Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin.

Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS.

The value of post-operative chemotherapy after chemoradiotherapy in patients with high-risk locally advanced rectal cancer-results from the RAPIDO trial.

BACKGROUND: Pre-operative chemoradiotherapy (CRT) rather than radiotherapy (RT) has resulted in fewer locoregional recurrences (LRRs), but no decrease in distant metastasis (DM) rate for patients with locally advanced rectal cancer (LARC). In many countries, patients receive post-operative chemotherapy (pCT) to improve oncological outcomes. We investigated the value of pCT after pre-operative CRT in the RAPIDO trial. PATIENTS AND METHODS: Patients were randomised between experimental (short-course RT, chemotherapy and surgery) and standard-of-care treatment (CRT, surgery and pCT depending on hospital policy). In this substudy, we compared curatively resected patients from the standard-of-care group who received pCT (pCT+ group) with those who did not (pCT- group). Subsequently, patients from the pCT+ group who received at least 75% of the prescribed chemotherapy cycles (pCT ≥75% group) were compared with patients who did not receive pCT (pCT-/- group). By propensity score stratification (PSS), we adjusted for the following unbalanced confounders: age, clinical extramural vascular invasion, distance to the anal verge, ypT stage, ypN stage, residual tumour, serious adverse event (SAE) and/or readmission within 6 weeks after surgery and SAE related to pre-operative CRT. Cumulative probability of disease-free survival (DFS), DM, LRR and overall survival (OS) was analysed by Cox regression. RESULTS: In total, 396/452 patients had a curative resection. The number of patients in the pCT+, pCT >75%, pCT- and pCT-/- groups was 184, 112, 154 and 149, respectively. The PSS-adjusted analyses for all endpoints demonstrated hazard ratios between approximately 0.7 and 0.8 (pCT+ versus pCT-), and 0.5 and 0.8 (pCT ≥75% versus pCT-/-). However, all 95% confidence intervals included 1. CONCLUSIONS: These data suggest a benefit of pCT after pre-operative CRT for patients with high-risk LARC, with approximately 20%-25% improvement in DFS and OS and 20%-25% risk reductions in DM and LRR. Compliance with pCT additionally reduces or improves all endpoints by 10%-20%. However, differences are not statistically significant.

A phase II study of retifanlimab (INCMGA00012) in patients with squamous carcinoma of the anal canal who have progressed following platinum-based chemotherapy (POD1UM-202).

BACKGROUND: Locally advanced or metastatic squamous carcinoma of the anal canal (SCAC) has poor prognosis following platinum-based chemotherapy. Retifanlimab (INCMGA00012), a humanized monoclonal antibody targeting programmed death protein-1 (PD-1), demonstrated clinical activity across a range of solid tumors in clinical trials. We present results from POD1UM-202 (NCT03597295), an open-label, single-arm, multicenter, phase II study evaluating retifanlimab in patients with previously treated advanced or metastatic SCAC. PATIENTS AND METHODS: Patients ≥18 years of age had measurable disease and had progressed following, or were ineligible for, platinum-based therapy. Retifanlimab 500 mg was administered intravenously every 4 weeks. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Overall, 94 patients were enrolled. At a median follow-up of 7.1 months (range, 0.9-19.4 months), ORR was 13.8% [95% confidence interval (CI) 7.6% to 22.5%], with one complete response (1.1%) and 12 partial responses (12.8%). Responses were observed regardless of human immunodeficiency virus or human papillomavirus status, programmed death ligand 1 (PD-L1) expression, or liver metastases. Stable disease was observed in 33 patients (35.1%) for a DCR of 48.9% (95% CI 38.5% to 59.5%). Median DOR was 9.5 months (range, 5.6 months-not estimable). Median (95% CI) PFS and OS were 2.3 (1.9-3.6) and 10.1 (7.9-not estimable) months, respectively. Retifanlimab safety in this population was consistent with previous experience for the PD-(L)1 inhibitor class. CONCLUSIONS: Retifanlimab demonstrated clinically meaningful and durable antitumor activity, and an acceptable safety profile in patients with previously treated locally advanced or metastatic SCAC who have progressed on or are intolerant to platinum-based chemotherapy.

Optimal symptom combinations to aid COVID-19 case identification: Analysis from a community-based, prospective, observational cohort.

