Cumulative incidence and risk factors for cutaneous squamous cell carcinoma metastases in organ transplant recipients: The Skin Care in Organ Transplant Patients in Europe-International Transplant Skin Cancer Collaborative metastases study, a prospective multicenter study.

INTRODUCTION: Solid organ transplant recipients (SOTRs) are believed to have an increased risk of metastatic cutaneous squamous cell carcinoma (cSCC), but reliable data are lacking regarding the precise incidence and associated risk factors. METHODS: In a prospective cohort study, including 19 specialist dermatology outpatient clinics in 15 countries, patient and tumor characteristics were collected using standardized questionnaires when SOTRs presented with a new cSCC. After a minimum of 2 years of follow-up, relevant data for all SOTRs were collected. Cumulative incidence of metastases was calculated by the Aalen-Johansen estimator. Fine and Gray models were used to assess multiple risk factors for metastases. RESULTS: Of 514 SOTRs who presented with 623 primary cSCCs, metastases developed in 37 with a 2-year patient-based cumulative incidence of 6.2%. Risk factors for metastases included location in the head and neck area, local recurrence, size > 2 cm, clinical ulceration, poor differentiation grade, perineural invasion, and deep invasion. A high-stage tumor that is also ulcerated showed the highest risk of metastasis, with a 2-year cumulative incidence of 46.2% (31.9%-68.4%). CONCLUSIONS: SOTRs have a high risk of cSCC metastases and well-established clinical and histologic risk factors have been confirmed. High-stage, ulcerated cSCCs have the highest risk of metastasis.

Chronic Use of Hydrochlorothiazide and Risk of Skin Cancer in Caucasian Adults: A PharmLines Initiative Inception Cohort Study.

Photosensitizing properties of hydrochlorothiazide may increase skin cancer risk. To date, study findings on the association between hydrochlorothiazide use and skin cancer risk are inconsistent, notably regarding confounding and dose-response. The aim of this study was to investigate the association between hydrochlorothiazide use and incidence of skin cancer in a cohort of unselected Caucasian adults, taking dosing into account. As part of the PharmLines Initiative, which links data from the Lifelines Cohort Study and prescription database IADB.nl, patients aged ≥ 40 years were included from Lifelines, a prospective population-based cohort study in the north of the Netherlands. Skin cancer incidence was compared between subjects starting hydrochlorothiazide treatment (n = 608), subjects starting treatment with other antihypertensives (n = 508), and non-antihypertensive long-term medication users (n = 1,710). Cox regression analyses were performed to obtain hazard ratios, adjusted for potential confounders. The risk of any skin cancer, keratinocyte carcinoma, basal cell carcinoma and squamous cell carcinoma was not significantly increased in general hydrochlorothiazide users. A clear association was observed between high cumulative hydrochlorothiazide use (≥ 5,000 defined daily dose; ≥ 125,000 mg) and the risk of any skin cancer (adjusted hazard ratio 5.32, 95% confidence interval (95% CI) 2.40-11.81), keratinocyte carcinoma (adjusted hazard ratio 7.31, 95% CI 3.12-17.13), basal cell carcinoma (adjusted hazard ratio 7.72, 95% CI 3.11-19.16) and squamous cell carcinoma (adjusted hazard ratio 19.63, 95% CI 3.12-123.56). These findings should lead to awareness with high use of hydrochlorothiazide in Caucasian adults.

Influence of Frailty and Life Expectancy on Guideline Adherence and Outcomes in Cutaneous Squamous Cell Carcinoma of the Head and Neck: A Prospective Pilot Study.

BACKGROUND: Cutaneous squamous cell carcinoma is the second most common malignancy of the skin, often occurring in older patients and in the head and neck area (cSCCHN). Age, life expectancy, and frailty are not taken into consideration by current guidelines. OBJECTIVES: The objective of this study was to evaluate the influence of frailty and life expectancy on guideline deviation, treatment outcomes, and quality of life (QoL) after treatment in patients with cSCCHN. METHODS: Patients with cSCCHN were prospectively included. A geriatric assessment was performed, including the Geriatric 8 (G8), Groningen Frailty Indicator, and Timed Up and Go test (TUG). The Lee index was used to predict a limited life expectancy, and the Adult Comorbidity Evaluation-27 was used as a comorbidity index. QoL was assessed by the Basal and Squamous cell carcinoma Quality of Life (BaSQoL) questionnaire at three time points. RESULTS: Seventy-seven patients with cSCCHN were included. Frail patients had significantly more high-risk tumours. Guideline deviation occurred in 7.8% and was more common in patients who were frail (G8), with high-risk tumours (≥T2), with a limited life expectancy or an increased TUG. Guideline deviation did not lead more often to progression of disease in our study. No predictors for post-operative complications were found. BaSQoL subscores were very low at each time point and did not change significantly with time in the total group. Frail patients reported more fear of recurrence or new tumours 3 months after treatment, and less concern about other people's skin 6 months after treatment, compared to non-frail patients. Complication rate, gender, or guideline deviation did not affect any subscale scores. CONCLUSIONS: Assessment of frailty and life expectancy can guide physicians and patients in treatment decisions. Deviation from guidelines towards less aggressive treatment schedules can be considered in frail patients with a limited life expectancy, since it did not negatively affect short-term outcomes or QoL in patients with cSCCHN in our study. However, these results should be confirmed by other, larger prospective studies with a longer follow-up period.

