Dermatitis herpetiformis: clinical and immunological aspects

Although many workers have demonstrated that the rash of dermatitis herpetiformis responds to withdrawal of gluten from the diet, there are many who remain sceptical. The role of a gluten free diet in the management of patients with dermatitis herpetiformis was re-examined and its beneficial effects confirmed. Furthermore, a gluten free diet was shown to protect patients with dermatitis herpetiformis from developing lymphoma but the diet had to be strict and the protective effect only became apparent once the diet had been adhered to for five years. Relatives of three patients (with a family history of dermatitis herpetiformis/coeliac disease) were screened in order to detect the clinical carrier rate for the genes for dermatitis herpetiformis and coeliac disease within these families. The carrier rate in the three families studied varied from 23% to 57%. This study demonstrated that many so-called "unaffected" relatives of patients with dermatitis herpetiformis may have silent or latent coeliac disease. Screening by means of serology alone was shown to be unreliable. The pathogenic mechanisms leading to the development of the rash and enteropathy are poorly understood. An infiltrate of T cells, composed mainly of activated CD4 positive memory cells, was shown to be present in the dermis of dermatitis herpetiformis lesional skin. Moreover, these T cells demonstrated over-representation of specific TCR Vβ subsets, namely Vβ2, Vβ5.2/5.3 and Vβ5.3. These findings would indicate that these T cells recognise a specific, but as yet unknown, antigen; the antigen is unlikely to be gluten because intradermal injection of Frazer's fraction III failed to elicit the rash of dermatitis herpetiformis in patients. An infiltrate of T cells is also found in the small intestinal mucosa of patients with dermatitis herpetiformis and coeliac disease. It has been proposed that these T cells belong predominantly to the TH1 group of cells and it has been suggested that IFN-γ, which is produced by these cells, plays a key role in the production of the small intestinal pathology. However, this hypothesis has not been supported by others. Reverse transcriptase-polymerase chain reaction and immunostaining demonstrated no statistically significant differences in the detection of mRNA for IFN-γ and IL-2 or their proteins when biopsies from patients with dermatitis herpetiformis who had villous atrophy were compared with a control group of patients. Finally, possible mechanisms, whereby ingestion of gluten in susceptible individuals leads to the rash of dermatitis herpetiformis, are discussed

Predictive indicators for revisional surgery in nasal reconstruction after Mohs surgery

Background: Reconstruction of nasal lesions is complex due to the topography, mobile free margins and borders of anatomical subunits. Reconstructive challenges can lead to multiple revisional surgeries to achieve the final aesthetic result. This study aimed to evaluate risk factors and predictors of revisional surgery in patients undergoing reconstruction after Mohs micrographic surgery for nasal tumours. Methods: This was a prospective cohort study from April 2, 2008 to February 26, 2019. The study population included all consecutive patients who underwent Mohs micrographic surgery for nasal skin cancer. Resection and reconstruction of nasal skin cancer was performed by the Mohs team. Results: A total of 988 cases met our study inclusion criteria with 64 (6.5%) cases requiring unplanned surgical revision. Revision rates were highest in the ala (9.0%, p < 0.05) and complex anatomical subunits (16.7%, p < 0.0001). In contrast, revision rates for dorsum lesions were lowest (1.8%, p < 0.001). In terms of reconstructive modalities, local flaps resulted in significantly higher rates of revision when compared to grafts (relative risk, 2.37; 95% CI, 1.15–5.0; p < 0.01). In terms of histological diagnosis, squamous cell carcinoma had significantly higher revision rates when compared to basal cell carcinoma (p < 0.05). Conclusions: To our knowledge, this is the first study to report the risk factors and predictors of revision surgery in patients undergoing MMS for nasal tumours. This study highlights that the reconstructive modality utilised affects the functional and cosmetic outcome of MMS. We note that ala complex subunit lesions, squamous cell carcinoma and flap reconstruction were associated with an increased risk of revision after Mohs reconstruction of nasal lesions. Level of evidence: Level III, risk/prognostic; therapeutic study. Trial registration number: (Ref: PLA-19-20_A03) 04/02/2020

Risk Stratification of Sentinel Node Metastasis Disease Burden and Phenotype in Stage III Melanoma Patients

Background: Currently, all patients with American Joint Committee on Cancer (AJCC) pT2b-pT4b melanomas and a positive sentinel node biopsy are now considered for adjuvant systemic therapy without consideration of the burden of disease in the metastatic nodes. Methods: This was a retrospective cohort analysis of 1377 pT1-pT4b melanoma patients treated at an academic cancer center. Standard variables regarding patient, primary tumor, and sentinel node characteristics, in addition to sentinel node metastasis maximum tumor deposit size (MTDS) in millimeters and extracapsular spread (ECS) status, were analyzed for predicting disease-specific survival (DSS). Results: The incidence of SN+ was 17.3% (238/1377) and ECS was 10.5% (25/238). Increasing AJCC N stage was associated with worse DSS. There was no difference in DSS between the IIIB and IIIC groups. Subgroup analyses showed that the optimal MTDS cut-point was 0.7 mm for the pT1b-pT4a SN+ subgroups, but there was no cut-point for the pT4b SN+ subgroup. Patients with MTDS <0.7 mm and no ECS had similar survival outcomes as the N0 patients with the same T stage. Nodal risk categories were developed using the 0.7 mm MTDS cut-point and ECS status. The incidence of low-risk disease, according to the new nodal risk model, was 22.3% (53/238) in the stage III cohort, with 49% (26/53) in the pT2b-pT3a and pT3b-pT4a subgroups and none in the pT4b subgroup. Similar outcomes were observed for overall and distant metastasis-free survival. Conclusion: We propose a more granular classification system, based on tumor burden and ECS status in the sentinel node, that identifies low-risk patients in the AJCC IIIB and IIIC subgroups who may otherwise be observed

