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Cancer Statistics
Population in 2012: 10.7m
People newly diagnosed with cancer (excluding NMSC) / yr: 49,200
Age-standardised rate, incidence per 100,000 people/yr: 246.2
Risk of getting cancer before age 75:24.4%
People dying from cancer /yr: 24,100
Data from IARC GlobalCan (2012)
Portugal Cancer Organisations and Resources
Latest Research Publications Related to Portugal

Portugal Cancer Organisations and Resources (5 links)

Latest Research Publications Related to Portugal

Lopes MB, Casimiro S, Vinga S
Twiner: correlation-based regularization for identifying common cancer gene signatures.
BMC Bioinformatics. 2019; 20(1):356 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Breast and prostate cancers are typical examples of hormone-dependent cancers, showing remarkable similarities at the hormone-related signaling pathways level, and exhibiting a high tropism to bone. While the identification of genes playing a specific role in each cancer type brings invaluable insights for gene therapy research by targeting disease-specific cell functions not accounted so far, identifying a common gene signature to breast and prostate cancers could unravel new targets to tackle shared hormone-dependent disease features, like bone relapse. This would potentially allow the development of new targeted therapies directed to genes regulating both cancer types, with a consequent positive impact in cancer management and health economics.
RESULTS: We address the challenge of extracting gene signatures from transcriptomic data of prostate adenocarcinoma (PRAD) and breast invasive carcinoma (BRCA) samples, particularly estrogen positive (ER+), and androgen positive (AR+) triple-negative breast cancer (TNBC), using sparse logistic regression. The introduction of gene network information based on the distances between BRCA and PRAD correlation matrices is investigated, through the proposed twin networks recovery (twiner) penalty, as a strategy to ensure similarly correlated gene features in two diseases to be less penalized during the feature selection procedure.
CONCLUSIONS: Our analysis led to the identification of genes that show a similar correlation pattern in BRCA and PRAD transcriptomic data, and are selected as key players in the classification of breast and prostate samples into ER+ BRCA/AR+ TNBC/PRAD tumor and normal tissues, and also associated with survival time distributions. The results obtained are supported by the literature and are expected to unveil the similarities between the diseases, disclose common disease biomarkers, and help in the definition of new strategies for more effective therapies.

Morais A, Come J, Selemane C, et al.
Understanding the bricks to build better surgical oncology unit at Maputo Central Hospital: prevalent surgical cancers and residents knowledge.
Pan Afr Med J. 2019; 32:83 [PubMed] Free Access to Full Article Related Publications
Introduction: Cancer is a growing concern in Mozambique. However, the country has limited facilities and few oncologists. Surgical oncologists are an unmet need. The aim of this study was to assess residents' knowledge in prevalent cancer domains and to identify and characterize prevalent cancers treated by surgery at Maputo Central Hospital, the largest hospital in Mozambique. The expectations were that the findings shall inform the development of a comprehensive curriculum in surgical oncology fellowship fit for the Hospital.
Methods: To identify and characterize prevalent cancers, we performed a retrospective analysis of individual cancer patient registries of Maputo Central Hospital (MCH), Mozambique. Information was recorded into data collection sheets and analyzed with SPSS
Results: The study covered a period of 3 years and 203 patients. The most prevalent malignant tumors treated by general and thoracic surgery in MCH cancer registry were esophageal (7%), female breast (6.5%) and colorectal cancer (2.8%). Globally these malignancies were diagnosed at an advanced stage of the disease and required a multimodal treatment. The mean percent correct score of residents was 37.3%. The dimension with the highest percent correct score were clinical management (46%) and surgical oncology (28%) showed the lowest correct score.
Conclusion: In Maputo, Mozambique esophageal, breast and colorectal cancer were the most prevalent malignancies treated, with surgery, by thoracic or general surgery in MCH. The test scores suggest that, among residents, the knowledge in oncology needs to be improved, rendering support to the need of a surgical oncology training tailored to suit the local needs. Specific training should take into account local cancer prevalence, resources, their quality and the support of surgical oncology services with volume and experience.