OBJECTIVES: Diagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health. METHODS: UK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case [TPC]) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity. FINDINGS: UK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC. INTERPRETATION: We confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.

Optimal symptom combinations to aid COVID-19 case identification: analysis from a community-based, prospective, observational cohort.

OBJECTIVES: Diagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health. METHODS: UK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case [TPC]) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity. FINDINGS: UK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC. INTERPRETATION: We confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.

Fusobacterium nucleatum persistence and risk of recurrence after preoperative treatment in locally advanced rectal cancer.

BACKGROUND: Accumulating evidence has identified Fusobacterium as an important pathogenic gut bacterium associated with colorectal cancer. Nevertheless, only limited data exist about the role of this bacterium in locally advanced rectal cancer (LARC). In this study, we quantified Fusobacterium nucleatum in untreated and post-neoadjuvant chemoradiotherapy (nCRT) samples from LARC patients and investigated its association with therapy response and survival. PATIENTS AND METHODS: A total of 254 samples from 143 patients with rectal adenocarcinomas were analyzed for the presence and abundance of F. nucleatum using RNA in situ hybridization and digital image analysis. Assay accuracy was determined using infected cell lines and tumor samples with available quantitative PCR data. We studied the impact of F. nucleatum load on pathologic complete response and relapse-free survival. Treatment-induced changes were evaluated in paired pre- and post-nCRT samples (n = 71). Finally, tumor microenvironment changes during nCRT were assessed in paired samples (n = 45) by immune contexture analysis. RESULTS: F. nucleatum tissue levels by RNA in situ hybridization strongly correlated with quantitative PCR (r = 0.804, P < 0.001). F. nucleatum abundance was higher in untreated [median, 7.4; 95% confidence interval (3.7-16.2)] compared with treated [median, 1.6; 95% confidence interval (1.3-2.4)] tumors (P <0.001) with 58% (73/126) and 26% (22/85) positive tumors, respectively (P < 0.001). Baseline F. nucleatum levels were not associated with pathologic complete response. F. nucleatum positivity after nCRT, but not baseline status, significantly increased risk of relapse [hazard ratio = 7.5, 95% confidence interval (3.0-19.0); P < 0.001]. Tumors that turned F. nucleatum-negative after nCRT had a strong increase in CD8+ T cells post-nCRT (P < 0.001), while those that persisted F. nucleatum-positive after nCRT lacked CD8+ T cells induction in post-nCRT samples compared with baseline (P = 0.69). CONCLUSION: F. nucleatum persistence post-nCRT is associated with high relapse rates in LARC, potentially linked to suppression of immune cytotoxicity.

SEOM clinical guideline thyroid cancer (2019).

Thyroid carcinoma is the most frequent endocrine malignancy and accounts for around 3% of global cancer incidence. Different histologies and clinical scenarios make necessary a multidisciplinary approach that includes new diagnostic methods and surgical, radiopharmaceutical and systemic therapies. This guideline updates several aspects of management of thyroid cancer.

La comorbilidad en salud mental en los pacientes diagnosticados de enfermedad pulmonar obstructiva crónica / Comorbidity in mental health in patients diagnosed with chronic obstructive pulmonary disease

OBJETIVO: La ansiedad y la depresión juegan un papel importante en la enfermedad pulmonar obstructiva crónica aunque son escasos los estudios que han tratado de determinar su asociación con la exacerbación y todavía menos los que han tratado de cuantificar el número de exacerbaciones asociadas. El objetivo del estudio fue estudiar el riesgo de las exacerbaciones asociadas a la de ansiedad y depresión en los pacientes diagnosticados de enfermedad pulmonar obstructiva crónica. MATERIAL Y MÉTODOS: Estudio de cohortes prospectivas que analizó los factores asociados a la exacerbación en 512 enfermos durante 2 años. Las exacerbaciones se definieron como moderadas, aquellas que requirieron antibiótico/s y/o corticoides sistémicos; y graves, las que precisaron de hospitalización. Para cada paciente se registró la ansiedad y depresión (Hospital Anxiety and Depression Scale) y se cuantificaron el número de exacerbaciones durante el periodo de seguimiento. RESULTADOS: La prevalencia de ansiedad/depresión al inicio del estudio fue del 15,6%. Durante los 2 años de seguimiento la media de exacerbaciones fue de 2,21. Los pacientes que además presentaban ansiedad/depresión al inicio del estudio presentaron una media de exacerbaciones mayor, de 2,8 (p = 0,001). La ansiedad/depresión se asociaron con un mayor número de exacerbaciones moderadas-graves en el análisis ajustado (IRRa=1,48). Los otros factores de riesgo asociados a un mayor número de exacerbaciones fueron el antecedente de exacerbación grave previa (IRRa=1,50; la obesidad (IRRa=1,27); el sobrepeso (IRRa=1,23); el FEV1 ≤ 77% (IRRa=0,84); y una mayor disnea (IRRa=1,14). CONCLUSIONES: Los enfermos con ansiedad/depresión presentan un mayor número de exacerbaciones y tienen un 48% más de riesgo de padecer una exacerbación respecto a los enfermedad pulmonar obstructiva crónica sin ansiedad/depresión

