Merkel Cell Carcinoma: Integrating Epidemiology, Immunology, and Therapeutic Updates.

Merkel cell carcinoma (MCC) is a rare skin cancer characterized by neuroendocrine differentiation. Its carcinogenesis is based either on the integration of the Merkel cell polyomavirus or on ultraviolet (UV) mutagenesis, both of which lead to high immunogenicity either through the expression of viral proteins or neoantigens. Despite this immunogenicity resulting from viral or UV-associated carcinogenesis, it exhibits highly aggressive behavior. However, owing to the rarity of MCC and the lack of epidemiologic registries with detailed clinical data, there is some uncertainty regarding the spontaneous course of the disease. Historically, advanced MCC patients were treated with conventional cytotoxic chemotherapy yielding a median response duration of only 3 months. Starting in 2017, four programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors-avelumab, pembrolizumab, nivolumab (utilized in both neoadjuvant and adjuvant settings), and retifanlimab-have demonstrated efficacy in treating patients with disseminated MCC on the basis of prospective clinical trials. However, generating clinical evidence for rare cancers, such as MCC, is challenging owing to difficulties in conducting large-scale trials, resulting in small sample sizes and therefore lacking statistical power. Thus, to comprehensively understand the available clinical evidence on various immunotherapy approaches for MCC, we also delve into the epidemiology and immune biology of this cancer. Nevertheless, while randomized studies directly comparing immune checkpoint inhibitors and chemotherapy in MCC are lacking, immunotherapy shows response rates comparable to those previously reported with chemotherapy but with more enduring responses. Notably, adjuvant nivolumab has proven superiority to the standard-of-care therapy (observation) in the adjuvant setting.

Differences in Anthropometric Measures Based on Sex, Age, and Health Status: Findings From the German National Cohort (NAKO).

BACKGROUND: Obesity is a worldwide health problem. We conducted detailed analyses of anthropometric measures in a comprehensive, population-based, current cohort in Germany. METHODS: In the German National Cohort (NAKO), we analyzed cross-sectional data on body-mass index (BMI), waist and hip circumference, subcutaneous (SAT) and visceral adipose tissue (VAT) as measured by ultrasound, and body fat percentage. The data were stratified by sex, age, and self-reported physicians' diagnoses of cardiovascular diseases (CVD), metabolic diseases (MetD), cardiometabolic diseases (CMD), and cancer. RESULTS: Data were available from 204 751 participants (age, 49.9 ± 12.8 years; 50.5% women). Body size measures generally increased with age. Men had a higher BMI, larger waist circumference, and more VAT than women, while women had a larger hip circumference, more SAT, and a higher body fat percentage than men. For example, the mean BMI of participants over age 60 was 28.3 kg/m2 in men and 27.6 kg/m2 in women. CVD, MetD, and CMD were associated with higher anthropometric values, while cancer was not. For example, the mean BMI was 25.3 kg/m2 in healthy women, 29.4 kg/m2 in women with CMD, and 25.4 kg/m2 in women with cancer. CONCLUSION: Obesity is widespread in Germany, with notable differences between the sexes in anthropometric values. Obesity was more common in older participants and those with chronic diseases other than cancer. Elevated values were especially common in multimorbid individuals.

Association of antibiotic treatment with survival outcomes in treatment-naïve melanoma patients receiving immune checkpoint blockade.

