[Correction to the Article "Hansen's Disease: An Unusual Manifestation of an Ancient Disease", Published on Acta Med Port 2024 Mar;37(3):215-219]. / Errata ao Artigo "Doença de Hansen: Apresentação Incomum de uma Doença Antiga", Publicado em Acta Med Port 2024 Mar;37(3):215-219.

On page 215, list of authors, where it reads (in red): Mário FERREIRA1, Carlos GRIJÓ2, Joana PAULO1, Marta FONSECA1, Zélia NEVES1 It should read (in bold): Mário FERREIRA1, Carlos GRIJÓ2, Joana PAULO1, Marta FONSECA1, Zélia NEVES1, Rita BOUCEIRO MENDES3, Pedro VASCONCELOS3 On the same page 215, footer (authors affiliation), where it reads (in red): 1. Medicina III. Hospital Fernando Fonseca. Amadora. Portugal. 2. Serviço de Medicina Interna. Centro Hospitalar Universitário de São João. Porto. Portugal. It should read (in bold): 1. Medicina III. Hospital Fernando Fonseca. Amadora. Portugal. 2. Serviço de Medicina Interna. Centro Hospitalar Universitário de São João. Porto. Portugal. 3. Serviço de Dermatologia. Hospital de Santa Maria. Centro Hospitalar Universitário Lisboa Norte. Lisboa. Portugal. Article published with errors: https://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/20599.

Na página 215, na linha de autoria onde se lê, (a vermelho): Mário FERREIRA1, Carlos GRIJÓ2, Joana PAULO1, Marta FONSECA1, Zélia NEVES1 Deverá ler-se (a negrito): Mário FERREIRA1, Carlos GRIJÓ2, Joana PAULO1, Marta FONSECA1, Zélia NEVES1, Rita BOUCEIRO MENDES3, Pedro VASCONCELOS3 Na mesma página 215, em rodapé (afiliação dos autores), onde se lê (a vermelho): 1. Medicina III. Hospital Fernando Fonseca. Amadora. Portugal. 2. Serviço de Medicina Interna. Centro Hospitalar Universitário de São João. Porto. Portugal. Deverá ler-se (a negrito): 1. Medicina III. Hospital Fernando Fonseca. Amadora. Portugal. 2. Serviço de Medicina Interna. Centro Hospitalar Universitário de São João. Porto. Portugal. 3. Serviço de Dermatologia. Hospital de Santa Maria. Centro Hospitalar Universitário Lisboa Norte. Lisboa. Portugal. Artigo publicado com erros: https://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/20599.

Pancreatic cancer biomarkers: A pathway to advance in personalized treatment selection.

Pancreatic cancer is one of the tumors with the worst prognosis, and unlike other cancers, few advances have been made in recent years. The only curative option is surgery, but only 15-20% of patients are candidates, with a high risk of relapse. In advanced pancreatic cancer there are few first-line treatment options and no validated biomarkers for better treatment selection. The development of targeted therapies in pancreatic cancer is increasingly feasible due to tumor-agnostic treatments, such as PARP inhibitors in patients with BRCA1, BRCA2 or PALB2 alterations or immunotherapies in patients with high microsatellite instability/tumor mutational burden. In addition, other therapeutic molecules have been developed for patients with KRAS G12C mutation or fusions in NTRK or NRG1. Consequently, there has been a growing interest in biomarkers that may help guide targeted therapy in pancreatic cancer. Therefore, this review aims to offer an updated perspective on biomarkers with therapeutic potential in pancreatic cancer.

[Hansen's Disease: An Unusual Manifestation of an Ancient Disease]. / Doença de Hansen: Apresentação Incomum de uma Doença Antiga.

Hansen's disease, commonly known as leprosy, is an infectious disease caused by Mycobacterium leprae. Being rare in developed countries, it is an increasingly common imported disease due to the migratory flow from countries where it is endemic. We present the case of a 21-year-old man who went to the emergency department with complaints of additive polyarthralgia involving large joints, papules, and erythematous plaques on the limbs with bullae and central necrosis and fever with chills for one week. Skin biopsy was performed revealing neutrophilic infiltrate with perineural granulomas. The bacilloscopy detected acid-alcohol resistant bacilli. The diagnosis of multibacillary HD with type 2 lepromatous reaction (erythema nodosum leprosum - ENL) was established, showing clinical improvement under corticosteroid therapy. ENL usually presents with painful lesions, being an atypical presentation of leprosy, especially in the presence of bullae and necrosis, making diagnosis difficult and challenging. Social stigma is often present making it difficult to accept the disease as well as adherence to treatment.