OBJECTIVE: Anxiety and depression play an important role in chronic obstructive pulmonary disease, although there are a limited number of studies that have attempted to determine their relationship with exacerbations, and even less have tried to quantify the number of associated exacerbations. The aim of this study was to determine the risk of exacerbations associated with anxiety and depression in patients diagnosed with chronic obstructive pulmonary disease. MATERIAL AND METHODS: A prospective cohort study was conducted that analysed the factors associated with exacerbations in 512 patients over a 2-year period. The exacerbations that required antibiotics and/or systemic corticosteroids were defined as moderate, and those that required hospital admission, as severe. The Hospital Anxiety and Depression Scale was applied to each patient, and the number of exacerbations during follow-up were quantified. RESULTS: The prevalence of anxiety/depression at the beginning of the study was 15.6%. During the 2 years of follow-up, the mean number of exacerbations was 2.21. The patients that also had anxiety/depression at the beginning of the study had a higher mean number of exacerbations (2.8; P=.001). Anxiety/depression was associated with an increased number of moderate-severe exacerbations in the adjusted analysis (IRRa=1.48). The other risk factors associated with a higher mean number of exacerbations were, a history of a previous severe exacerbation (IRRa=1.50; obesity (IRRa=1.27); overweight (IRRa=1.23); FEV1 ≤ 77% (IRRa=0.84); and more dyspnoea (IRRa=1.14). CONCLUSIONS: Patients with anxiety/depression have a greater number of exacerbations, and have a 48% higher risk of suffering an exacerbation compared to those with chronic obstructive pulmonary disease with no anxiety/depression

Interhospital Sepsis Code in Catalonia (Spain): Territorial model for initial care of patients with sepsis. / Código Sepsis Interhospitalario en Catalunya: modelo organizativo territorial para la atención inicial al paciente con sepsis.

Sepsis is a syndromic entity with high prevalence and mortality. The management of sepsis is standardized and exhibits time-dependent efficiency. However, the management of patients with sepsis is complex. The heterogeneity of the forms of presentation can make it difficult to detect and manage such cases, in the same way as differences in training, professional competences or the availability of health resources. The Advisory Commission for Patient Care with Sepsis (CAAPAS), comprising 7 scientific societies, the Emergency Medical System (SEM) and the Catalan Health Service (CatSalut), have developed the Interhospital Sepsis Code (CSI) in Catalonia (Spain). The general objective of the CSI is to increase awareness, promote early detection and facilitate initial care and interhospital coordination to attend septic patients in a homogeneous manner throughout Catalonia.

[Comorbidity in mental health in patients diagnosed with chronic obstructive pulmonary disease]. / La comorbilidad en salud mental en los pacientes diagnosticados de enfermedad pulmonar obstructiva crónica.