PURPOSE: The interaction of gut microbiome and immune system is being studied with increasing interest. Disturbing factors, such as antibiotics may impact the immune system via gut and interfere with tumor response to immune checkpoint blockade (ICB). METHODS: In this multicenter retrospective cohort study exclusively treatment-naïve patients with cutaneous or mucosal melanoma treated with first-line anti-PD-1 based ICB for advanced, non-resectable disease between 06/2013 and 09/2018 were included. Progression-free (PFS), and overall survival (OS) according to antibiotic exposure (within 60 days prior to ICB and after the start of ICB vs. no antibiotic exposure) were analyzed. To account for immortal time bias, data from patients with antibiotics during ICB were analyzed separately in the time periods before and after start of antibiotics. RESULTS: Among 578 patients with first-line anti-PD1 based ICB, 7% of patients received antibiotics within 60 days prior to ICB and 19% after starting ICB. Antibiotic exposure prior to ICB was associated with worse PFS (adjusted HR 1.75 [95% CI 1.22-2.52]) and OS (adjusted HR 1.64 [95% CI 1.04-2.58]) by multivariate analysis adjusting for potential confounders. The use of antibiotics after the start of ICB had no effect on either PFS (adjusted HR 1.19; 95% CI 0.89-1.60) or OS (adjusted HR 1.08; 95% CI 0.75-1.57). CONCLUSIONS: Antibiotic exposure within 60 days prior to ICB seems to be associated with worse PFS and OS in melanoma patients receiving first-line anti-PD1 based therapy, whereas antibiotics after the start of ICB do not appear to affect PFS or OS.

Testicular cancer mortality in Latin America and the Caribbean: trend analysis from 1997 to 2019.

BACKGROUND: In the last decades, an increasing incidence of testicular cancer has been observed in several countries worldwide. Although mortality rates have been variable in many countries, little information is available from Latin America and the Caribbean (LAC). Therefore, we examined mortality trends of testicular cancer in the last two decades. METHODS: Age-standardized mortality rates (ASMR) of testicular cancer per 100,000 men-years were estimated using the World Health Organization mortality database from 1997 to 2019. We examined the mortality trends and computed annual percent change (APC) for all ages and the following age groups, 15-29, 30-44, 15-44, and ≥ 45 years. RESULTS: Ten countries had mortality rates greater than 0.43 per 100,000 men, with the highest rates for Chile, Mexico, and Argentina. Significant increases in mortality rates were observed in Argentina, Brazil Colombia, and Mexico in all ages, and < 45 years, while Colombia, Ecuador, Mexico, and Peru reported significant downward trends in males aged ≥ 45 years. Only Chile showed significant decreases for all ages and age groups studied. CONCLUSION: Mortality by testicular cancer increased among LAC countries in males of all ages and across age groups. A reduction in mortality rates was observed only in Chilean males of all ages and in men ≥ 45 years in several countries. Strengthening of early detection among symptomatic males may decrease the mortality by this neoplasm.

Distance-Metric Learning for Personalized Survival Analysis.

Personalized time-to-event or survival prediction with right-censored outcomes is a pervasive challenge in healthcare research. Although various supervised machine learning methods, such as random survival forests or neural networks, have been adapted to handle such outcomes effectively, they do not provide explanations for their predictions, lacking interpretability. In this paper, an alternative method for survival prediction by weighted nearest neighbors is proposed. Fitting this model to data entails optimizing the weights by learning a metric. An individual prediction of this method can be explained by providing the user with the most influential data points for this prediction, i.e., the closest data points and their weights. The strengths and weaknesses in terms of predictive performance are highlighted on simulated data and an application of the method on two different real-world datasets of breast cancer patients shows its competitiveness with established methods.

Population-Based Clinical Cancer Registration in Germany.

INTRODUCTION: In 2013, a new federal law obligated all German federal states to collect additional clinical data in population-based cancer registries as an active tool for monitoring and improving the quality of cancer care, increasing transparency and promoting health research. Now, 10 years later, the current status of the expanded cancer registration is presented, including current figures on cancer in Germany. METHODS: Reporting of cancer is mandatory for physicians, and about 5 to 10 reports from different healthcare providers are expected for each case. A uniform national dataset of about 130 items is used, and reports are usually sent electronically to the registry. We used the most recent data available from cancer registries up to the year of diagnosis in 2019. We calculated incidence rates and 5-year relative survival (5YRS) for common cancers. Data on clinical outcomes and benchmarking based on quality indicators (QIs) from guidelines were provided by the Cancer Registry Schleswig-Holstein (CR SH). RESULTS: All federal state cancer registries met most of the previously defined national eligibility criteria. Approximately 505,000 cancer cases were registered in 2019, with breast, prostate, colorectal and lung cancer being the most common cancers. The age-standardised cancer incidence has slightly decreased during the last decade. and spatial heterogeneity can be observed within Germany. 5YRS for all cancers was 67% and 63% for women and men, respectively. Therapy data for rectal cancer in 2019-2021 from the CR SH are shown as an example: 69% of the registered patients underwent surgery, mostly with curative intent (84%) and tumour-free resection (91%). Radiotherapy was given to 33% of the patients, and chemotherapy was given to 40%. Three selected QIs showed differences between involved healthcare providers. DISCUSSION: The implementation of population-based clinical cancer registration can be considered a success. Comprehensive recording of diagnosis, treatment and disease progression and the use of registry data for quality assurance, benchmarking and feedback have been implemented.