Towards less mutilating treatments in patients with advanced non-melanoma skin cancers by earlier use of immune checkpoint inhibitors.

Merkel cell carcinoma (MCC), advanced cutaneous squamous cell carcinoma (cSCC), and advanced basal cell carcinoma (BCC) are rare, and the often frail patients may require potentially mutilating local treatments. Immune checkpoint inhibitors (ICIs) are effective in melanoma and are moving towards the neoadjuvant setting. This systematic review explores data supporting the transition of ICIs from the metastatic to the (neo)adjuvant setting non-melanoma skin cancer (NMSC) and describes how knowledge from melanoma can be utilized. ICI response rates in advanced NMSC and melanoma are comparable. Five early phase studies show effectivity of neoadjuvant ICIs in melanoma and adjuvant treatment is standard-of-care. Eight adjuvant and 12 neoadjuvant ICI studies are ongoing for NMSC. Encouragingly, data from two small neoadjuvant ICI studies in NMSC, demonstrated complete responses in approximately half of patients. In conclusion, neoadjuvant ICI treatment has potential to avert mutilating treatments in NMSC. Progress can be accelerated by learning from melanoma.

The Effect of Tumor Characteristics and Location on the Extent of Lymph Node Metastases of Head and Neck Cutaneous Squamous Cell Carcinoma.

Background: The extent of a neck dissection for patients with metastasis of cutaneous squamous cell carcinoma of the head and neck (HNcSCC) is still subject to debate and clear guidelines are lacking. Tumor characteristics like size, differentiation and tumor location are known risk factors for lymph node metastasis (LNM). There is some evidence that, depending on tumor location, LNM follows a specific pattern. This study aims to identify which tumor characteristics can predict the pattern and extent of LNM. Method: In this cohort study 80 patients were included, who underwent a primary neck dissection for LNM of HNcSCC between 2003 and 2018 at the University Medical Center Groningen, the Netherlands. Retrospective data was collected for primary tumor characteristics and LNM and included surgical and follow-up data. Influence of tumor characteristics on the extent of LNM was analyzed using non-parametric tests. Logistic regression analysis were used to identify a metastasis pattern based on the primary tumor location. Results: Only primary tumor location was associated with the pattern of LNM. HNcSCC of the ear metastasized to level II (OR = 2.6) and the parotid gland (OR = 3.6). Cutaneous lip carcinoma metastasized to ipsilateral and contralateral level I (OR = 5.3). Posterior scalp tumors showed a metastasis pattern to level II (OR = 5.6); level III (OR = 11.2), level IV (OR = 4.7) and the parotid gland (OR = 10.8). Ear canal tumors showed a low risk of LNM for all levels. The extent of LNM was not related to age or any tumor characteristics i.e. tumor diameter, infiltration depth, differentiation grade, perineural growth and vascular invasion. Conclusion: Primary tumor location determines the LNM pattern. Whereas known unfavorable tumor characteristics did not relate to the extent of LNM. Location guided limited neck dissection combined with parotidectomy will treat most patients adequately.

Experiences of patients and health care professionals on the quality of telephone follow-up care during the COVID-19 pandemic: a large qualitative study in a multidisciplinary academic setting.