A doença de Hansen, vulgarmente conhecida como lepra, é uma doença infecciosa causada por Mycobacterium leprae. Sendo rara nos países desenvolvidos, configura uma doença de importação cada vez mais frequente considerando o fluxo migratório de países onde é endémica. Apresentamos o caso de um homem de 21 anos que recorreu ao serviço de urgência por poliartralgias de caráter aditivo envolvendo grandes articulações, pápulas e placas eritematosas nos membros com bolhas e necrose central e febre com calafrio com uma semana de evolução. Foi realizada biópsia cutânea que revelou infiltrado neutrofílico com granulomas de distribuição perineural e baciloscopia com deteção de bacilos ácido-álcool resistentes. Foi estabelecido o diagnóstico de DH multibacilar com reação lepromatosa tipo 2 (eritema nodoso leproso), apresentando melhoria clínica sob corticoterapia. O eritema nodoso leproso cursa habitualmente com lesões dolorosas, configurando uma apresentação atípica de lepra, sobretudo na presença de bolhas e necrose, tornando este diagnóstico altamente desafiante. O estigma social é frequentemente limitativo na aceitação da doença e adesão ao tratamento.

The effectiveness of concept mapping as a tool for developing critical thinking in undergraduate medical education - a BEME systematic review: BEME Guide No. 81.

BACKGROUND: Concept maps (CMs) visually represent hierarchical connections among related ideas. They foster logical organization and clarify idea relationships, potentially aiding medical students in critical thinking (to think clearly and rationally about what to do or what to believe). However, there are inconsistent claims about the use of CMs in undergraduate medical education. Our three research questions are 1) What studies have been published on concept mapping in undergraduate medical education; 2) What was the impact of CMs on students' critical thinking; 3) How and why have these interventions had an educational impact? METHODS: Eight databases were systematically searched (plus a manual and an additional search were conducted). After eliminating duplicate entries, titles and abstracts and full-texts were independently screened by two authors. Data extraction and quality assessment of the studies were independently performed by two authors. Qualitative and quantitative data were integrated using mixed-methods. The results were reported using the STructured apprOach to the Reporting In healthcare education of Evidence Synthesis statement and BEME guidance. RESULTS: Thirty-nine studies were included from 26 journals (19 quantitative, 8 qualitative and 12 mixed-methods studies). CMs were considered as a tool to promote critical thinking, both in the perception of students and tutors, as well as in assessing students' knowledge and/or skills. In addition to their role as facilitators of knowledge integration and critical thinking, CMs were considered both a teaching and a learning methods. CONCLUSIONS: CMs are teaching and learning tools which seem to help medical students develop critical thinking. This is due to the flexibility of the tool as a facilitator of knowledge integration, as a learning and teaching method. The wide range of contexts, purposes, and variations in how CMs and instruments to assess critical thinking are used increases our confidence that the positive effects are consistent.

Clinical significance of glycogen synthase kinase 3 (GSK-3) expression and tumor budding grade in colorectal cancer: Implications for targeted therapy.

INTRODUCTION: Glycogen synthase kinase 3 (GSK-3) has been proposed as a novel cancer target due to its regulating role in both tumor and immune cells. However, the connection between GSK-3 and immunoevasive contexture, including tumor budding (TB) has not been previously examined. METHODS: we investigated the expression levels of total GSK-3 as well as its isoforms (GSK-3ß and GSK-3α) and examined their potential correlation with TB grade and the programmed cell death-ligand 1 (PD-L1) in colorectal cancer (CRC) tumor samples. Additionally, we compared the efficacy of GSK-3-inhibition with PD-1/PD-L1 blockade in humanized patient-derived (PDXs) xenografts models of high-grade TB CRC. RESULTS: we show that high-grade (BD3) TB CRC is associated with elevated expression levels of total GSK-3, specifically the GSK-3ß isoform, along with increased expression of PD-L1 in tumor cells. Moreover, we define an improved risk stratification of CRC patients based on the presence of GSK-3+/PD-L1+/BD3 tumors, which are associated with a worse prognosis. Significantly, in contrast to the PD-L1/PD-1 blockade approach, the inhibition GSK-3 demonstrated a remarkable enhancement in the antitumor response. This was achieved through the reduction of tumor buds via necrosis and apoptosis pathways, along with a notable increase of activated tumor-infiltrating CD8+ T cells, NK cells, and CD4- CD8- T cells. CONCLUSIONS: our study provides compelling evidence for the clinical significance of GSK-3 expression and TB grade in risk stratification of CRC patients. Moreover, our findings strongly support GSK-3 inhibition as an effective therapy specifically targeting high-grade TB in CRC.