Conventional Imaging, MRI and 18F-FDG PET/MRI for N and M Staging in Patients with Newly Diagnosed Breast Cancer.

Background: This study compares the diagnostic potential of conventional staging (computed tomography (CT), axillary sonography and bone scintigraphy), whole-body magnetic resonance imaging (MRI) and whole-body 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/)MRI for N and M staging in newly diagnosed breast cancer. Methods: A total of 208 patients with newly diagnosed breast cancer were prospectively included in this study and underwent contrast-enhanced thoracoabdominal CT, bone scintigraphy and axillary sonography as well as contrast-enhanced whole-body 18F-FDG PET/MRI. The datasets were analyzed with respect to lesion localization and characterization. Histopathology and follow-up imaging served as the reference standard. A McNemar test was used to compare the diagnostic performance of conventional staging, MRI and 18F-FDG PET/MRI and a Wilcoxon test was used to compare differences in true positive findings for nodal staging. Results: Conventional staging determined the N stage with a sensitivity of 80.9%, a specificity of 99.2%, a PPV (positive predictive value) of 98.6% and a NPV (negative predictive value) of 87.4%. The corresponding results for MRI were 79.6%, 100%, 100% and 87.0%, and were 86.5%, 94.1%, 91.7% and 90.3% for 18F-FDG PET/MRI. 18F-FDG PET/MRI was significantly more sensitive in determining malignant lymph nodes than conventional imaging and MRI (p < 0.0001 and p = 0.0005). Furthermore, 18F-FDG PET/MRI accurately estimated the clinical lymph node stage in significantly more cases than conventional imaging and MRI (each p < 0.05). Sensitivity, specificity, PPV and NPV for the M stage in conventional staging were 83.3%, 98.5%, 76.9% and 98.9%, respectively. The corresponding results for both MRI and 18F-FDG PET/MRI were 100.0%, 98.5%, 80.0% and 100.0%. No significant differences between the imaging modalities were seen for the staging of distant metastases. Conclusions:18F-FDG PET/MRI detects lymph node metastases in significantly more patients and estimates clinical lymph node stage more accurately than conventional imaging and MRI. No significant differences were found between imaging modalities with respect to the detection of distant metastases.

Accuracy of a Smartphone-Based Artificial Intelligence Application for Classification of Melanomas, Melanocytic Nevi, and Seborrheic Keratoses.

Current artificial intelligence algorithms can classify melanomas at a level equivalent to that of experienced dermatologists. The objective of this study was to assess the accuracy of a smartphone-based "You Only Look Once" neural network model for the classification of melanomas, melanocytic nevi, and seborrheic keratoses. The algorithm was trained using 59,090 dermatoscopic images. Testing was performed on histologically confirmed lesions: 32 melanomas, 35 melanocytic nevi, and 33 seborrheic keratoses. The results of the algorithm's decisions were compared with those of two skilled dermatologists and five beginners in dermatoscopy. The algorithm's sensitivity and specificity for melanomas were 0.88 (0.71-0.96) and 0.87 (0.76-0.94), respectively. The algorithm surpassed the beginner dermatologists, who achieved a sensitivity of 0.83 (0.77-0.87). For melanocytic nevi, the algorithm outclassed each group of dermatologists, attaining a sensitivity of 0.77 (0.60-0.90). The algorithm's sensitivity for seborrheic keratoses was 0.52 (0.34-0.69). The smartphone-based "You Only Look Once" neural network model achieved a high sensitivity and specificity in the classification of melanomas and melanocytic nevi with an accuracy similar to that of skilled dermatologists. However, a bigger dataset is required in order to increase the algorithm's sensitivity for seborrheic keratoses.