Silva-Santos B, Mensurado S, Coffelt SB
γδ T cells: pleiotropic immune effectors with therapeutic potential in cancer.
Nat Rev Cancer. 2019; 19(7):392-404 [PubMed] Related Publications
The potential of cancer immunotherapy relies on the mobilization of immune cells capable of producing antitumour cytokines and effectively killing tumour cells. These are major attributes of γδ T cells, a lymphoid lineage that is often underestimated despite its major role in tumour immune surveillance, which has been established in a variety of preclinical cancer models. This situation notwithstanding, in particular instances the tumour microenvironment seemingly mobilizes γδ T cells with immunosuppressive or tumour-promoting functions, thus emphasizing the importance of regulating γδ T cell responses in order to realize their translation into effective cancer immunotherapies. In this Review we outline both seminal work and recent advances in our understanding of how γδ T cells participate in tumour immunity and how their functions are regulated in experimental models of cancer. We also discuss the current strategies aimed at maximizing the therapeutic potential of human γδ T cells, on the eve of their exploration in cancer clinical trials that may position them as key players in cancer immunotherapy.

Jorda R, Lopes SMM, Řezníčková E, et al.
Tetrahydropyrazolo[1,5-a]pyridine-fused steroids and their in vitro biological evaluation in prostate cancer.
Eur J Med Chem. 2019; 178:168-176 [PubMed] Related Publications
The androgen receptor (AR) is a steroid hormone receptor and its high expression and disruption of its regulation are strongly implicated in prostate cancer (PCa) development. One of the current therapies includes application of steroidal antiandrogens leading to blockade of the AR action by the abrogation of AR-mediated signaling. We introduced here novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused steroidal compounds, described their synthesis based on [8π+2π] cycloaddition reactions of diazafulvenium methides with different steroidal scaffolds and showed their biological evaluation in different prostate cancer cell lines in vitro. Our results showed the ability of novel compounds to suppress the expression of known androgen receptor targets, Nkx3.1 and PSA in two prostate cell lines, 22Rv1 and VCaP. Candidate compound diminished the transcription of AR-regulated genes in the reporter cell line in a concentration-dependent manner. Antiproliferative activity of the most promising steroid was studied by clonogenic assay and induction of apoptosis in treated cells was documented by immunoblot detection of cleaved PARP.

Meißner R, Kočišek J, Feketeová L, et al.
Low-energy electrons transform the nimorazole molecule into a radiosensitiser.
Nat Commun. 2019; 10(1):2388 [PubMed] Free Access to Full Article Related Publications
While matter is irradiated with highly-energetic particles, it may become chemically modified. Thereby, the reactions of free low-energy electrons (LEEs) formed as secondary particles play an important role. It is unknown to what degree and by which mechanism LEEs contribute to the action of electron-affinic radiosensitisers applied in radiotherapy of hypoxic tumours. Here we show that LEEs effectively cause the reduction of the radiosensitiser nimorazole via associative electron attachment with the cross-section exceeding most of known molecules. This supports the hypothesis that nimorazole is selectively cytotoxic to tumour cells due to reduction of the molecule as prerequisite for accumulation in the cell. In contrast, dissociative electron attachment, commonly believed to be the source of chemical activity of LEEs, represents only a minor reaction channel which is further suppressed upon hydration. Our results show that LEEs may strongly contribute to the radiosensitising effect of nimorazole via associative electron attachment.

