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- Adult B-Cell Acute Lymphoblastic Leukemia Cells Display Decreased PTEN Activity and Constitutive Hyperactivation of PI3K/Akt Pathway Despite High PTEN Protein LevelsPublication . Gomes, AM; Soares, M; Ribeiro, P; Caldas, J; PĆ³voa, V; Martins, L; MelĆ£o, A; Serra-Caetano, A; Botelho de Sousa, A; Lacerda, J; Barata, JAdult B-cell acute lymphoblastic leukemia remains a major therapeutic challenge, requiring a better characterization of the molecular determinants underlying disease progression and resistance to treatment. Here, using a phospho-flow cytometry approach we show that adult diagnostic B-cell acute lymphoblastic leukemia specimens display PI3K/Akt pathway hyperactivation, irrespective of their BCR-ABL status and despite paradoxically high basal expression of PTEN, the major negative regulator of the pathway. Protein kinase CK2 is known to phosphorylate PTEN thereby driving PTEN protein stabilization and concomitant PTEN functional inactivation. In agreement, we found that adult B-cell acute lymphoblastic leukemia samples show significantly higher CK2 kinase activity and lower PTEN lipid phosphatase activity than healthy controls. Moreover, the clinical-grade CK2 inhibitor CX-4945 (Silmitasertib) reversed PTEN levels in leukemia cells to those observed in healthy controls, and promoted leukemia cell death without significantly affecting normal bone marrow cells. Our studies indicate that CK2-mediated PTEN posttranslational inactivation, associated with PI3K/Akt pathway hyperactivation, are a common event in adult B-cell acute lymphoblastic leukemia and suggest that CK2 inhibition may constitute a valid, novel therapeutic tool in this malignancy.
- AssociaĆ§Ć£o da Intensidade de Dor no Tempo AtĆ© Ć Morte dos Doentes OncolĆ³gicos Referenciados aos Cuidados PaliativosPublication . Barata, P; Santos, F; Mesquita, G; Cardoso, A; CustĆ³dio, MP; Alves, M; Papoila, AL; Barbosa, A; Lawlor, PIntroduĆ§Ć£o: A dor Ć© uma experiĆŖncia frequente nos doentes com cancro, especialmente naqueles em fase final de vida. Com este estudo, pretendemos estudar a intensidade de dor nos doentes com cancro avanƧado, referenciados aos cuidados paliativos, analisar os factores associados Ć ocorrĆŖncia de dor moderada ou intensa e avaliar a sua relaĆ§Ć£o com o tempo atĆ© Ć morte destes doentes. Material e MĆ©todos: Estudo prospectivo observacional que incluiu consecutivamente todos os doentes referenciados aos cuidados paliativos com tumores sĆ³lidos metastizados e sem tratamento oncolĆ³gico especĆfico. Foi considerada a intensidade de dor da escala de Edmonton, de acordo com a graduaĆ§Ć£o zero a 10, onde 0 = ausĆŖncia de dor e 10 = mĆ”xima dor possĆvel. Resultados: Entre outubro de 2012 e junho de 2015, foram incluĆdos 301 doentes, com idade mediana de 69 anos (37 - 94), 57% homens e 64,8% dos doentes com performance status 3/4. Aproximadamente 42% dos doentes apresentaram dor ā„ 4 e cerca de 74,4% estavam medicados com analgesia opiĆ³ide. A intensidade de dor esteve associada ao performance status dos doentes, de acordo com a anĆ”lise multivariĆ”vel (OR: 1,7; IC 95%: 1,0 - 2,7; p = 0,045). A mediana do tempo de sobrevivĆŖncia foi de 37 dias (IC 95%: 28 - 46), tendo os doentes com dor moderada ou intensa (intensidade de dor ā„ 4) uma mediana de sobrevivĆŖncia de 29 dias (IC 95%: 21 - 37), comparada com os 49 dias (IC 95%: 35 - 63) para os doentes sem dor ou dor ligeira (p = 0,022). DiscussĆ£o: O performance status, para alĆ©m de ter estado associado a uma maior intensidade de dor, esteve associado a um menor tempo atĆ© Ć morte dos doentes com cancro avanƧado referenciados aos cuidados paliativos. TambĆ©m o internamento, a presenƧa de metastizaĆ§Ć£o intra-abdominal e a analgesia opiĆ³ide estiveram associados de forma negativa ao tempo atĆ© Ć morte destes doentes. ConclusĆ£o: A dor oncolĆ³gica continua a ser um problema clinicamente relevante nos doentes com cancro avanƧado.