Adjuvant treatment and outcome of stage III melanoma patients: Results of a multicenter real-world German Dermatologic Cooperative Oncology Group (DeCOG) study.

PURPOSE: Clinical trials demonstrated significantly improved recurrence-free survival (RFS) of melanoma patients receiving adjuvant treatment. As data from controlled trials are based on selected populations, we investigated adjuvantly treated stage III melanoma patients under real-world conditions. PATIENTS AND METHODS: In a prior multicenter cohort study, stage III-IV melanoma patients were analysed for their choice of adjuvant therapy. In this follow-up study, we examined RFS, overall and melanoma-specific survival (MSS) and response to the subsequent treatment of 589 stage III patients (232 BRAF-mutated) receiving adjuvant PD-1 inhibitors (PD1; n = 479) or targeted therapy (TT; n = 110). RESULTS: The median follow-up of the total cohort was 25.7 months. The main reason for premature discontinuation of adjuvant therapy was disease progression in PD1- (28.8%, n = 138/479) and adverse events in TT-treated patients (28.2%, n = 31/110). Among BRAF-mutated patients, RFS at 24 months was 49% (95% CI 40.6-59.0%) for PD1- and 67% (95% CI 58-77%) for TT-treated patients. The risk of recurrence was higher for BRAF-mutated PD1 than TT (hazard ratio 1.99; 95% CI 1.34-2.96; hazard ratio adjusted for age, sex and tumour stage, 2.21; 95% CI 1.48-3.30). Twenty-four months MSS was 87% (95% CI 81.0-94.1) for PD1 and 92% (95% CI 86.6-97.0) for TT. Response to subsequent systemic treatment for unresectable disease was 22% for all PD1- and 16% for TT-treated patients. CONCLUSIONS: PD1-treated patients had more and earlier recurrences than TT patients. In BRAF-mutated patients, adjuvant TT might prevent early recurrences more effectively than PD1 treatment. Management of recurrence despite adjuvant treatment is challenging, with low response to current therapeutic options.

No evidence for seasonal variations of the incidence of testicular germ cell tumours in Germany.

The pathogenesis of testicular germ cell tumours (GCTs) is still incompletely understood. Any progress in its understanding must derive from observational studies. Recently, it has been suggested that the incidence of GCTs may follow a seasonal pattern based on circannual changes in the Vitamin D serum levels, with maximum incidence rates in winter months. To examine this promising hypothesis, we studied monthly incidence rates of testicular GCTs in Germany by analysing 30,988 GCT cases aged 15-69 years, diagnosed during 2009-2019. Monthly incident case numbers with data regarding histology and patient age were obtained from the Robert Koch Institut, Berlin, along with annual male population counts. We used precision weighting for deriving pooled monthly incidence rates for GCTs of the period 2009-2019. We stratified pooled rates by histology (seminoma and nonseminoma) and age (15-39 and 40-69 years). By assuming a cyclical effect, we used an estimator of the intensity of seasonal occurrence and report seasonal relative risks (RR). The mean monthly incidence rate was 11.93/105 person-months. The seasonal RR for testicular cancer over-all is 1.022 (95% CI 1.000-1.054). The highest seasonal RR was found in the subgroup of nonseminoma aged 15-39 years, with a RR 1.044 (95% CI 1.000-1.112). The comparison of the pooled monthly rates of the winter months (October-March) with the summer months (April-September) revealed a maximum relative difference of 5% (95% CI 1-10%) for nonseminoma, aged 15-39 years. We conclude that there is no evidence of a seasonal variation of incidence rates of testicular cancer. Our results are at odds with an Austrian study, but the present data appear sound because the results were obtained with precision weighted monthly incidence rates in a large population of GCT cases.

Time trends in survival and causes of death in multiple myeloma: a population-based study from Germany.