OBJECTIVE: To evaluate the perceived quality of follow-up telephone consultations (TCs) from the perspective of patients and healthcare professionals (HCPs) of multiple medical disciplines during the COVID-19 pandemic. DESIGN: A qualitative study using semi-structured interviews and reflexive thematic analysis. SETTING: Seven medical disciplines (general dermatology, dermato-oncology, head and neck oncology, internal medicine, medical oncology, gynaecological oncology and surgical oncology) at a large university hospital in the Netherlands. PARTICIPANTS: Patients who received and HCPs who provided TCs as a substitute for outpatient follow-up appointments during the COVID-19 pandemic. RESULTS: Eighty-two patients and 58 HCPs were interviewed. Predominantly, patients and HCPs were satisfied with the quality of care by TCs. They regarded TCs as efficient, accessible and of acceptable quality, provided there was an established patient-HCP relationship, medical complaints were absent and physical examination was not indicated. However, most patients were worried about the accuracy of their health assessment in the absence of physical examination and non-verbal communication. Both patients and HCPs wish to use TCs in the future alternatively with face-to-face consultations. CONCLUSION: This study concludes that TCs seem a valuable contribution to the context of follow-up care and could partially replace face-to-face consultations. TCs can be performed in stable, chronic patients with whom a doctor-patient relationship has already been established. Face-to-face consultations are considered more appropriate in the case of new patients, challenging or emotionally charged consultations and when clinically relevant physical examination is indicated. Due to the context-dependent nature of experiences of patients and HCPs, TCs should be used with an individually customised approach based on patient and disease specifics, in which shared decision-making plays an extensive role. Before major implementation is considered, sufficient data on the safety regarding missed diagnoses or cancer recurrences should be assembled first.

Age-related Differences in Tumour Characteristics and Prognostic Factors for Disease Progression in Cutaneous Squamous Cell Carcinoma of the Head and Neck.

Guidelines for cutaneous squamous cell carcinoma of the head and neck do not take the age of the patient into account, but instead assume equal tumour characteristics and prognostic factors for poor outcome in younger and elderly patients. The aim of this study was to compare tumour characteristics of younger (< 75 years) and elderly (≥ 75 years) patients and identify age-specific risk factors for progression of disease, comprising local recurrence, nodal metastasis and distant metastasis. Patient and tumour characteristics were compared using χ2 or Fisher's exact tests. Multivariable competing risk analyses were performed to compare risk factors for progression of disease, incorporating the risk of dying before developing progression of disease. A total of 672 patients with primary cutaneous squamous cell carcinoma of the head and neck were retrospectively included. Larger tumour diameter, worse differentiation grade and deeper invasion were observed in older patients. In elderly patients, but not in younger patients, tumour diameter ≥ 40 mm, moderate differentiation grade and an invasion depth ≥ 2 mm were independent risk factors for progression of disease.

Consensus-Based Recommendations on the Prevention of Squamous Cell Carcinoma in Solid Organ Transplant Recipients: A Delphi Consensus Statement.

IMPORTANCE: There is a paucity of evidence to guide physicians regarding prevention strategies for cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients (SOTRs). OBJECTIVE: To examine the development and results of a Delphi process initiated to identify consensus-based medical management recommendations for prevention of CSCC in SOTRs. EVIDENCE REVIEW: Dermatologists with more than 5 years' experience treating SOTRs were invited to participate. A novel actinic damage and skin cancer index (AD-SCI), consisting of 6 ordinal stages corresponding to an increasing burden of actinic damage and CSCC, was used to guide survey design. Three sequential web-based surveys were administered from January 1, 2019, to December 31, 2020. Pursuant to Delphi principles, respondents thoroughly reviewed all peer responses between rounds. Supplemental questions were also asked to better understand panelists' rationale for their responses. FINDINGS: The Delphi panel comprised 48 dermatologists. Respondents represented 13 countries, with 27 (56%) from the US. Twenty-nine respondents (60%) were Mohs surgeons. Consensus was reached with 80% or higher concordance among respondents when presented with a statement, question, or management strategy pertaining to prevention of CSCC in SOTRs. A near-consensus category of 70% to less than 80% concordance was also defined. The AD-SCI stage-based recommendations were established if consensus or near-consensus was achieved. The panel was able to make recommendations for 5 of 6 AD-SCI stages. Key recommendations include the following: cryotherapy for scattered actinic keratosis (AK); field therapy for AK when grouped in 1 anatomical area, unless AKs are thick in which case field therapy and cryotherapy were recommended; combination lesion directed and field therapy with fluorouracil for field cancerized skin; and initiation of acitretin therapy and discussion of immunosuppression reduction or modification for patients who develop multiple skin cancers at a high rate (10 CSCCs per year) or develop high-risk CSCC (defined by a tumor with approximately ≥20% risk of nodal metastasis). No consensus recommendation was achieved for SOTRs with a first low risk CSCC. CONCLUSIONS AND RELEVANCE: Physicians may consider implementation of panel recommendations for prevention of CSCC in SOTRs while awaiting high-level-of-evidence data. Additional clinical trials are needed in areas where consensus was not reached.