Diagnosing and monitoring pancreatic cancer through cell-free DNA methylation: progress and prospects.

Pancreatic cancer is one of the most challenging cancers due to its high mortality rates. Considering the late diagnosis and the limited survival benefit with current treatment options, it becomes imperative to optimize early detection, prognosis and prediction of treatment response. To address these challenges, significant research efforts have been undertaken in recent years to develop liquid-biopsy-based biomarkers for pancreatic cancer. In particular, an increasing number of studies point to cell-free DNA (cfDNA) methylation analysis as a promising non-invasive approach for the discovery and validation of epigenetic biomarkers with diagnostic or prognostic potential. In this review we provide an update on recent advancements in the field of cfDNA methylation analysis in pancreatic cancer. We discuss the relevance of DNA methylation in the context of pancreatic cancer, recent cfDNA methylation research, its clinical utility, and future directions for integrating cfDNA methylation analysis into routine clinical practice.

Circulating NPTX2 methylation as a non-invasive biomarker for prognosis and monitoring of metastatic pancreatic cancer.

BACKGROUND: Pancreatic cancer is the most lethal cancer with a dismal prognosis mainly due to diagnosis at advanced stage and ineffective treatments. CA19-9 levels and computed tomography (CT) imaging are the main standard criteria for evaluating disease progression and treatment response. In this study we explored liquid biopsy-based epigenetic biomarkers for prognosis and monitoring disease in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). METHODS: Plasma samples were collected from 44 mPDAC patients at the time of diagnosis, and in 15 of them, additional samples were obtained during follow-up of the disease. After cell-free DNA (cfDNA), isolation circulating levels of methylated NPTX2, SPARC, BMP3, SFRP1 and TFPI2 genes were measured using digital droplet PCR (ddPCR). BEAMing technique was performed for quantitation of RAS mutations in cfDNA, and CA19-9 was measured using standard techniques. RESULTS: NPTX2 was the most highly and frequently methylated gene in cfDNA samples from mPDAC patients. Higher circulating NPTX2 methylation levels at diagnosis were associated with poor prognosis and efficiently stratified patients for prediction of overall survival (6.06% cut-off, p = 0.0067). Dynamics of circulating NPTX2 methylation levels correlated with disease progression and response to therapy and predicted better than CA19-9 the evolution of disease in mPDAC patients. Remarkably, in many cases the disease progression detected by CT scan was anticipated by an increase in circulating NPTX2 methylation levels. CONCLUSIONS: Our study supports circulating NPTX2 methylation levels as a promising liquid biopsy-based clinical tool for non-invasive prognosis, monitoring disease evolution and response to treatment in mPDAC patients.

Results of haploidentical transplant in patients with donor-specific antibodies: a survey on behalf of the Spanish Group of Hematopoietic Transplant and Cell Therapy.