BACKGROUND: Steady evolution of therapies has improved prognosis of patients with multiple myeloma (MM) over the past two decades. Yet, knowledge about survival trends and causes of death in MM might play a crucial role in long-term management of this patient collective. Here, we investigate time trends in myeloma-specific survival at the population level over two decades and analyse causes of death in times of prolonged survival. METHODS: Age-standardised and age group-specific relative survival (RS) of MM patients aged < 80 years at diagnosis was estimated for consecutive time periods from 2000-2019 using data from the Cancer Registry of North Rhine-Westphalia in Germany. Conditional RS was estimated for patients who already survived one to five years post diagnosis. Causes of death in MM patients were analysed and compared to the general population using standardised mortality ratios (SMR). RESULTS: Three thousand three hundred thirty-six MM cases were included in the time trend analysis. Over two decades, age-standardised 5-year RS increased from 37 to 62%. Age-specific survival improved from 41% in period 2000-2004 to 69% in period 2015-2019 in the age group 15-69 years, and from 23 to 47% in the age group 70-79 years. Conditional 5-year RS of patients who survived five years after diagnosis slightly improved as compared to unconditional 5-year RS at diagnosis. MM patients are two times more likely to die from non-myeloma malignancies (SMR = 1.97, 95% CI 1.81-2.15) and from cardiovascular diseases (SMR = 2.01, 95% CI 1.86-2.18) than the general population. CONCLUSIONS: Prognosis of patients with MM has markedly improved since the year 2000 due to therapeutic advances. Nevertheless, late mortality remains a major concern. As survival improves, second primary malignancies and cardiovascular events deserve increased attention.

The Epidemiology of Colorectal Cancer in Younger and Older Patients.

BACKGROUND: Recent studies have shown that the incidence of colorectal cancer among younger persons is rising. We investigated incidence trends and survival in the German federal state of North Rhine-Westphalia. METHODS: Cancer registry data from the period 2008-2019 were classified into two age groups (15-54 and 55-99). In each age group, the standardized incidence, average annual percent change (AAPC), and relative 5-year survival (RS) were calculated and stratified according to the site, histology, size, and grade of the colorectal tumor. RESULTS: 167 919 cases were included, with adenocarcinoma accounting for 86.4%. In 2019, the age-standardized incidence per 100 000 person-years was 13.8 and 10.3 among men and women (respectively) in the younger age group, compared with 197.9 and 126.3 in the older age group. Over the study period from 2008 to 2019, the incidence declined among older men and women (AAPC -2.6% and -2.9%) but remained nearly constant among younger men and women (-0.5% and -0.4%). The incidence of neuroendocrine, T1, and G2 tumors rose in both age groups (AAPC range: 2.3%-12.2%; 2.2%-8.3%, 6.3%-8.8%). Younger patients have a better RS, with the largest difference between age groups being found for neuroendocrine tumors (88% and 83% in younger men and women, 65% and 61% in older men and women). CONCLUSION: The incidence of colorectal tumors has remained constant in persons under age 55 and declined in persons aged 55 and older. Nonetheless, the incidence of neuroendocrine tumors and of small and well-differentiated tumors has risen in both age groups. The trends among younger persons and the rise in neuroendocrine tumors merit further study.

Skin Cancer Screening and Medical Treatment Intensity in Patients with Malignant Melanoma and Non-Melanocytic Skin Cancer.

BACKGROUND: This cohort study concerns the effect of skin cancer screening (SCS) on medical treatment intensity in patients with skin cancer. METHODS: Routine data from persons aged 35 to 99 who were insured by the AOK health insurance company were used to identify persons who received a diagnosis of malignant melanoma or a non-melanocytic skin cancer in 2014 or 2015, either through skin cancer screening or without screening. These persons were included in cohort studies. The routine data contained no information on tumor stages or grading. Tumor-associated rates of hospital admission, contact with physicians in outpatient practice, and intensity of surgical treatment were determined; rate ratios (RR) and their 95% confidence intervals (CI) were estimated. RESULTS: The cohort studies included 13 633 patients with melanoma (6480 with SCS and 7153 without) and 118 168 patients with non-melanocytic skin cancer (43 308 with screening and 74 860 without). Patients whose melanomas had been detected by screening had a lower medical treatment intensity than unscreened patients (intensity of tumor-associated surgical treatment (RR = 0.79, 95% CI [0.74; 0.85]), hospital contact rate (RR = 0.44, 95% CI: [0.38; 0.50]), contact with physicians in outpatient practice (RR = 0.79, 95% CI: [0.73; 0.85]). Among patients with non-melanocytic skin cancer, the screened patients displayed a lower hospital contact rate (RR = 0.52, 95% CI: [0.49; 0.56]), a higher contact rate in the outpatient sector (RR = 1.11, 95% CI: [1.08; 1.13]), and no difference in surgical treatment intensity (RR = 0.98, 95% CI: [0.96; 1.00]). CONCLUSION: SCS is associated with lower medical treatment intensity in the first 12 months after diagnosis in patients with melanoma. Among patients with non-melanocytic skin cancer, those who had been screened had lower hospital contact rates, but there was no observed lowering of other rates reflecting treatment intensity.