- Body Composition Analysis in Metastatic Non-Small-Cell Lung Cancer: Depicting Sarcopenia in Portuguese Tertiary Care.Publication . LeĆ£o Mendes, JosĆ©; Ferreira, Rita Quaresma; Mata, InĆŖs; Vasco Barreira, JoĆ£o; Rodrigues, Ysel Chiara; Silva Dias, David; Capelas, Manuel LuĆs; MƤkitie, Antti; Guerreiro, InĆŖs; Pimenta, Nuno M; Ravasco, PaulaSarcopenia is an emergent prognostic biomarker in clinical oncology. Albeit increasingly defined through skeletal muscle index (SMI) thresholding, the literature cut-offs fail to discern heterogeneous baseline muscularity across populations. This study assesses the prognostic impact of using cohort-specific SMI thresholds in a Portuguese metastatic non-small-cell lung cancer (mNSCLC) cohort. : Retrospective study including mNSCLC patients treated between January 2017 and December 2022. ImageJ v1.54 g was used to assess cross-sectional CT imaging at the third lumbar vertebra (L3) and calculate L3SMI. Sarcopenia was defined both according to Prado et al. and L3SMI thresholds derived from receiver operating characteristic analysis. Overall survival (OS) was the primary endpoint. Secondary endpoints included first-line (1L) progression-free survival (PFS) and sarcopenia subgroup analysis regarding body mass index impact on OS. : The initial cohort included 197 patients. Mean age was 65 years (Ā±11.31). Most tumors were adenocarcinomas ( = 165) and presented with metastasis ( = 154). SMI was evaluable in 184 patients: cohort-specific thresholds (<49.96 cm/m for men; <34.02 cm/m for women) yielded 46.74% sarcopenic patients ( = 86) versus 66.30% ( = 122) per the literature definition. Cohort-specific thresholds predicted both OS (12.75 versus 21.13 months, hazard ratio [HR] 1.654, = 0.002) and PFS (7.92 versus 9.56 months, HR 1.503, = 0.01). Among sarcopenic patients, overweight (HR 0.417, = 0.01) and obesity (HR 2.723, = 0.039) had contrasting impacts on OS. : Amid reclassification of nearly one-fifth of the cohort, cohort-specific thresholds improved sarcopenia prognostication in mNSCLC. Homogeneity regarding both cancer treatment setting and ethnicity could be key to defining sarcopenia based on SMI.
- Breast Cancer Presents With a Paraneoplastic Neurologic SyndromePublication . Coelho Barata, P; Morgado, J; Sousa, AP; Duarte de Oliveira, S; CustĆ³dio, MP; Bruno da Costa, L; Esteves Pena, JBACKGROUND: Paraneoplastic neurologic syndromes (PNS) pose quite an uncommon neurological complication, affecting less than 1% of patients with breast cancer. Nearly one third of these patients lack detectable onconeural antibodies (ONAs), and improvement in neurologic deficits with concomitant cancer treatments is achieved in less than 30% of cases. CASE PRESENTATION: A 42-year-old, premenopausal woman presented with facial paralysis on the central left side accompanied by a left tongue deviation, an upward vertical nystagmus, moderate spastic paraparesis, dystonic posturing of the left foot, lower limb hyperreflexia and bilateral extensor plantar reflex. After ruling out all other potential neurologic causes, PNS was suspected but no ONAs were found. A PET-CT scan detected increased metabolism in the right breast, as well as an ipsilateral thoracic interpectoral adenopathy. Core biopsy confirmed the presence of an infiltrating duct carcinoma. After breast surgery, the neurologic symptoms disappeared. One week later, the patient was readmitted to the hospital with a bilateral fatigable eyelid ptosis, and two weeks later, there was a noticeable improvement in eyelid ptosis, accompanied by a rapid and progressive development of lower spastic paraparesis. She started adjuvant treatment with chemotherapy with marked clinical and neurological improvement, and by the end of radiotherapy, there were no signs of neurologic impairment. CONCLUSION: This case study highlights the importance of a high level of vigilance for the detection of PNS, even when ONAs are not detected, as the rapid identification and treatment of the underlying tumor offers the best chance for a full recovery.