Background: Donor-specific antibodies (DSAs) are IgG allo-antibodies against mismatched donor HLA molecules and can cause graft failure (GF) in the setting of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Our aim was to report the experience of the Spanish Group of Hematopoietic Transplant (GETH-TC) in DSA-positive patients who had undergone haplo-HSCT. Methods: We conducted a survey of patients who underwent haplo-HSCT in GETH-TC centers between 2012 and 2021. Data were collected on the DSA assay used, monitoring strategy, complement fixation, criteria for desensitization, desensitization strategies and transplant outcomes. Results: Fifteen centers from the GETH-TC responded to the survey. During the study period, 1,454 patients underwent haplo-HSCT. Seventy of the transplants were performed in 69 DSA-positive patients, all of whom lacked a suitable alternative donor; 61 (88%) patients were female (90% with prior pregnancies). All patients received post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis. Regarding baseline DSA intensity, 46 (67%) patients presented mean fluorescence intensity (MFI) >5,000, including 21 (30%) with MFI >10,000 and three (4%) with MFI >20,000. Six patients did not receive desensitization treatment, four of them with MFI <5,000. Of 63 patients receiving desensitization treatment, 48 (76%) were tested after desensitization therapy, and a reduction in intensity was confirmed in 45 (71%). Three patients (5%) experienced an increase in MFI after desensitization, two of whom experienced primary GF. Cumulative incidence of neutrophil engraftment at day 28 was 74% in a median of 18 days (IQR, 15─20); six patients died before engraftment due to toxicity or infection and eight patients had primary GF despite desensitization in seven of them. After a median follow-up of 30 months, two-year overall and event-free survival were 46.5% and 39%, respectively. The two-year cumulative incidence of relapse was 16% and non-relapse mortality (NRM) was 43%. Infection was the most frequent cause of NRM, followed by endothelial toxicity. Multivariate analysis identified baseline MFI >20,000 as an independent risk factor for survival and an increase in titers after infusion as an independent risk factor for GF. Conclusions: Haplo-HSCT is feasible in DSA-positive patients, with high rates of engraftment after desensitization guided by DSA intensity. Baseline MFI >20,000 and increased intensity after infusion are risk factors for survival and GF.

LOCUS (LOng Covid-Understanding Symptoms, events and use of services in Portugal): A three-component study protocol.

Approximately 10% of patients experience symptoms of Post COVID-19 Condition (PCC) after a SARS-CoV-2 infection. Akin acute COVID-19, PCC may impact a multitude of organs and systems, such as the cardiovascular, respiratory, musculoskeletal, and neurological systems. The frequency and associated risk factors of PCC are still unclear among both community and hospital settings in individuals with a history of COVID-19. The LOCUS study was designed to clarify the PCC's burden and associated risk factors. LOCUS is a multi-component study that encompasses three complementary building blocks. The "Cardiovascular and respiratory events following COVID-19" component is set to estimate the incidence of cardiovascular and respiratory events after COVID-19 in eight Portuguese hospitals via electronic health records consultation. The "Physical and mental symptoms following COVID-19" component aims to address the community prevalence of self-reported PCC symptoms through a questionnaire-based approach. Finally, the "Treating and living with Post COVID-19 Condition" component will employ semi-structured interviews and focus groups to characterise reported experiences of using or working in healthcare and community services for the treatment of PCC symptoms. This multi-component study represents an innovative approach to exploring the health consequences of PCC. Its results are expected to provide a key contribution to the optimisation of healthcare services design.

Metabolic shift underlies tumor progression and immune evasion in S-nitrosoglutathione reductase-deficient cancer.

S-nitrosoglutathione reductase (GSNOR) is a denitrosylase enzyme that has been suggested to play a tumor suppressor role, although the mechanisms responsible are still largely unclear. In this study, we show that GSNOR deficiency in tumors is associated with poor prognostic histopathological features and poor survival in patients with colorectal cancer (CRC). GSNOR-low tumors were characterized by an immunosuppressive microenvironment with exclusion of cytotoxic CD8+ T cells. Notably, GSNOR-low tumors exhibited an immune evasive proteomic signature along with an altered energy metabolism characterized by impaired oxidative phosphorylation (OXPHOS) and energetic dependence on glycolytic activity. CRISPR-Cas9-mediated generation of GSNOR gene knockout (KO) CRC cells confirmed in vitro and in vivo that GSNOR-deficiency conferred higher tumorigenic and tumor-initiating capacities. Moreover, GSNOR-KO cells possessed enhanced immune evasive properties and resistance to immunotherapy, as revealed following xenografting them into humanized mouse models. Importantly, GSNOR-KO cells were characterized by a metabolic shift from OXPHOS to glycolysis to produce energy, as indicated by increased lactate secretion, higher sensitivity to 2-deoxyglucose (2DG), and a fragmented mitochondrial network. Real-time metabolic analysis revealed that GSNOR-KO cells operated close to their maximal glycolytic rate, as a compensation for lower OXPHOS levels, explaining their higher sensitivity to 2DG. Remarkably, this higher susceptibility to glycolysis inhibition with 2DG was validated in patient-derived xenografts and organoids from clinical GSNOR-low tumors. In conclusion, our data support the idea that metabolic reprogramming induced by GSNOR deficiency is an important mechanism for tumor progression and immune evasion in CRC and that the metabolic vulnerabilities associated with the deficiency of this denitrosylase can be exploited therapeutically. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

From Temporal Cell Arteritis to Giant Cell Aortitis Presenting as a Constitutional Syndrome: A Case Report.