The MelFo Study UK: Effects of a reduced-frequency, stage-adjusted follow-up schedule for cutaneous melanoma 1B to 2C patients after 3-years

Background: Evidence-based guidelines for follow-up treatment of American Joint Committee on Cancer (AJCC) stages 1B to 2C melanoma patients are lacking. The MELanoma FOllow-up study is an international phase 3 randomized trial, and the 3-year interim data were recently reported from the Netherlands. The study was undertaken concurrently with a British cohort for comparison and validation of the Dutch study.  Methods: The study enrolled and stratified 207 patients by AJCC stage. The conventional schedule group (CSG; n = 103) cohort was reviewed as per UK guidelines. The experimental schedule group (ESG; n = 104) cohort was reviewed in a reduced-frequency nurse-led, consultant-supervised clinic. Quality of life (QoL) was measured at baseline (T1), a 1 year (T2), and at 3 years (T3) using the State-Trait Anxiety Inventory, the Cancer Worry Scale, the Impact-of-Event Scale, and the Mental and Physical Component scales (PCS/MCS) of the RAND-36.  Results: Of the 207 QoL questionnaires, 170 (82.1%) were completed at T3. Both cohorts expressed high satisfaction (' 93%) with their regimens. At T3, no significant group effect was found on any patient-reported outcome measures scores, indicating no QoL difference between the follow-up protocols. Recurrence had developed in 33 patients Conventional follow-up (CFU), 16 [15.5%]; Experimental follow-up (EFU), 17 [16.3%]. Self-examination was the method of detection for 12 ESG patients (70.6%) and 11 CSG patients (68.8%). The melanoma-specific survival was identical.  Conclusion: The UK 3-year data were consistent with the previous Dutch report. The reduced follow-up strategy was shown to be safe, with significant resource usage benefits for national cancer services. Patient anxiety levels were not increased by a less-intensive follow-up regimen, and acceptance was high. The study data indicate that patient self-examination is very effective for recurrence detection

Follow-up Schedule for Patients With Sentinel Node-negative Cutaneous Melanoma (The MELFO Study) An International Phase III Randomized Clinical Trial

Objectives and Design: The MELFO (MELanoma FOllow-up) study is an international phase III randomized controlled trial comparing an experimental low-intensity schedule against current national guidelines. Background: Evidence-based guidelines for the follow-up of sentinel node-negative melanoma patients are lacking. Methods: Overall, 388 adult patients diagnosed with sentinel node-negative primary melanoma patients were randomized in cancer centers in the Netherlands and United Kingdom between 2006 and 2016. The conventional schedule group (control: n=196) was reviewed as per current national guidelines. The experimental schedule group (n=192) was reviewed in a reduced-frequency schedule. Quality of life was the primary outcome measurement. Detection rates and survival outcomes were recorded. Patient satisfaction rates and compliance with allocated schedules were compared. Results: At 5 years, both arms expressed high satisfaction with their regimens (>97%). This study found no significant group effect on any patient-reported outcome measure scores between the follow-up protocols. In total, 75/388 (19.4%) patients recurred, with no difference in incidence found between the 2 arms (hazard ratio=0.87, 95% confidence interval: 0.54-1.39, P=0.57). Self-examination was the method of detection for 25 experimental patients and 32 control patients (75.8% vs. 76.2%; P=0.41). This study found no difference in any survival outcomes between the 2 study arms (disease-free survival: hazard ratio=1.00, 95% confidence interval: 0.49-2.07, P=0.99). Conclusions: A reduced-intensity, American Joint Committee on Cancer (AJCC) stage-adjusted follow-up schedule for sentinel node-negative melanoma patients is a safe strategy, and patient self-examination is effective for recurrence detection with no evidence of diagnostic delay. Patients' acceptance is very high

Cross-cultural development of a quality-of-life measure for patients with melanoma: phase 3 testing of an EORTC Melanoma Module

Melanoma is an increasingly common skin cancer worldwide. Recent treatment advances have provided patients and healthcare professionals (HCPs) with choices where quality of life (QoL) and toxicity are important considerations. A melanoma-specific QoL questionnaire is being developed in a cross-cultural setting using a four phase process developed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Group. In phase 1, a literature search identified a list of pertinent QoL issues; this was shown to HCPs and patients in eight countries and rated for importance and relevance. Questions were constructed for the highest-rated issues (phase 2) and piloted in another patient sample (phase 3). Using EORTC Quality of Life Group criteria and sequential use of factor and Rasch analysis, scales were hypothesized for field testing (phase 4). Seven QoL domains (disease symptoms, treatment issues, financial issues, access/quality of information, satisfaction with care, psychosocial issues and support), comprising 73 QoL issues, were rated by 46 HCPs and 78 patients. Fifty-six issues were rephrased as questions and piloted with 132 patients. A 38-item questionnaire (QLQ-MEL38) is available for field testing in conjunction with the EORTC QLQ-C30. This study has shown that melanoma patients have important QoL issues that have been incorporated into a new cross-culturally validated instrument. Future testing of this EORTC module is planned and will be an important step forward in providing reliable QoL data to aid future decision-making in the management and clinical trials of this complex group of patients