- Burden of Disease and Cost of Illness of Triple-Negative Breast Cancer in Portugal.Publication . Silva, Joana; Sousa, Gabriela; Costa, LuĆs; Brito, Margarida; Oliveira, SĆ³nia; Rodrigues, Bernardo; Ferreira, JoĆ£o; Borges, Margarida; Miguel, LuĆsBackground: Triple-negative breast cancer accounts for 15% of all breast cancer cases, and it has a lower survival rate and higher incidence of early recurrence, particularly during the first 10 years after diagnosis. Objective: This study aimed to estimate the cost and burden of triple-negative breast cancer among the female population in 2019 in Portugal from a societal perspective. Methods: The prevalence of triple-negative breast cancer was calculated using a cumulative incidence model on the basis of national epidemiological data. The burden of disease was expressed as disability-adjusted life years, including the years lost due to disability and years of life lost. Healthcare resource utilization was quantified with input from an expert panel, and costs were estimated on the basis of diagnosis-related groups. Indirect costs were established following the human capital approach and supported by inputs from an expert panel. Results: Considering a prevalence of 7052 cases of triple-negative breast cancer in 2019, the expert panel confirmed that approximately 24%, 29%, 28% and 19% of the patients were in stages I, II, III and IV, respectively. The burden of this disease in Portugal was estimated at 22,566 disability-adjusted life years per year, 94% of which resulted from premature deaths. The total annual cost was equal to ā¬50,351,934, with direct and indirect costs representing 56% and 44%, respectively. The average cost per patient with triple-negative breast cancer was ā¬7140. Direct costs accounted for ā¬28 million and were associated mainly with triple-negative breast cancer locoregional stage treatment and follow-up (65%). Indirect costs represented ā¬22 million and were largely linked to withdrawal from the job market (94%). Conclusion: Triple-negative breast cancer is an impactful disease with high humanistic and economic costs at the national level. The high mortality and low survival rates of this subtype mean that most disability-adjusted life years are due to years of life lost rather than years lost due to disability. Its prevalence is greater among women aged 45-49 years, suggesting a considerable burden regarding labour absenteeism and withdrawal from the job market.
- Cardiotoxicity in Breast Cancer Treatment: What About Left Ventricular Diastolic Function and Left Atrial Function?Publication . TimĆ³teo, AT; Branco, LM; Filipe, F; Galrinho, A; Rio, P; Portugal, G; Oliveira, S; Cruz Ferreira, RAims: Cardiotoxicity is a possible complication of cancer treatment, particularly with anthracyclines and anti-HER2 drugs. Systolic dysfunction has already been described. Diastolic dysfunction and left atrial function are less studied. We sought to analyze the impact of cardiotoxic treatments on left ventricular diastolic function and left atrial (LA) function. Methods and results: Retrospective study of 100 patients (all women, with a mean age of 54 Ā± 12 years) with three exams in the span of 1 year during treatment for breast cancer. Patients with previous cancer treatment, coronary artery disease, significant valvular disease, and atrial arrhythmias were excluded. Diastolic dysfunction was classified according to international guidelines and left atrial strain was analyzed by two-dimensional speckle tracking. In our sample, 74% received anthracyclines, 83% anti-HER2, and 76% radiation treatment. In the follow-up, 20% developed new or worsening diastolic dysfunction. Age was the only independent predictor (OR 1.93, 95% CI 1.04-3.58, P = .037). In left atrial function, only the contractile function was significantly reduced in 20.8% of the patients and age was also the only independent predictor, but with a protective effect (OR 0.51, 95% CI 0.28-0.91, P = .023). Conclusions: During breast cancer treatment, 20% of the patients develop new or worsening diastolic dysfunction, being age the main determinant, suggesting higher impact of chemotherapy in older patients. Contractile left atrial function is also compromised but, in this case, age seems to be protective. Our results support a stricter surveillance in older patients together to eventually adjust chemotherapy regimens.
- A Case of Post-Radiotherapy Gastritis: Radiation Does Not Explain EverythingPublication . Abrunhosa-Branquinho, A; Barata, P; Vitorino, E; Oliveira, E; Bujor, L; Jorge, MHemorrhagic gastritis is a possible late toxicity outcome after radical radiotherapy but it is nowadays a very rare condition and most likely depends on other clinical factors. We report the case of a 77-year-old woman with a symptomatic solitary extramedullary intra-abdominal plasmacytoma and multiple gastric comorbidities, treated with external beam radiotherapy. Despite the good response to radiotherapy, the patient experienced multiple gastric bleeding a few months later, with the need of multiple treatments for its control. In this paper we will discuss in detail all aspects related to the different causes of hemorrhagic gastritis.