Giant cell arteritis (GCA) is the most common form of systemic vasculitis in adults, especially in patients over the age of 50. It manifests most commonly with an intense headache and visual symptoms. Although constitutional symptoms are also frequent in GCA, these can be dominant in 15% of patients at first presentation and 20% of patients when relapsing. Treatment with high-dose steroids should be initiated as soon as possible to rapidly control the inflammatory symptoms and prevent ischemic complications, the most feared being blindness from anterior ischemic optic neuropathy. We present a case of a 72-year-old man who presented to the emergency department with a right temporal headache with retroocular radiation associated with scalp hyperesthesia, without any visual symptoms. The patient also reported low-grade fever, night sweats, anorexia, and weight loss over the last two months. The physical exam revealed a tortuous and indurated right superficial temporal artery, which was tender to palpation. The ophthalmological examination was normal. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were elevated, and he also had inflammatory anemia with a hemoglobin of 11.7 g/L. Due to this clinical presentation as well as the elevation of inflammatory markers, the diagnosis of temporal arteritis was suspected, and the patient was started on prednisolone (1 mg/kg). A right temporal artery biopsy was performed on the first week after the initiation of corticotherapy and was negative. After treatment initiation, there was a remission of symptoms accompanied by a decrease and normalization of inflammatory markers. However, after steroid tapering, there was a reappearance of constitutional symptoms but without any other organ-specific symptoms, such as headache, visual loss, arthralgia, or other. The corticosteroid dose was increased to the initial dosage, but there was no improvement in the symptoms this time. After the exclusion of other causes of the constitutional syndrome, a positron-emission tomography (PET) scan was performed, which showed a grade 2 aortitis. The diagnosis of giant cell aortitis was assumed, and given the lack of clinical response to corticotherapy, tocilizumab was initiated with a resolution of constitutional symptoms as well as a normalization of inflammatory markers. In conclusion, we report a case of temporal cell arteritis that further progressed to aortitis manifesting solely with constitutional symptoms. Furthermore, there was no optimal response to corticotherapy and no improvement with tocilizumab, therefore making this a case with a unique and infrequent clinical course. GCA is characterized by a wide variety of symptoms and organ involvement, and although it most frequently affects temporal arteries, it can be associated with aortic involvement that can cause life-threatening structural complications, highlighting the need for a high suspicion index for this condition.

A Refractory Case of Amiodarone Thyrotoxicosis.

Amiodarone is frequently used to control cardiac arrhythmias, like atrial fibrillation. Despite its benefits, it has many adverse effects, particularly on the thyroid gland. We describe the case of a patient treated with amiodarone for paroxysmal atrial fibrillation, admitted to the emergency room with atrial fibrillation with a rapid ventricular response. Type II thyrotoxicosis was identified as the cause of the refractory arrhythmia. Since its refractoriness to both pharmacological and electrical therapy, there was a need to proceed with plasmapheresis and total thyroidectomy for hormonal and cardiac rhythm control. Therefore, it is essential to monitor the toxicity of amiodarone, a drug that can have both beneficial and devastating effects.

Chronic thromboembolic pulmonary hypertension: A 10-year analysis from a Portuguese referral center.

