J cm(-2) ) (P = 0·5) was observed. CONCLUSIONS: No significant difference in response rate or response duration was observed in this study. However, there was a trend towards fewer PUVA sessions and lower UVA dose required to achieve CCR in the combination arm (PUVA + bexarotene) but this did not achieve statistical significance due to insufficient power.