OBJECTIVE: Anxiety and depression play an important role in chronic obstructive pulmonary disease, although there are a limited number of studies that have attempted to determine their relationship with exacerbations, and even less have tried to quantify the number of associated exacerbations. The aim of this study was to determine the risk of exacerbations associated with anxiety and depression in patients diagnosed with chronic obstructive pulmonary disease. MATERIAL AND METHODS: A prospective cohort study was conducted that analysed the factors associated with exacerbations in 512 patients over a 2-year period. The exacerbations that required antibiotics and/or systemic corticosteroids were defined as moderate, and those that required hospital admission, as severe. The Hospital Anxiety and Depression Scale was applied to each patient, and the number of exacerbations during follow-up were quantified. RESULTS: The prevalence of anxiety/depression at the beginning of the study was 15.6%. During the 2 years of follow-up, the mean number of exacerbations was 2.21. The patients that also had anxiety/depression at the beginning of the study had a higher mean number of exacerbations (2.8; P=.001). Anxiety/depression was associated with an increased number of moderate-severe exacerbations in the adjusted analysis (IRRa=1.48). The other risk factors associated with a higher mean number of exacerbations were, a history of a previous severe exacerbation (IRRa=1.50; obesity (IRRa=1.27); overweight (IRRa=1.23); FEV1 ≤ 77% (IRRa=0.84); and more dyspnoea (IRRa=1.14). CONCLUSIONS: Patients with anxiety/depression have a greater number of exacerbations, and have a 48% higher risk of suffering an exacerbation compared to those with chronic obstructive pulmonary disease with no anxiety/depression.

Patient, radiological, and operative factors associated with surgical difficulty in the extraction of third molars: a systematic review.

The aim of this systematic review was to determine the patient, radiological, and operative variables associated with surgical difficulty in the extraction of third molars, according to a visual analogue scale completed by the surgeon, operative time, or surgical technique. Searches of the PubMed (MEDLINE), Scopus, and Cochrane Library databases were conducted by two independent reviewers. Randomized and non-randomized clinical trials and prospective cohort studies evaluating surgical difficulty in the extraction of impacted mandibular or maxillary third molars according to patient, radiological, and operative variables were included. The full texts of 21 of the 859 articles initially retrieved were analysed, and 15 articles were included in the final systematic review. All 15 reported prospective cohort studies. The following variables were found to be on the spectrum of highly difficult or complex cases: older patient age and being overweight (patient variables), surgeons with little experience and the use of complex surgical techniques requiring tooth sectioning linked to hard tissue impaction (operative variables), and adverse radiological factors such as deep impaction, unfavourable angulation and root morphology, and a close relationship with the second molar, maxillary sinus, or the inferior alveolar nerve canal (radiological variables).

SEOM clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2018)

NENs are a heterogeneous family of tumors of challenging diagnosis and clinical management. Their incidence and prevalence continue to rise across all sites, stages and grades. Although improved diagnostic techniques have led to earlier detection and stage migration, the improved prognosis documented over time for advanced gastrointestinal and pancreatic neuroendocrine tumors also reflect improvements in therapy. The aim of this guideline is to update practical recommendations for the diagnosis and treatment of gastroenteropancreatic and lung NENs. Diagnostic procedures, histological classification and therapeutic options are briefly discussed, including surgery, liver-directed therapy, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, and treatment algorithms are provided

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Detection of pancreatic neuroendocrine tumors: 23 years of experience. / Detección de tumores neuroendocrinos pancreáticos: 23 años de experiencia.

INTRODUCTION AND AIMS: Neuroendocrine tumors are of great scientific interest, given that they are difficult to diagnose and treat. Despite being relatively rare (< 1/100,000 individuals, 1-2% of the gastrointestinal neoplasias) and indolent, their potential malignancy must not be forgotten. An increase in the number of diagnosed tumors has been observed in recent years. The aim of the present study was to update a published case series of 19 patients suspected of presenting with pancreatic neuroendocrine tumor with 51 current cases, to study and compare the new results with those of the previous case series, as well as with other recent publications from Spain, the United States, China, and India. MATERIALS AND METHODS: A retrospective, multicenter case series was conducted on 70 patients (19 cases published in 2011), whose data has been collected over a period of 23 years. The variables analyzed were: age, sex, symptomatology, tumor size, location, metastasis, final diagnosis, and surgery, among others. RESULTS: Mean patient age was 55 years and 60% of the patients were men. Disease location was the pancreatic head in 28.5% of the patients and the tail in 27.1%, mean tumor size was 3.9cm (0.2-10cm), 71.4% of the patients had non-functioning tumors, 32.8% had metastases (100% to the liver), 74.2% of the patients were operated on, and actuarial survival was 75%. CONCLUSIONS: Differences were observed between the previously published case series and the current results. There was an increase in incidentalomas and non-functioning tumors, but no variation in the overall survival rate. The differences with other case series (age, sex, and tumor location) were dependent on the country where the cases were compiled. The increase in tumors could be related to a higher number of diagnoses made through imaging studies and to the greater sensitivity of the devices employed.

