Autoimmunity Against Surfactant Protein B Is Associated with Pneumonitis During Checkpoint Blockade.

RATIONALE: Immune checkpoint inhibitor-related pneumonitis is a serious autoimmune event affecting up to 20% of patients with non-small cell lung cancer, yet the factors underpinning its development in some patients and not others are poorly understood. OBJECTIVES: To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. METHODS: The study cohort consisted of non-small cell lung cancer patients who gave blood samples before and during immune checkpoint inhibitor treatment. Serum was used for proteomics analyses and to detect autoantibodies present during pneumonitis. T cell stimulation assays and single-cell RNA sequencing were performed to investigate the specificity and functionality of peripheral autoreactive T cells. The findings were confirmed in a validation cohort comprising patients with non-small cell lung cancer and patients with melanoma. MEASUREMENTS AND MAIN RESULTS: Across both cohorts, patients who developed pneumonitis had higher pre-treatment levels of immunoglobulin G autoantibodies targeting surfactant protein-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4+ interferon-gamma-positive surfactant protein B-specific T cells, and expanding T cell clonotypes recognizing this protein, accompanied by a pro-inflammatory serum proteomic profile. CONCLUSIONS: Our data suggest that the co-occurrence of surfactant protein-B-specific immunoglobulin G autoantibodies and CD4+ T cells is associated with the development of pneumonitis during ICI therapy. Pre-treatment levels of these antibodies may represent a potential biomarker for elevated risk of developing pneumonitis and on-treatment levels may provide a diagnostic aid. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Histopathologic regression in patients with primary cutaneous melanoma undergoing sentinel lymph node biopsy is associated with favorable survival and, after metastasis, with improved progression-free survival on immune checkpoint inhibitor therapy: A single-institutional cohort study.

BACKGROUND: Histopathologic regression of cutaneous melanoma is considered a favorable prognostic factor, but its significance in clinical practice remains controversial. OBJECTIVE: To investigate the prognostic importance of regression in patients with primary cutaneous melanoma undergoing sentinel lymph node (SLN) biopsy and to assess its significance in patients progressing to an unresectable stage requiring systemic therapy. METHODS: We retrospectively reviewed patients with newly diagnosed melanoma undergoing SLN biopsy between 2010 and 2015 and available information on histopathologic regression (n = 1179). Survival data and associations of clinical variables with SLN status were assessed. RESULTS: Patients with regressive melanoma showed favorable relapse-free (hazard ratio [HR], 0.52; P = .00013), distant metastasis-free (HR, 0.56; P = .0020), and melanoma-specific survival (HR, 0.35; P = .00053). Regression was associated with negative SLN (odds ratio, 0.48; P = .0077). In patients who progressed to an unresectable stage, regression was associated with favorable progression-free survival under immune checkpoint inhibition (HR, 0.43; P = .031) but not under targeted therapy (HR, 1.14; P = .73) or chemotherapy (HR, 3.65; P = .0095). LIMITATIONS: Retrospective, single-institutional design. CONCLUSIONS: Regression of cutaneous melanoma is associated with improved prognosis in patients eligible for SLN biopsy as well as in patients with unresectable disease receiving systemic therapy with immune checkpoint inhibitors.

Associations of medicine use and ejection fraction with the coexistence of frailty and sarcopenia in a sample of heart failure outpatients: a cross-sectional study.