Temporal trends in referrals of RET gene carriers for neck surgery to a tertiary surgical center in the era of international management guidelines.

PURPOSE: Thirty years into the genomic era, this study sought to explore events that helped transform the clinical landscape of hereditary medullary thyroid cancer (MTC). METHOD: This retrospective analysis of prospectively collected data included all RET carriers referred to a tertiary center for neck surgery that was performed between 1986 and 2021, using descriptive statistics and Poisson regression analysis. RESULTS: Altogether, 496 RET carriers were referred for thyroidectomy (388 carriers) or neck reoperation (108 carriers). Of these, 44 carriers had highest risk mutations (p.Met918Thr), 164 carriers high risk mutations (p.Cys634Arg/Gly/Phe/Ser/Trp/Tyr/insHisGluLeuCys), 116 carriers moderate-high risk mutations (p.Cys609/611/618/620/630Arg/Gly/Phe/Ser/Tyr) and 172 carriers low-moderate risk mutations (p.Glu768Asp, p.Leu790Phe, p.Val804Leu/Met, or p.Ser891Ala). Three event clusters drove referral numbers upward: a string of first reports of causative RET mutations between 1993 and 1998; the international consensus guidelines for diagnosis and therapy of MEN type 1 and type 2 in 2001; and the revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma in 2015. Referrals for neck reoperation declined sluggishly over 30 years, ending in 2018. Index patients continued to be referred into 2021. Referrals for thyroidectomy, grouped in 5-year increments, peaked in 1996-2000 for carriers of highest and high risk mutations, and in 2006-2010 for carriers of moderate-high and low-moderate risk mutations, some 10 years later. CONCLUSION: International management guidelines are critical in building and increasing the pressure towards screening of sporadic-appearing disease and offspring of known gene families by encompassing the complete disease spectrum early on.

Age-incidence patterns of seminoma and nonseminoma among males and females in Germany and the United States, 2008-2016.

BACKGROUND & OBJECTIVES: The comparison of the incidence of gonadal germ cell tumors among males and females can provide insights that cannot be gained by separately studying these tumors. MATERIAL AND METHODS: Incidence data on male and female gonadal germ cell tumors were drawn from the cancer registries of North Rhine-Westphalia, Germany, and the United States Surveillance, Epidemiology and End Results program, for non-Hispanic White persons only, for the years 2008-2016. We estimated age-standardized and age-, and histology-specific incidence rates. RESULTS: We included 21,840 male and 716 female gonadal germ cell tumors. Incidence rates among males were higher in Germany (95.8 per million, standard error [SE] 1.1) than in the United States (68.0, SE 0.6), while incidence rates among females were lower in Germany (1.9, SE 0.2) than in the United States (2.6, SE 0.1). The characteristic peak of infantile (age 0-4 years) germ cell tumors among males were missing among females. The age peak of ovarian germ cell tumors occurred 15-20 years earlier (Germany: 10-14 years, United States: 15-19 years) than the age peak of testicular germ cell tumors (30-34 years). The three most common testicular germ cell tumors histologies were seminoma, mixed germ cell tumors, and embryonal carcinoma Among females, the three most common ovarian germ cell tumors histologies were teratoma, yolk sac tumor, monodermal teratomas, and somatic-type tumors arising from dermoid cysts in both countries. DISCUSSION: The characteristic peak of infantile (age 0-4 years) germ cell tumors among males was missing among females. The shapes of the age-specific incidence curves are similar for males and females in Germany and the United States, though with much lower incidence rates in females, suggesting a common pathogenesis. CONCLUSION: The lower rates among females may be due to the lower number of initiated tumors in the absence of the Y-chromosome, and the earlier peak among females may be due to a younger age at puberty.