SEOM clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2018).

NENs are a heterogeneous family of tumors of challenging diagnosis and clinical management. Their incidence and prevalence continue to rise across all sites, stages and grades. Although improved diagnostic techniques have led to earlier detection and stage migration, the improved prognosis documented over time for advanced gastrointestinal and pancreatic neuroendocrine tumors also reflect improvements in therapy. The aim of this guideline is to update practical recommendations for the diagnosis and treatment of gastroenteropancreatic and lung NENs. Diagnostic procedures, histological classification and therapeutic options are briefly discussed, including surgery, liver-directed therapy, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, and treatment algorithms are provided.

Consensus document on the progression and treatment response criteria in gastroenteropancreatic neuroendocrine tumors

Purpose: Gastroenteropancreatic neuroendocrine tumors are a heterogeneous group of low incidence neoplasms characterized by a low proliferative activity and slow growth. Their response to targeted therapies is heterogeneous and often does not lead to tumor shrinkage. Thus, evaluation of the therapeutic response should differ from other kind of tumors. Methods: To answer relevant questions about which techniques are best in the assessment of progression or treatment response a RAND/UCLA-based consensus process was implemented. Relevant clinical questions were listed followed by a systematic search of the literature. The expert panel answered all questions with recommendations, combining available evidence and expert opinion. Recommendations were validated through a questionnaire and a participatory meeting. Results: Expert recommendations regarding imaging tools for tumor assessment and evaluation of progression were agreed upon. Available imaging techniques were reviewed and recommendations for best patient monitoring practice and the best way to evaluate treatment response were formulated

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Consensus document on the progression and treatment response criteria in gastroenteropancreatic neuroendocrine tumors.

PURPOSE: Gastroenteropancreatic neuroendocrine tumors are a heterogeneous group of low incidence neoplasms characterized by a low proliferative activity and slow growth. Their response to targeted therapies is heterogeneous and often does not lead to tumor shrinkage. Thus, evaluation of the therapeutic response should differ from other kind of tumors. METHODS: To answer relevant questions about which techniques are best in the assessment of progression or treatment response a RAND/UCLA-based consensus process was implemented. Relevant clinical questions were listed followed by a systematic search of the literature. The expert panel answered all questions with recommendations, combining available evidence and expert opinion. Recommendations were validated through a questionnaire and a participatory meeting. RESULTS: Expert recommendations regarding imaging tools for tumor assessment and evaluation of progression were agreed upon. Available imaging techniques were reviewed and recommendations for best patient monitoring practice and the best way to evaluate treatment response were formulated.

Early evolutionary divergence between papillary and anaplastic thyroid cancers.

Background: Papillary thyroid cancer (PTC) is the most common thyroid carcinoma and exhibits an almost uniformly good prognosis, while anaplastic thyroid cancer (ATC) is less frequent and is one of the most aggressive cancers usually resistant to conventional treatment. Current hypothesis posits that ATC derives from PTC through the progressive acquisition of a discrete number of genomic alterations and implies that the mutational landscape of ATC resembles that of PTC. However, the clinical behaviour of ATC and PTC is radically different. We decided to address the disconnection between the clinical behaviour of ATC and PTC and the proposed model of the progressive development of ATC from PTC. Patients and methods: We carried out exome sequencing of DNA from 14 ATC specimens including three cases of concomitant ATC and PTC as well as their corresponding normal DNA from 14 patients. The sequencing results were validated using droplet digital PCR. We carried out immunohistochemistry and immunofluorescence studies of the concomitant ATC and PTC cases. In addition, we integrated our sequencing results with the existing TCGA data. Results: Most of the somatic mutations identified in the ATC component differed from the ones in PTC in the cases of concomitant ATC and PTC. The trunks of the phylogenetic trees representing the somatic mutations were short with long branches. In one case of concomitant PTC and ATC specimens, we observed an infiltration of PTC cells within the ATC component. Moreover, we integrated our results with data obtained from TCGA and observed that the most frequent mutations found in ATC presented high cancer cell fraction values and were significantly different from the PTC ones. Conclusion: ATC diverge from PTC early in tumour development and both tumour types evolve independently. Our work allows the understanding of the relationship between ATC and PTC facilitating the clinical management of these malignancies.