BACKGROUND: Frailty and sarcopenia have been extensively studied in heart failure (HF) patients, but their coexistence is unknown. The aim of this work is to describe the coexistence of these conditions in a sample of HF outpatients and its association with the use of medication and left-ventricular ejection fraction. METHODS: Participants in this cross-sectional study were recruited from a HF outpatients' clinic in northern Portugal. Frailty phenotype was assessed according to Fried et al. Sarcopenia was evaluated according to the revised consensus of the European Working Group on Sarcopenia in Older People. RESULTS: A total of 136 HF outpatients (33.8% women, median age 59 years) integrated this study. Frailty and sarcopenia accounted for 15.4% and 18.4% of the sample, respectively. Coexistence of frailty and sarcopenia was found in 8.1% of the participants, while 17.6% had only one of the conditions. In multivariable analysis (n = 132), increasing age (OR = 1.13;95%CI = 1.06,1.20), being a woman (OR = 65.65;95%CI = 13.50, 319.15), having heart failure with preserved ejection fraction (HFpEF) (OR = 5.61; 95%CI = 1.22, 25.76), and using antidepressants (OR = 11.05; 95%CI = 2.50, 48.82), anticoagulants (OR = 6.11; 95%CI = 1.69, 22.07), furosemide (OR = 3.95; 95%CI = 1.07, 14.55), and acetylsalicylic acid (OR = 5.01; 95%CI = 1.10, 22.90) were associated with increased likelihood of having coexistence of frailty and sarcopenia, while using statins showed the inverse effect (OR = 0.06; 95%CI = 0.01, 0.30). CONCLUSIONS: The relatively low frequency of coexistence of frailty and sarcopenia signifies that each of these two conditions still deserve individual attention from health professionals in their clinical practice and should be screened separately. Being a woman, older age, having HFpEF, using anticoagulants, antidepressants, loop diuretics and acetylsalicylic acid, and not using statins, were associated with having concomitant frailty and sarcopenia. These patients can potentially benefit from interventions that impact their quality of life such as nutritional and mental health interventions and exercise training.

Real-world outcomes using PD-1 antibodies and BRAF + MEK inhibitors for adjuvant melanoma treatment from 39 skin cancer centers in Germany, Austria and Switzerland.

BACKGROUND: Programmed death-1 (PD-1) antibodies and BRAF + MEK inhibitors are widely used for adjuvant therapy of fully resected high-risk melanoma. Little is known about treatment efficacy outside of phase III trials. This real-world study reports on clinical outcomes of modern adjuvant melanoma treatment in specialized skin cancer centers in Germany, Austria and Switzerland. METHODS: Multicenter, retrospective study investigating stage III-IV melanoma patients receiving adjuvant nivolumab (NIV), pembrolizumab (PEM) or dabrafenib + trametinib (D + T) between 1/2017 and 10/2021. The primary endpoint was 12-month recurrence-free survival (RFS). Further analyses included descriptive and correlative statistics, and a multivariate linear-regression machine learning model to assess the risk of early melanoma recurrence. RESULTS: In total, 1198 patients from 39 skin cancer centers from Germany, Austria and Switzerland were analysed. The vast majority received anti PD-1 therapies (n = 1003). Twelve-month RFS for anti PD-1 and BRAF + MEK inhibitor-treated patients were 78.1% and 86.5%, respectively (hazard ratio [HR] 1.998 [95% CI 1.335-2.991]; p = 0.001). There was no statistically significant difference in overall survival (OS) in anti PD-1 (95.8%) and BRAF + MEK inhibitor (96.9%) treated patients (p > 0.05) during the median follow-up of 17 months. Data indicates that anti PD-1 treated patients who develop immune-related adverse events (irAEs) have lower recurrence rates compared to patients with no irAEs (HR 0.578 [95% CI 0.443-0.754], p = 0.001). BRAF mutation status did not affect overall efficacy of anti PD-1 treatment (p > 0.05). In both, anti PD-1 and BRAF + MEK inhibitor treated cohorts, data did not show any difference in 12-month RFS and 12-month OS comparing patients receiving total lymph node dissection (TLND) versus sentinel lymph node biopsy only (p > 0.05). The recurrence prediction model reached high specificity but only low sensitivity with an AUC = 0.65. No new safety signals were detected. Overall, recorded numbers and severity of adverse events were lower than reported in pivotal phase III trials. CONCLUSIONS: Despite recent advances in adjuvant melanoma treatment, early recurrence remains a significant clinical challenge. This study shows that TLND does not reduce the risk of early melanoma recurrence and should only be considered in selected patients. Data further highlight that variables collected during clinical routine are unlikely to allow for a clinically relevant prediction of individual recurrence risk.

Prognosis in stage II melanoma of the head and neck depends on the histological subtype.