Clinical Decision Support for Axillary Lymph Node Staging in Newly Diagnosed Breast Cancer Patients Based on 18F-FDG PET/MRI and Machine Learning.

In addition to its high prognostic value, the involvement of axillary lymph nodes in breast cancer patients also plays an important role in therapy planning. Therefore, an imaging modality that can determine nodal status with high accuracy in patients with primary breast cancer is desirable. Our purpose was to investigate whether, in newly diagnosed breast cancer patients, machine-learning prediction models based on simple assessable imaging features on MRI or PET/MRI are able to determine nodal status with performance comparable to that of experienced radiologists; whether such models can be adjusted to achieve low rates of false-negatives such that invasive procedures might potentially be omitted; and whether a clinical framework for decision support based on simple imaging features can be derived from these models. Methods: Between August 2017 and September 2020, 303 participants from 3 centers prospectively underwent dedicated whole-body 18F-FDG PET/MRI. Imaging datasets were evaluated for axillary lymph node metastases based on morphologic and metabolic features. Predictive models were developed for MRI and PET/MRI separately using random forest classifiers on data from 2 centers and were tested on data from the third center. Results: The diagnostic accuracy for MRI features was 87.5% both for radiologists and for the machine-learning algorithm. For PET/MRI, the diagnostic accuracy was 89.3% for the radiologists and 91.2% for the machine-learning algorithm, with no significant differences in diagnostic performance between radiologists and the machine-learning algorithm for MRI (P = 0.671) or PET/MRI (P = 0.683). The most important lymph node feature was tracer uptake, followed by lymph node size. With an adjusted threshold, a sensitivity of 96.2% was achieved by the random forest classifier, whereas specificity, positive predictive value, negative predictive value, and accuracy were 68.2%, 78.1%, 93.8%, and 83.3%, respectively. A decision tree based on 3 simple imaging features could be established for MRI and PET/MRI. Conclusion: Applying a high-sensitivity threshold to the random forest results might potentially avoid invasive procedures such as sentinel lymph node biopsy in 68.2% of the patients.

[Regional Differences in Thyroid Function Parameters: A Comparison of European Cohort Studies]. / Regionale Unterschiede von Schilddrüsenfunktionsparametern: ein Vergleich europäischer Kohortenstudien.

AIM OF THE STUDY: The aim of the project was to investigate regional differences in thyroid stimulating hormone (TSH), and free thyroxine (fT4) concentrations and iodine status in comparable German and European cohort studies. METHODS: Sex- and age-stratified TSH, fT4, and urine iodine concentrations of thyroid-healthy participants (age group 45-75 years) of the HNR (Heinz Nixdorf Recall) Study in the Ruhr region of Germany, the southern German KORA (Cooperative Health Research in the Augsburg Region) and northeastern German SHIP (Study of Health in Pomerania) studies, as well as the Norwegian HUNT (Nord-Trøndelag Health) study (age group 40-79 years), the English EPIC (European Prospective Investigation of Cancer)-Norfolk study, and the Dutch Rotterdam study were compared. The TSH reference range for the HNR study population was calculated and compared to the KORA and SHIP studies. RESULTS: Regional differences showed a stronger influence on TSH and fT4 concentrations than sex and age of the subjects in the 45- to 75-year age group. The estimated difference in medians, as measured by the HNR study, was lowest in the SHIP study, -0.47 (95% CI: -0.53; -0.41) for men and -0.41 (-0.53; -0.41) for women. The Rotterdam study had the highest difference in medians for both men and women (men: 0.56 with 0.44; 0.68 and women: 0.62 with 0.46; 0.78). The lowest median TSH concentrations, across all age categories considered, were seen in the German cohorts. CONCLUSIONS: Comparison of thyroid function parameters and iodine in elderly subjects between six comparable cohort studies from Germany and Europe showed a significant influence of region, which exceeded the sex and age dependence of the parameters.