Beca F, Schmitt FC
Ancillary Tests in Breast Cytology: A Practical Guide.
Acta Cytol. 2019; 63(4):302-313 [PubMed] Related Publications
Utilization of fine-needle aspiration biopsy (FNAB) cytology for the diagnosis of diseases of the breast has been met with both excitement and uncertainty during the last couple of decades. Presently, FNAB for the diagnosis of primary and metastatic breast lesions is on the rise again. This is probably due to its fast turnaround time, cost efficiency, and minimal invasiveness, characteristics of this sampling modality which are particularly crucial for patients requiring frequent repeat biopsy in the setting of metastatic lesions. In this article, we will briefly review the main modern applications of FNAB of the breast when coupled with contemporary ancillary techniques. Such contemporary ancillary techniques range from classic immunocytochemistry (ICC) to the most modern molecular techniques, particularly next-generation sequencing. Coupled with contemporary ICC and molecular methods, FNAB of the breast can be used for several applications. The applications reviewed in this article include the primary diagnosis of a breast lesion, the identification of the breast as a primary source of a metastatic lesion, the evaluation of breast prognostic/predictive markers, and the tracking of tumor evolution. In our opinion, FNAB of the breast is an ideal sampling method, sharing many of the advantages of truly liquid and of tissue biopsies. Ultimately, we aim at demystifying the complexity of many of the challenges traditionally associated with the application of ancillary techniques to FNAB of the breast and provide insights into some of the most cutting-edge and clinically useful application scenarios.

von Moos R, Costa L, Gonzalez-Suarez E, et al.
Management of bone health in solid tumours: From bisphosphonates to a monoclonal antibody.
Cancer Treat Rev. 2019; 76:57-67 [PubMed] Related Publications
Patients with solid tumours are at risk of impaired bone health from metastases and cancer therapy-induced bone loss (CTIBL). We review medical management of bone health in patients with solid tumours over the past 30 years, from first-generation bisphosphonates to the receptor activator of nuclear factor κB ligand (RANKL)-targeted monoclonal antibody, denosumab. In the 1980s, first-generation bisphosphonates were shown to reduce the incidence of skeletal-related events (SREs) in patients with breast cancer. Subsequently, more potent second- and third-generation bisphosphonates were developed, particularly zoledronic acid (ZA). Head-to-head studies showed that ZA was significantly more effective than pamidronate for reducing SREs in patients with breast and castrate-resistant prostate cancer (CRPC), becoming the standard of care for more than a decade. The RANKL inhibitor denosumab was licensed in 2010, and head-to-head studies and integrated analyses confirmed its superiority to ZA for preventing SREs, particularly in breast cancer and CRPC. Bisphosphonates and denosumab have also been investigated for prevention of CTIBL in patients receiving hormonal therapy for breast and prostate cancer, and denosumab is licensed in this indication. Despite advances in management of bone health, several issues remain, notably the optimal time to initiate therapy, duration of therapy, and dosing frequency, and how to avoid toxicity, particularly with long-term treatment. In summary, introduction of ZA and denosumab has protected patients with bone metastasis from serious bone complications and improved their quality of life. Ongoing research will hopefully guide the optimal use of these agents to help maintain bone health in patients with solid tumours.

Sousa B, Ribeiro AS, Paredes J
Heterogeneity and Plasticity of Breast Cancer Stem Cells.
Adv Exp Med Biol. 2019; 1139:83-103 [PubMed] Related Publications
In the last 20 years, the conventional view of breast cancer as a homogeneous collection of highly proliferating malignant cells was totally replaced by a model of increased complexity, which points out that breast carcinomas are tissues composed of multiple populations of transformed cells. A large diversity of host cells and structural components of the extracellular matrix constitute the mammary tumour microenvironment, which supports its growth and progression, where individual cancer cells evolve with cumulative phenotypic and genetic heterogeneity. Moreover, contributing to this heterogeneity, it has been demonstrated that breast cancers can exhibit a hierarchical organization composed of tumour cells displaying divergent lineage biomarkers and where, at the apex of this hierarchy, some neoplastic cells are able to self-renew and to aberrantly differentiate. Breast cancer stem cells (BCSCs), as they were entitled, not only drive tumourigenesis, but also mediate metastasis and contribute to therapy resistance.Recently, adding more complexity to the system, it has been demonstrated that BCSCs maintain high levels of plasticity, being able to change between mesenchymal-like and epithelial-like states in a process regulated by the tumour microenvironment. These stem cell state transitions play a fundamental role in the process of tumour metastasis, as well as in the resistance to putative therapeutic strategies to target these cells. In this chapter, it will be mainly discussed the emerging knowledge regarding the contribution of BCSCs to tumour heterogeneity, their plasticity, and the role that this plasticity can play in the establishment of distant metastasis. A major focus will also be given to potential clinical implications of these discoveries in breast cancer recurrence and to possible BCSC targeted therapeutics by the use of specific biomarkers.