BACKGROUND AND OBJECTIVES: The melanoma guideline is mainly based on the AJCC stage. There is no difference according to histological subtypes such as superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM) or nodular malignant melanoma (NM). We aimed to evaluate whether patients with LMM have a different clinical course from patients with SSM/NM. This is particularly important as adjuvant anti-PD-1 therapy is approved for stage IIB and IIC melanoma. PATIENTS AND METHODS: Data were extracted from the Central Registry of Malignant Melanoma. Only patients with LMM, SSM, and NM of the head and neck with primary diagnosis between 01/01/2000 and 12/31/2019 were included. Progression-free survival (PFS), melanoma-specific survival (MSS), and pattern of metastases were analyzed for the LMM group compared to SSM/NM. RESULTS: The LMM cohort (n = 902) had significantly better MSS than the SSM/NM cohort (n = 604). There was no difference in PFS. The 5-year MSS of the stage II LMM cohort was 88.5% (95% CI 81.4-95.6) compared to 79.7% (95% CI 72.8-86.6) in the stage II SSM/NM cohort. CONCLUSION: It does not appear appropriate to use adjuvant therapy in stage II LMM patients to the same extent as in patients with SSM/NM.

S3 guideline "actinic keratosis and cutaneous squamous cell carcinoma" - update 2023, part 2: epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.

Actinic keratosis (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline "actinic keratosis and cutaneous squamous cell carcinoma" was updated and expanded by the topics cutaneous squamous cell carcinoma in situ (Bowen's disease) and actinic cheilitis. The guideline is aimed at dermatologists, general practitioners, ear nose and throat specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings, as well as other medical specialties, policy makers and insurance funds involved in the diagnosis and treatment of patients with AK and cSCC. A separate guideline exists for patients and their relatives. In this part, we will address aspects relating to epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.

Statins are associated with reduced likelihood of sarcopenia in a sample of heart failure outpatients: a cross-sectional study.

BACKGROUND: Sarcopenia is prevalent in heart failure (HF) patients, contributing to its poor prognosis. Statin use is postulated as a probable risk for developing sarcopenia, but little is known regarding this association in HF patients. This work aims at classifying and characterising sarcopenia and at describing the association of statin use with sarcopenia in a sample of Portuguese HF outpatients. METHODS: In this cross-sectional study, a sample of 136 HF patients (median age: 59 years, 33.8% women) was recruited from an HF outpatients' clinic of a University Hospital in Portugal. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People 2. Clinical, nutritional, and dietary data were collected. RESULTS: A total of 25 (18.4%) individuals were categorised as sarcopenic, ranging from 12.2% in younger (< 65 years) participants vs. 30.4% in older ones and from 3.3% in men vs. 47.8% in women. Severe sarcopenia accounted for 7.4% of the sample and sarcopenic obesity was identified in 5.1% of the individuals. A total of 65.4% of the participants were statin users. In multivariable analysis (n = 132, 25 sarcopenic), the use of statins was inversely associated with sarcopenia (OR = 0.03; 95% CI = 0.01, 0.30). Each additional age year was associated with a 9% increase in the likelihood of being sarcopenic (OR = 1.09; 95% CI = 1.01, 1.17), and each Kg.m-2 increment in body mass index was associated with a 21% decrease in the likelihood of sarcopenia (OR = 0.79; 95% CI = 0.65, 0.96). The daily use of five or more medicines was also directly associated with sarcopenia (OR = 26.87; 95% CI = 2.01, 359.26). On the other hand, being a man and being physically active were inversely associated with sarcopenia (OR = 0.01; 95% CI = 0.00, 0.07 and OR = 0.09; 95% CI = 0.01, 0.65, respectively). CONCLUSIONS: Contrary to what was expected, patients medicated with statins were less likely to be sarcopenic. Although this finding deserves further research, we hypothesise that this might be related to the pleiotropic effects of statins on endothelial function, contributing to better neuromuscular fitness.

Are older adults with excessive sodium intake at increased risk of hypohydration?

BACKGROUND: Sodium intake is expected to affect water needs, although compensation mechanisms may not work efficiently particularly in older adults. The aim of this cross-sectional study was to quantify the association between sodium excretion and hydration status in a representative sample of Portuguese older adults. METHODS: A cluster sampling approach was used, representing Portuguese older adults (≥65 years) according to sex, education level and region. From a sample size of 1500 participants, 1318 were eligible for the present analysis. A 24-h urine sample was collected, and volume, osmolality, creatinine and sodium were quantified. Free water reserve (FWR) was used to assess hydration status. Excessive sodium intake was defined as above 2000 mg day-1 as recommended by the World Health Organization. A multivariable binary logistic regression model was used to estimate the association between FWR and sodium excretion. Odds ratios (OR) and respective 95% confidence intervals (95% CI) were calculated. RESULTS: Excessive sodium excretion was observed in 80.0% of women and 91.5% of men, whereas hypohydration affected 10.9% of women and 23.6% of men. After adjusting for confounders, excessive sodium excretion was associated with an increased risk of hypohydration among men (OR = 2.75; 95% CI = 1.06-7.15). CONCLUSIONS: These results stress the positive association between excessive sodium intake and hypohydration in men and highlight the need for implementing strategies regarding the reduction of salt consumption and the promotion of water intake.