INTRODUCTION AND OBJECTIVES: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive, but potentially curable, form of pulmonary hypertension. Pulmonary endarterectomy (PEA) is a complex surgery that frequently achieves hemodynamic normalization and symptom resolution, although not all patients are suitable for the procedure. We aimed to assess long-term outcomes of CTEPH, namely all-cause mortality and hospital admission for decompensated heart failure, according to treatment modalities in patients who underwent PEA or non-surgical therapy. METHODS: A 10-year retrospective study of patients with CTEPH at a referral center was conducted. Forty-five patients were included and median follow-up time was 57 (IQR 24-93) months. Survival analysis was performed and a multivariate Cox regression model was used to identify independent predictors of outcomes. RESULTS: Patients were mostly female (59%) and mean age was 63±16 years. Two-thirds were severely symptomatic at diagnosis, with 62.2% of patients presenting in WHO functional class (WHO FC) III or IV. One-, two- and three-year survival was 93.3%, 82.4% and 75.9%, respectively. Serum BNP (HR 1.003; 95% CI: 1.001-1.005; p=0.003) and creatinine (HR 12.092; 95% CI: 1.121-130.390; p=0.040) were predictors of death. Mortality was numerically lower in those who underwent PEA (p=0.135). PEA was associated with decreased risk of the combined endpoint of all-cause mortality and hospital admission for decompensated heart failure (HR 0.198; 95% CI: 0.040-0.982; p=0.047), as were lower serum BNP (HR 1.003; 95% CI: 1.001-1.005; p=0.008) and mPAP (HR 1.073; 95% CI: 1.022-1.128; p=0.005) at diagnosis. Most patients who underwent PEA presented improved WHO FC (92.9%) and post-surgical residual pulmonary hypertension was identified in only 21.4%. CONCLUSION: PEA provided a better overall prognosis than non-surgical therapy, improving symptoms and frequently achieving hemodynamic normalization, with a numerical trend for lower mortality. Higher serum BNP, creatinine and mPAP at diagnosis were independently associated with worse outcomes.

Basal VEGF-A and ACE Plasma Levels of Metastatic Colorectal Cancer Patients Have Prognostic Value for First-Line Treatment with Chemotherapy Plus Bevacizumab.

The identification of factors that respond to anti-angiogenic therapy would represent a significant advance in the therapeutic management of metastatic-colorectal-cancer (mCRC) patients. We previously reported the relevance of VEGF-A and some components of the renin-angiotensin-aldosterone system (RAAS) in the response to anti-angiogenic therapy in cancer patients. Therefore, this prospective study aims to evaluate the prognostic value of basal plasma levels of VEGF-A and angiotensin-converting enzyme (ACE) in 73 mCRC patients who were to receive bevacizumab-based therapies as a first-line treatment. We found that high basal VEGF-A plasma levels were significantly associated with worse overall survival (OS) and progression-free survival (FPS). On the other hand, low ACE levels were significantly associated with poor OS. Importantly, a simple scoring system combining the basal plasma levels of VEGF-A and ACE efficiently stratified mCRC patients, according to OS, into high-risk or low-risk groups, prior to their treatment with bevacizumab. In conclusion, our study supports that VEGF-A and ACE may be potential biomarkers for selecting those mCRC patients who will most benefit from receiving chemotherapy plus bevacizumab treatment in first-line therapy. Additionally, our data reinforce the notion of a close association between the RAAS and the anti-angiogenic response in cancer.

Post-Transplantation Cyclophosphamide After HLA Identical Compared to Haploidentical Donor Transplant in Acute Myeloid Leukemia: A Study on Behalf of GETH-TC.

Post-transplantation cyclophosphamide (PTCY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplantation (HSCT) and achieves low rates of GVHD in HLA-identical transplantation. To compare the outcomes of haploidentical versus HLA identical HSCT in patients undergoing HSCT for acute myeloid leukemia (AML) using PTCY. We conducted a retrospective study of 229 patients undergoing first HSCT for AML using PTCY with additional immunosuppression, 99 from matched sibling or unrelated donor (MSD/MUD) performed in 3 hospitals and 130 from haploidentical donors (haplo group) performed in 20 hospitals within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cellular Therapy. Peripheral blood stem cells were used as graft in 89% of patients; myeloablative conditioning was used in 56%. There were significantly more patients with active disease (5% versus 20%, P = .001), high/very high disease risk index (DRI) (32% versus 67%, P = .000) and prior auto-HSCT (2% versus 11%, P = .010) in the haplo group. Median follow-up was 27 and 62.5 months for MSD/MUD and haplo, respectively. At 2 years, no significant differences were observed in overall survival (OS) (72% versus 62%, P = .07), event-free survival (EFS) (70% versus 54%, P = .055), cumulative incidence of relapse (19% versus 25%, P = .13), non-relapse mortality (14% versus 19%, P = .145), and the composite endpoint of GVHD and relapse-free survival (49% versus 42%, P = .249). Multivariate analysis identified only age and active disease as significant risk factors for OS and EFS; reduced-intensity conditioning, high/very high DRI, and haplo donor were nearly statistically significant for these outcomes. Grade II-IV acute GVHD was lower in MSD/MUD (14% versus 47%, P = .000). Cumulative incidences of grade III-IV acute GVHD (4% versus 9%, P = .14) and moderate-severe chronic GVHD (22% versus 19%, P = .28) were similar. Limitations of our study include limited sample size, differences between haplo and MSD/MUD groups and heterogeneous additional immunosuppression and PTCY timing in MSD/MUD. The use of an HLA-identical donor with PTCY in patients with AML showed lower incidence of clinically significant grade II-IV acute GVHD compared to haplo donors. Further studies with larger sample sizes should be performed to establish a possible benefit of HLA-identical donor on survival. © 2022 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Effect of aflibercept plus FOLFIRI and potential efficacy biomarkers in patients with metastatic colorectal cancer: the POLAF trial.