- Full Recovery of a Stage IV Cancer Patient Facing COVID-19 PandemicPublication . Parmanande, A; SimĆ£o, D; Sardinha, M; Palma dos Reis, AF; Spencer, AS; Barreira, JV; Luz, RCoronavirus disease 2019 (COVID-19), first recognized in Wuhan, China, was recently declared a global pandemic by the World Health Organization (WHO). Advanced age and comorbid disease, well-known characteristics in the solid tumor population, have been reported as risk factors for severe disease and death. Cancer-related immunosuppression and its treatments also seem to play an active role in the prognosis, response, and clinical outcomes of these patients. The most effective combination therapy for COVID-19 is still under investigation, and the use of corticosteroids is controversial. Although, as a group, metastatic cancer patients are often considered not to be good candidates for ICU treatment, the individual prognosis should always come into consideration, even in a context of high pressure on medical facilities. We report the case of a stage IV prostate cancer patient infected with SARS-CoV-2 who required ICU admission and recovered from COVID-19 infection. Further studies are needed in order to identify accurate clinical prognostic criteria and provide the best treatment for these challenging patients.
- Global and Regional Patterns of Longitudinal Strain in Screening for Chemotherapy-Induced CardiotoxicityPublication . Portugal, G; Branco, LM; Galrinho, A; Mota Carmo, M; TimĆ³teo, AT; Feliciano, J; Abreu, J; Duarte Oliveira, S; Batarda, L; Cruz Ferreira, RINTRODUCTION: Serial echocardiographic assessment of left ventricular ejection fraction (LVEF) is the gold standard in screening for chemotherapy-induced cardiotoxicity (CIC). Measurement of myocardial deformation using speckle tracking enables more detailed assessment of myocardial contractility. The aim of this study was to determine the relationship between global and regional longitudinal strain and CIC. METHODS: This was a prospective study of 158 breast cancer patients undergoing chemotherapy with anthracyclines with or without adjuvant trastuzumab who underwent serial monitoring by transthoracic echocardiography with assessment of myocardial deformation. CIC was defined as a decrease in LVEF to <53%. Global longitudinal strain (GLS) was estimated using EchoPAC BT12 software on a GE Vivid E9 cardiac ultrasound system. Patients were classified according to the 2015 ASE/EACVI criteria as having impaired myocardial deformation when GLS was reduced (less negative), with a cutoff of -18%. RESULTS: During a mean follow-up of 5.4 months (1-48 months), the incidence of CIC was 18.9%. A decrease in GLS was observed during follow-up for the entire cohort (baseline GLS -20.1Ā±3.5% vs. -18.7Ā±3.4% at last follow-up assessment, p=0.001). A total of 97 patients (61.4%) were observed to have impaired myocardial deformation (GLS ā„18%) at some point during follow-up. This decrease was more significant in patients who eventually developed CIC (GLS -17.2Ā±2.5%, p=0.02). On analysis of regional strain, impaired contractility was observed in the septal (6 out of 6) and anterior (2 out of 3) segments. Multivariate logistic regression showed that patients who developed impaired longitudinal strain had a 4.9-fold increased risk of developing CIC (odds ratio 4.88, confidence interval 1.32-18.0, p=0.017). CONCLUSIONS: Worsening of myocardial deformation as assessed by speckle tracking is common in breast cancer patients undergoing chemotherapy, with predominantly septal and anterior wall involvement. Impaired myocardial deformation was independently associated with increased incidence of CIC.
- Hyperleukocytosis in Solid Tumors: a Rare Paraneoplastic Syndrome Associated with Poor PrognosisPublication . FerrĆ£o, J; Sardinha, M; Dutra, EHematological paraneoplastic syndromes are fairly uncommon. While mild leukocytosis in solid tumors is well reported, white blood cell (WBC) count over 50,000 u/L, described as paraneoplastic leukemoid reaction (PLR), is not. Indeed, when found, it is usually associated with a higher burden of disease, tumor activity and worse clinical outcomes. We report the case of a challenging and burdensome diagnosis of a presumptive hematological paraneoplastic syndrome in a patient with a locally advanced lung cancer admitted in the Internal Medicine ward. After the end of chemotherapy, clinical and laboratory benefit was observed; however, the aggressive course of the disease became clear, with progression and downhill course that was unresponsive to treatment.