Field AS, Raymond WA, Rickard M, et al.
The International Academy of Cytology Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy Cytopathology.
Acta Cytol. 2019; 63(4):257-273 [PubMed] Related Publications
The International Academy of Cytology (IAC) gathered together a group of cytopathologists expert in breast cytology who, working with clinicians expert in breast diagnostics and management, have developed the IAC Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy (FNAB) Cytology. The project was initiated with the first cytopathology group meeting in Yokohama at the 2016 International Congress of Cytology. This IAC Yokohama System defines five categories for reporting breast cytology, each with a clear descriptive term for the category, a definition, a risk of malignancy (ROM) and a suggested management algorithm. The key diagnostic cytopathology features of each of the lesions within each category will be presented more fully in a subsequent atlas. The System emphasizes that the crucial requirements for diagnostic breast FNAB cytology are a high standard for the performance of the FNAB and for the making of direct smears, and well-trained experienced cytopathologists to interpret the material. The performance indicators of breast FNAB, including specificity and sensitivity, negative predictive value, positive predictive value and ROM stated in this article have been derived from the recent literature. The current practice of breast FNAB has evolved with the increasing use of ultrasound guidance and rapid on-site evaluation. Two recent publications have shown a range of ROM for the insufficient/inadequate category of 2.6-4.8%, benign 1.4-2.3%, atypical 13-15.7%, suspicious of malignancy 84.6-97.1%, and malignant 99.0-100%. The management algorithm in the System provides options because there are variations in the management of breast lesions using FNAB and core-needle biopsy in those countries utilizing the "triple test" of clinical, imaging, and FNAB assessment, and also variations in the availability of CNB and imaging in low- and middle-income countries. The System will stimulate further discussion and research, particularly in the cytological diagnostic features of specific lesions within each category and in management recommendations. This will lead to continuing improvements in the care of patients with breast lesions and possible modifications to the IAC Yokohama System.

Dolmans MM, Lambertini M, Macklon KT, et al.
EUropean REcommendations for female FERtility preservation (EU-REFER): A joint collaboration between oncologists and fertility specialists.
Crit Rev Oncol Hematol. 2019; 138:233-240 [PubMed] Related Publications
In recent years, following the improved prognosis of patients with cancer, interest and attention has grown around fertility issues in these patients. International guidelines on fertility preservation in patients with cancer recommend that physicians discuss with all patients of reproductive age (or their parents/guardians, if children) the risk of infertility arising from their cancer or its treatment. Oncofertility counselling is recommended at the earliest opportunity and prior to cancer treatment, to help patients make informed decisions on pursuing fertility preservation. Currently, however, such discussions are not being routinely held. In June 2017, an esteemed group of European oncofertility experts met to discuss current unfulfilled needs in oncofertility for female cancer patients. This expert group has produced here a number of key recommendations in order to guide oncologists, haematologists, and other involved professionals with oncofertility discussions and appropriate referrals for further fertility preservation counselling and follow-up.