BACKGROUND: Aflibercept is an antiangiogenic drug against metastatic colorectal cancer (mCRC) combined with 5-fluorouracil/leucovorin/irinotecan (FOLFIRI); however, no antiangiogenic biomarker has yet been validated. We assessed aflibercept plus FOLFIRI, investigating the biomarker role of baseline vascular endothelial growth factor A (VEGF-A) and angiotensin-converting enzyme (ACE). METHODS: Phase II trial in oxaliplatin-treated mCRC patients who received aflibercept plus FOLFIRI. The reported 135 ng/mL ACE cut-off was used and ROC analysis was performed to assess the optimal VEGF-A cut-off for progression-free survival (PFS). Overall survival (OS), time to progression (TTP), time to treatment failure (TTF), overall response rate (ORR) and disease control rate (DCR) were also assessed. RESULTS: In total, 101 patients were followed for a median of 12 (6-17) months. The 1941 pg/mL VEGF-A was an optimal cut-off, with a longer median PFS when VEGF-A was <1941 versus ≥1941 pg/mL (9 versus 4 months). Patients with VEGF-A < 1941 pg/mL showed longer median OS (19 versus 8 months), TTP (9 versus 4 months) and TTF (8 versus 4 months), along with higher ORR (26% versus 9%) and DCR (81% versus 55%). No differences were identified according to ACE levels. CONCLUSIONS: This study supports aflibercept plus FOLFIRI benefits, suggesting VEGF-A as a potential biomarker to predict better outcomes.

Bradyarrhythmias in Cardio-Oncology.

The relationship between bradyarrhythmias and cancer therapies has not been well described but is increasingly recognized. There have been extensive advances in oncological pharmacotherapy, with several new classes of drugs available including targeted agents, immune checkpoint inhibitors and CAR T cell therapy. This increasing repertoire of available drugs has revolutionized overall prognosis and survival of cancer patients but the true extent of their cardiovascular toxicity is only beginning to be understood. Previous studies and published reviews have traditionally focused on conventional chemotherapies and in arrhythmias in general, particularly tachyarrhythmias. The number of patients with both cancer and cardiovascular problems is increasing globally and oncologists and cardiologists need to be adept at managing arrythmia based scenarios. Greater collaboration between the two specialties including studies with prospective data collection in Cardio-Oncology are much needed to fill in knowledge gaps in this arena. This case-based review summarizes current available evidence of cancer treatment-related bradyarrhythmia incidence (including its different subtypes), possible mechanisms and outcomes. Furthermore, we propose a stepwise surveillance and management protocol for patients with suspected bradyarrhythmia related to cancer treatment.

Prolonged Right Ventricular Outflow Tract Endocardial Activation Duration and Presence of Deceleration Zones in Patients With Idiopathic Premature Ventricular Contractions. Association With Low Voltage Areas.