Prognostic Potential of the Baseline Pan-Immune-Inflammation Value and Neutrophil/Lymphocyte Ratio in Stage I to III Melanoma Patients.

Prognostic biomarkers derived from complete blood count (CBC) have received marked interest as an indirect measure of the inflammatory pressure in cancers such as metastatic melanoma. Here, we evaluated the novel pan-immune-inflammation value (PIV) and the frequently assessed neutrophil/lymphocyte ratio (NLR) in a large cohort of patients with cutaneous melanoma (CM) without distant metastases (stages I to III). PIV and NLR were calculated at CM diagnosis. Healthy controls were also included. We used the Kaplan-Meier method to estimate crude survival probabilities and used Cox proportional hazards regression for multiple adjustment of hazard ratios. We observed that higher PIV (HR: 1.72, 95% CI 1.14 to 2.58 and HR: 1.696, 95% CI 1.029 to 2.795, respectively) and NLR (HR: 1.70, 95% CI 1.10 to 2.62) values were associated with CM relapse and CM-specific death in the crude analysis. However, when adjusting for potential confounders, in particular age and tumor thickness, the total effect of PIV and NLR on CM-relapse-free (HR: 1.28, 95% CI 0.83 to 1.98 and HR: 1.26, 95% CI 0.80 to 1.98, respectively) and CM-specific survival (HR: 1.36, 95% CI 0.80 to 2.30 and HR: 1.37, 95% CI 0.80 to 2.33, respectively) was substantially reduced. However, both PIV and NLR were positively correlated with age and tumor thickness, which are important independent predictors for CM relapse and CM-specific death. In conclusion, in stage I to III CM patients PIV as well as NLR appear to be confounded by age and tumor thickness and probably have no potential to further improve the prediction of survival of stage I to III CM patients beyond standard prognostic factors.

Coronary Artery Calcium Score to Refine the Use of PCSK9i in Asymptomatic Individuals: A Multicohort Study.

Background The value of coronary artery calcium (CAC) in the allocation of PCSK9i (proprotein convertase subtilisin/kexin type 9 inhibitors) among individuals without clinically evident atherosclerotic cardiovascular disease (ASCVD) is unknown for indications that do not require confirmed familial hypercholesterolemia. We aimed to assess the ability of CAC to stratify ASCVD risk under 3 non-familial hypercholesterolemia PCSK9i allocation paradigms. Methods and Results We included participants without clinically evident ASCVD from MESA (Multi-Ethnic Study of Atherosclerosis), CARDIA (Coronary Artery Risk Development in Young Adults) study, DHS (Dallas Heart Study), and HNR (Heinz Nixdorf Recall) study. Three PCSK9i eligibility scenarios were defined: a broad scenario informed only by high low-density lipoprotein cholesterol levels (N=567), a restrictive one combining higher low-density lipoprotein cholesterol levels and presence of ≥2 additional risk factors (N=127), and a high-risk scenario where individuals with subclinical organ damage or high estimated risk would be treated to achieve low-density lipoprotein cholesterol <55 mg/dL (N=471). The high-risk scenario had the highest ASCVD event rates (27.8% at 10 years). CAC=0 was observed in 35% participants in the broad scenario, 25% in the restrictive scenario, and 16% in the high-risk scenario. In all, CAC=0 was associated with the lowest incident ASCVD rates at 5 and 10 years, and CAC burden was independently associated with ASCVD events adjusting for traditional risk factors. Conclusions CAC may be used to refine the allocation of PCSK9i, potentially leading to a more conservative use if CAC=0. The value of CAC testing is greater in scenarios that use low-density lipoprotein cholesterol levels and/or traditional risk factors to define PCSK9i eligibility (CAC=0 present in 1 of 3-4 patients), whereas its prevalence is lower when allocation is informed by presence of noncoronary subclinical organ damage.