Prediction equations for estimating body weight in older adults.

BACKGROUND: Assessing body weight in older adults may be challenging. Hence, the present study aimed to develop and cross-validate updated and reproducible equations to estimate body weight in a large sample of older adults, namely among the older-old. METHODS: In total, 1456 individuals aged ≥ 65 years, from the Nutrition UP 65 study, were included in the present analysis. The participants were randomly assigned to one of two sub-samples: development (n = 991) and validation samples (n = 465). Prediction equations using height, mid-upper arm circumference (MUAC), waist circumference (WC), calf circumference (CC) and triceps skinfold thickness (TST) were generated for the development sample using multiple regression analysis and then validated using the validation sample. RESULTS: The model with five predictor variables generated the following equations: females 65-79 years: -114.682 + 0.522 × height (cm) + 0.620 × MUAC (cm) + 0.517 × WC (cm) + 0.893 × CC (cm) + 0.111 × TST (mm) (adjusted r2  = 0.883, standard error of the estimate (SEE) = 4.4); females ≥ 80 years: -110.806 + 0.494 × height (cm) + 0.637 × MUAC (cm) + 0.500 × WC (cm) + 0.986 × CC (cm) + 0.021 × TST (mm) (adjusted r2  = 0.890, SEE = 3.9); males 65-79 years: -114.875 + 0.558 × height (cm) + 0.073 × MUAC (cm) + 0.671 × WC (cm) + 0.717 × CC (cm) + 0.182 × TST(mm) (adjusted r2  = 0.820, SEE=5.0); and males ≥ 80 years: -128.789 + 0.546 × height (cm) + 0.202 × MUAC (cm) + 0.612 × WC (cm) + 1.236 × CC (cm) + 0.093 × TST (mm) (adjusted r2  = 0.906, SEE = 3.5). CONCLUSIONS: Body weight can be estimated with good accuracy in older adults using these sex- and age-specific equations generated from regression models using three to five anthropometric predictor variables.

Handgrip Strength and Its Association With Hydration Status and Urinary Sodium-to-Potassium Ratio in Older Adults.

Objective: Older adults present higher risk of functional disability detected by handgrip strength and an increased risk of poor health conditions, such as dehydration and low values of the sodium-to-potassium (Na/K) ratio. This study aimed to quantify the association of hydration status and Na/K ratio with handgrip strength, based on the urinary excretion of older adults.Methods: A cross-sectional study was conducted in 735 older adults ≥ 65 years old. Handgrip strength was measured with a Jamar Dynamometer and low values were defined according to body mass index and to sex-specific cutoff points. The hydration status was evaluated based on free water reserve. Sodium and potassium intake were evaluated after converting 24-hour urinary sodium and potassium excretion, respectively. A logistic regression model was used to estimate the probability of presenting low handgrip strength, according to risk of hypohydration and to quartiles of Na/K, stratified by sex and adjusted for potential confounders.Results: The adjusted odds ratio (OR) for presenting low handgrip strength was higher in women at risk of hypohydration, but this association was not found in men. Both women and men with the highest values of Na/K ratio presented higher adjusted OR for low handgrip strength (OR in women was 2.03; 95% confidence interval [CI]: 1.12-3.68, and in men was 2.19; 95% CI: 1.11-4.29).Conclusions: The risk of hypohydration was directly associated with low handgrip strength in older women. In older adults, higher values of urinary Na/K ratio were also directly associated with low handgrip strength.

Indirect Comparison of Combined BRAF and MEK Inhibition in Melanoma Patients with Elevated Baseline Lactate Dehydrogenase.