BACKGROUND AND AIMS: The wavefront propagation velocity in the myocardium with fibrosis is characterized by the presence of deceleration zones and late activated zones, that are absent in the normal myocardium. Our aim was to study the right ventricular outflow tract (RVOT) endocardial activation duration in sinus rhythm, and assess the presence of deceleration zones, in patients with premature ventricular contractions (PVCs) and in controls. METHODS: We studied 29 patients with idiopathic PVCs from the outflow tract, subjected to catheter ablation that had an activation and voltage map of the RVOT in sinus rhythm. A control group of 15 patients without PVCs that underwent ablation of supraventricular arrhythmias was also studied. RVOT endocardial activation duration and number of 10 ms isochrones across the RVOT were assessed. Propagation speed was calculated at the zone with the higher number of isochrones per cm radius. Deceleration zones were defined as zones with >3 isochrones within 1 cm radius. Low voltage areas were defined as areas with local electrogram with amplitude <1.5 mV. RESULTS: The two groups did not differ in relation to age, gender or number of points in the map. RVOT endocardial activation duration and number of 10 ms isochrones were higher in the PVC group; 56 (41-66) ms vs. 39 (35-41) ms, p = 0.001 and 5 (4-8) vs. 4 (4-5), p = 0.001. Presence of deceleration zones and low voltage areas were more frequent in the PVC group; 20 (69%) vs. 0 (0%), p < 0.0001 and 21 (72%) vs. 0 (0%), p < 0.0001. The wavefront propagation speed was significantly lower in patients with PVCs than in the control group, 0.35 (0.27-0.40) vs. 0.63 (0.56-0.66) m/s, p < 0.0001. Patients with low voltage areas had longer activation duration 60 (52-67) vs. 36 (32-40) ms, p < 0.0001, more deceleration zones, 20 (95%) vs. 0 (0%), p < 0.0001, and lower wavefront propagation speed, 0.30 (0.26-0.36) vs. 0.54 (0.36-0.66) m/s, p = 0.002, than patients without low voltage areas. CONCLUSION: Right ventricular outflow tract endocardial activation duration was longer, propagation speed was lower and deceleration zones were more frequent in patients with PVCs than in controls and were associated with the presence of low voltage areas.

Entrectinib-related myocarditis in a young female patient with metastatic non-small cell lung cancer.

A 51-year-old woman presented with a 2-week history of off balance, left lower limb weakness and neglect and neck pain radiating down the right arm. Investigations revealed a metastatic, ROS1 fusion-positive, non-small cell lung cancer, and treatment with entrectinib, a recently approved multikinase inhibitor, was started. Two weeks after, she was admitted to the emergency department with new-onset pressure-like chest pain and dyspnoea. Laboratory evaluation showed elevated troponin and mild left ventricular systolic dysfunction with reduced global longitudinal strain on transthoracic echocardiogram. Cardiac magnetic resonance revealed mild oedema and non-ischaemic fibrosis. A diagnosis of drug-induced myocarditis was made. Cardioprotective medication with an angiotensin-converting enzyme inhibitor and a beta-blocker was started. Entrectinib was temporarily discontinued and restarted at a reduced dose after a multidisciplinary team meeting involving both the oncology and cardio-oncology teams. This is the second described case of entrectinib-induced myocarditis and the first one without eosinophilia.

The Combination of Neutrophil-Lymphocyte Ratio and Platelet-Lymphocyte Ratio with Liquid Biopsy Biomarkers Improves Prognosis Prediction in Metastatic Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a highly inflammatory microenvironment and liquid biopsy has emerged as a promising tool for the noninvasive analysis of this tumor. In this study, plasma was obtained from 58 metastatic PDAC patients, and neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), circulating cell-free DNA (cfDNA) concentration, and circulating RAS mutation were determined. We found that NLR was significantly associated with both overall survival (OS) and progression-free survival. Remarkably, NLR was an independent risk factor for poor OS. Moreover, NLR and PLR positively correlated, and combination of both inflammatory markers significantly improved the prognostic stratification of metastatic PDAC patients. NLR also showed a positive correlation with cfDNA levels and RAS mutant allelic fraction (MAF). Besides, we found that neutrophil activation contributed to cfDNA content in the plasma of metastatic PDAC patients. Finally, a multi-parameter prognosis model was designed by combining NLR, PLR, cfDNA levels, RAS mutation, RAS MAF, and CA19-9, which performs as a promising tool to predict the prognosis of metastatic PDAC patients. In conclusion, our study supports the idea that the use of systemic inflammatory markers along with circulating tumor-specific markers may constitute a valuable tool for the clinical management of metastatic PDAC patients.