Eight years of experience with vismodegib for advanced and multiple basal cell carcinoma patients in the Netherlands: a retrospective cohort study.

BACKGROUND: Vismodegib has been used for the treatment of locally advanced basal cell carcinoma (laBCC) and metastatic BCC (mBCC) since 2011. Most efficacy and safety data are provided by clinical trials. This study evaluates the effectiveness of vismodegib for the treatment of laBCC, mBCC and basal cell nevus syndrome (BCNS) patients, and the tumour characteristics associated with a higher probability of achieving a complete response in the Netherlands. METHODS: A retrospective cohort study that included all patients ≥18 years with histologically proven basal cell carcinoma that received ≥1 dose of vismodegib between July 2011 and September 2019 in the Netherlands. RESULTS: In total, 48 laBCC, 11 mBCC and 19 BCNS patients were included. Median progression-free survival was 10.3 months (95% confidence interval (CI), 7.5-22.6) for laBCC, 11.7 (95% CI, 5.2-17.5) for mBCC and 19.1 (95% CI, 7.4-20.2) for BCNS. Larger laBCCs were associated with a lower probability of complete response (hazard ratio (HR) 0.77 per increase in cm, p = 0.02). Of all BCNS patients, 63% received ≥2 treatment sequences with vismodegib; all achieved partial responses. CONCLUSIONS: Half of the aBCC patients progress within 1 year after the start of vismodegib treatment. More research is needed to investigate other treatment strategies after vismodegib progression and to evaluate long-term effects of repetitive vismodegib treatment.

Effect of Patient Characteristics on Treatment Decisions Regarding Keratinocyte Carcinoma in Elderly Patients: A Review of the Current Literature.

There are straightforward guidelines for treatment of keratinocyte carcinoma (formerly known as non-melanoma skin cancer); however, there are no clear recommendations specifically for elderly patients. The aim of this review was to provide an overview of the current literature about the effect of patient characteristics, specifically life expectancy, frailty and comorbidity, on treatment decisions in elderly patients with keratinocyte carcinoma, by searching PubMed database. It was found that the literature is limited and based mostly on small retrospective studies. Therefore, it is difficult to give firm recommendations about how to treat elderly people who have keratinocyte carcinoma. A "one-size-fits-all" approach to this population is not sufficient: life expectancy and frailty need to be considered in the decision-making process regarding treatment for elderly people with keratinocyte carcinoma. Among the comorbidity scores, Adult-Comorbidity-Evaluation-27-index seems to have the best prognostic value. Prospective studies are needed to generate more individualized recommendations for this increasing and often vulnerable group.

Geriatric assessment of patients treated for cutaneous head and neck malignancies in a tertiary referral center: Predictors of postoperative complications.

INTRODUCTION: As cutaneous head and neck malignancies are highly prevalent especially in older patients, the risk of surgical complications is substantial in this potentially vulnerable population. The objective of this study was to evaluate the value of geriatric assessment of this population with respect to postoperative complications. METHODS: Patients were prospectively included in OncoLifeS, a databiobank. Before surgery, patients underwent a geriatric assessment including multiple validated screening tools for frailty, comorbidity, polypharmacy, nutrition, functional status, social support, cognition and psychological status. Postoperatively, complications (Clavien-Dindo ≥ grade II) were registered. Uni- and multivariable logistic regression analyses were performed yielding odds ratios (ORs) and 95% confidence intervals (95%CIs). RESULTS: 151 patients undergoing surgery for cutaneous head and neck malignancies were included in this study (mean age 78.9 years, 73.5% male). In a multivariable analysis, frailty measured by the Geriatric 8 (G8) (OR = 6.34; 95%CI:1.73-23.25) was the strongest independent predictor of postoperative complications, among other predictors such as major treatment intensity (OR = 2.73; 95%CI:1.19-6.26) and general anesthesia (OR = 4.74; 95%CI:1.02-22.17), adjusted for age and sex. CONCLUSION: Frailty, measured by G8, is the strongest predictor of postoperative complications in patients undergoing surgery for cutaneous head and neck malignancies in addition to treatment intensity and type of anesthesia. Geriatric screening on multiple domains is recommended for patients with cutaneous malignancies undergoing head and neck surgery is recommended, as this population includes old patients and frequently suffers postoperative complications.

Azathioprine to mycophenolate mofetil transition and risk of squamous cell carcinoma after lung transplantation.