The approval of BRAF and MEK inhibitors has significantly improved treatment outcomes for patients with BRAF-mutated metastatic melanoma. The 3 first-line targeted therapy trials have provided similar results, and thus the identification of predictive biomarkers may generate a more precise basis for clinical decision-making. Elevated baseline lactate dehydrogenase (LDH) has already been determined as a strong prognostic factor. Therefore, this indirect analysis compared subgroups with elevated baseline LDH across the pivotal targeted therapy trials co-BRIM, COMBI-v and COLUMBUS part 1. The Bucher method was used to compare progression-free survival, objective response rate and overall survival indirectly. The results show a non-significant risk reduction for progression in the subgroup with elevated baseline LDH receiving vemurafenib plus cobimetinib compared with dabrafenib plus trametinib and encorafenib plus binimetinib. Although an indirect comparison, these data might provide some guidance for treatment recommendations in melanoma patients with elevated LDH.

S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma - short version, part 1: diagnosis, interventions for actinic keratoses, care structures and quality-of-care indicators.

Actinic keratoses (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline "actinic keratosis and cutaneous squamous cell carcinoma" was developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guideline is aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AK and cSCC. The guideline is also aimed at affected patients, their relatives, policy makers and insurance funds. In the first part, we will address aspects relating to diagnosis, interventions for AK, care structures and quality-of-care indicators.

S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma (cSCC) - short version, part 2: epidemiology, surgical and systemic treatment of cSCC, follow-up, prevention and occupational disease.

Actinic keratoses (AKs) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guidelines for actinic keratosis and cutaneous squamous cell carcinoma were developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guidelines are aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AKs and cSCC. The guidelines are also aimed at affected patients, their relatives, policy makers and insurance funds. In the second part, we will address aspects relating to epidemiology, etiology, surgical and systemic treatment of cSCC, follow-up and disease prevention, and discuss AKs and cSCC in the context of occupational disease regulations.

Malnutrition among older adults living in Portuguese nursing homes: the PEN-3S study.

OBJECTIVE: To characterise the nutritional status and to identify malnutrition-associated variables of older adults living in Portuguese nursing homes. DESIGN: Cross-sectional study. Data on demographic and socio-economic characteristics, self-reported morbidity, eating-related problems, nutritional status, cognitive function, depression symptoms, loneliness feelings and functional status were collected by trained nutritionists through a computer-assisted face-to-face structured interview followed by standardised anthropometric measurements. Logistic regression was used to identify factors associated with being at risk of malnutrition/malnourished. SETTING: Portuguese nursing homes. SUBJECTS: Nationally representative sample of the Portuguese population aged 65 years or over living in nursing homes. RESULTS: A total of 1186 individuals (mean age 83·4 years; 72·8 % women) accepted to participate. According to the Mini Nutritional Assessment, 4·8 (95 % CI 3·2, 7·3) % were identified as malnourished and 38·7 (95 % CI 33·5, 44·2) % were at risk of malnutrition. These percentages increased with age and were significantly higher for women. Logistic regression showed (OR; 95 % CI) that older adults reporting no or little appetite (6·5; 2·7, 15·3), those revealing symptoms of depression (2·6; 1·6, 4·2) and those who were more dependent in their daily living activities (4·7; 2·0, 11·1) were also at higher odds of being malnourished or at risk of malnutrition. CONCLUSIONS: Malnutrition and risk of malnutrition are prevalent among nursing home residents in Portugal. It is crucial to routinely screen for nutritional disorders, as well as risk factors such as symptoms of depression and lower functional status, to prevent and treat malnutrition.

Merkel cell carcinoma: Epidemiology, pathogenesis, diagnosis and therapy.

Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with a neuroendocrine phenotype. Incidence varies according to the geographic regions but is overall increasing. Different risk factors have been identified namely advanced age, immunosuppression, and ultraviolet light exposure. An association between MCC and polyomavirus infection is known. However, the exact mechanism that leads to carcinogenesis is yet to be fully understood. Surgery when feasible is the recommended treatment for localized disease, followed by adjuvant radiation or chemoradiation. In the metastatic setting, chemotherapy has been the standard treatment. However, two recently published trials with immune checkpoint inhibitors in first and second line showed promising results with a tolerable safety profile and these might become the standard therapy shortly. Somatostatin receptors are expressed in many MCC but such expression is not associated with disease severity. Presently there are no biomarkers predictive of response that could help to better select patients to these new therapies, and additional research is essential.