BACKGROUND: Chronic immunosuppression after solid-organ transplantation is a risk factor for cutaneous squamous cell carcinoma (cSCC) development. Certain immunosuppressant drugs, namely azathioprine and calcineurin inhibitors, increase this risk more than others. We investigated incidence of cSCC in a Dutch lung transplant recipient (LTR) cohort and analyzed associated risk factors. METHODS: All LTRs with post-transplant survival of >30 days were included. Data included indication for lung transplantation and duration of medication use. Skin cancer data were extracted from the Dutch nationwide registry of histopathology (PALGA). Uni- and multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression analyses. RESULTS: Five hundred forty-four patients were included with a median survival of 11.05 years. Fifty-two (9.6%) LTRs developed at least one cSCC, with a cumulative incidence of 3.9% and 15.3% after 5 and 10 years, respectively. Multivariate analyses showed that the sequential use of azathioprine and mycophenolate mofetil (MMF), both at for least 1 year, was associated with a lower risk of developing cSCC (hazard ratio [HR] 0.24; 95% confidence interval [CI] 0.10 to 0.56) compared with azathioprine use only. Furthermore, age at transplantation (HR 3.42; 95% CI 1.33 to 8.79), male gender (HR 1.75; 95% CI 1.00 to 3.05), previous skin cancer (HR 4.75; 95% CI 1.14 to 19.76), and history of smoking (HR 3.30; 95% CI 1.69 to 6.44) were associated with increased risk of developing cSCC in univariate analyses. CONCLUSIONS: Apart from known risk factors, we found that switching from azathioprine to MMF is associated with reduced incidence of cSCC in LTR, prompting a discussion of whether switching azathioprine to MMF should be considered in high-risk patients.

Rationale and design of TransplantLines: a prospective cohort study and biobank of solid organ transplant recipients.

INTRODUCTION: In the past decades, short-term results after solid organ transplantation have markedly improved. Disappointingly, this has not been accompanied by parallel improvements in long-term outcomes after transplantation. To improve graft and recipient outcomes, identification of potentially modifiable risk factors and development of biomarkers are required. We provide the rationale and design of a large prospective cohort study of solid organ transplant recipients (TransplantLines). METHODS AND ANALYSIS: TransplantLines is designed as a single-centre, prospective cohort study and biobank including all different types of solid organ transplant recipients as well as living organ donors. Data will be collected from transplant candidates before transplantation, during transplantation, at 3 months, 6 months, 1 year, 2 years and 5 years, and subsequently every 5 years after transplantation. Data from living organ donors will be collected before donation, during donation, at 3 months, 1 year and 5 years after donation, and subsequently every 5 years. The primary outcomes are mortality and graft failure. The secondary outcomes will be cause-specific mortality, cause-specific graft failure and rejection. The tertiary outcomes will be other health problems, including diabetes, obesity, hypertension, hypercholesterolaemia and cardiovascular disease, and disturbances that relate to quality of life, that is, physical and psychological functioning, including quality of sleep, and neurological problems such as tremor and polyneuropathy. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the relevant local ethics committee. The TransplantLines cohort study is designed to deliver pioneering insights into transplantation and donation outcomes. The study design allows comprehensive data collection on perioperative care, nutrition, social and psychological functioning, and biochemical parameters. This may provide a rationale for future intervention strategies to more individualised, patient-centred transplant care and individualisation of treatment. TRIAL REGISTRATION NUMBER: NCT03272841.

Phototherapy of Psoriasis, a Chronic Inflammatory Skin Disease.

Phototherapy is an effective treatment modality for several skin diseases which has been in use from the era of the Egyptians. Insight into its mode of action has gradually accumulated over the past decades. A crucial biological effect of ultraviolet radiation is the induction of apoptosis in T lymphocytes and in keratinocytes in the epidermis. Via this mechanism inflammation-induced pathological changes characteristic of psoriasis are counteracted.Phototherapy remains the only therapeutic option for certain patient groups where modification of the systemic immune reactions is contraindicated, such as by HIV, internal malignancy or pregnancy. UVB treatment is highly cost-effective, which is important in this age of increasing health care costs.

Phototherapy and photochemotherapy for psoriasis.

Phototherapy is a first-line option for the treatment of moderate to severe psoriasis. Systematic reviews indicate near comparable efficacy of the different forms of phototherapy. Localized phototherapy can be an adjunctive treatment of recalcitrant plaques during systemic treatment of psoriasis. More than 200 psoralen-UV-A therapy treatment sessions is associated with an increased risk of keratinocytic cancers, whereas no increased risk has been demonstrated for narrow-band UV-B therapy. The mechanism of action of phototherapy in psoriasis is via inhibition of keratinocyte proliferation; induction of apoptosis in keratinocytes, dendritic, and T cells; and inhibition of Th1 and Th17 pathways, but activation of Th2.