Ferreira G, Iravani A, Hofman MS, Hicks RJ
Intra-individual comparison of
Cancer Imaging. 2019; 19(1):23 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Detailed data comparing the biodistribution of PSMA radioligands is still scarce, raising concerns regarding the comparability of different compounds. We investigated differences in normal-organ biodistribution and uptake variability between the two most commonly PSMA tracers in clinical use,
METHODS: This retrospective analysis included 34 patients with low tumor burden referred for PET/CT imaging with
RESULTS: For both tracers the highest uptake was found in the kidneys and bladder and low background activity was noted across all scans. In the quantitative analysis there was significantly higher uptake of
CONCLUSION: Normal tissue biodistribution patterns of

Veccia A, Antonelli A, Francavilla S, et al.
Minimally Invasive Radical Prostatectomy after Previous Bladder Outlet Surgery: A Systematic Review and Pooled Analysis of Comparative Studies.
J Urol. 2019; 202(3):511-517 [PubMed] Related Publications
PURPOSE: Prostate cancer surgery after previous bladder outlet surgery of benign prostatic hyperplasia is an uncommon yet challenging scenario. We performed a systematic review and pooled analysis of comparative studies on laparoscopic and robotic minimally invasive radical prostatectomy after bladder outlet surgery.
MATERIALS AND METHODS: We searched the literature on PubMed®, Embase® and Web of Science™ up to February 2019 according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement to identify eligible studies. Surgical, oncologic and functional outcomes in patients who underwent minimally invasive radical prostatectomy after bladder outlet surgery were compared to those without a history of bladder outlet surgery. Sensitivity analysis was done according to surgical technique (laparoscopic or robotic). RevMan 5.3 was used for statistical analysis.
RESULTS: A total of 12 comparative studies were included in analysis. Patients who underwent minimally invasive radical prostatectomy after bladder outlet surgery were older (p ≤0.00001) and had a smaller prostate (p = 0.04) and lower prostate specific antigen (p = 0.003). The previous bladder outlet surgery group had lower odds of nerve sparing procedures, longer operative time, a higher rate of bladder neck reconstruction (each p <0.0001) and longer catheter time (p = 0.03). They were at higher risk for intraoperative (p = 0.001), overall (p <0.00001) and major complications (p = 0.0008), a higher positive surgical margin rate (p = 0.0005) and biochemical recurrence (p = 0.05). Moreover, potency (p = 0.03) and continence recovery (p = 0.007) at 12 months were lower in men with previous bladder outlet surgery. Robotic surgery seemed to offer better outcomes than laparoscopy.
CONCLUSIONS: Minimally invasive radical prostatectomy after previous bladder outlet surgery represents a challenging surgical task with a higher risk of complications, and higher odds of worse functional and oncologic outcomes. Patients should be aware of these drawbacks and these factors should be considered during patient counseling. When surgery is pursued, robot-assisted radical prostatectomy should be preferred over laparoscopic radical prostatectomy since it can offer superior outcomes. The overall literature on this topic is of low quality and further efforts should be made to obtain higher levels of evidence.

Marques RP, Heudtlass P, Pais HL, et al.
Patient-reported outcomes and health-related quality of life for cetuximab versus bevacizumab in metastatic colorectal cancer: a prospective cohort study.
J Cancer Res Clin Oncol. 2019; 145(7):1719-1728 [PubMed] Related Publications
PURPOSE: Uncertainty exists regarding Patient-Reported Outcomes (PROs) and Health-Related Quality of Life (HRQoL) of patients with metastatic colorectal cancer (mCRC) treated with cetuximab or bevacizumab. We conducted a prospective cohort study comparing PROs and HRQoL from both therapies.
METHODS: We assessed PROs and HRQoL from patients treated with cetuximab or bevacizumab using QLQ-C30 and QLQ-CR29 questionnaires at three sequential time points, including baseline. Global Health Status (GHS), functional and symptom scales, and Overall Treatment Utility (derived from clinical and patient-reported outcomes) were compared for the two treatment strategies.
RESULTS: Between January 2017 and April 2018, 44 patients were allocated to cetuximab (n = 19) or bevacizumab (n = 25). Except for RAS mutation status, patient baseline characteristics were generally well balanced across treatment groups. A higher proportion of patients experienced a deterioration in GHS (≥ 10%) in cetuximab arm - 53.8% (95% CI 25.1-80.8%) at 6 weeks and 66.7% (95% CI 29.9-92.5%) at 12 weeks-comparing to bevacizumab cohort: 18.2% (95% CI 5.2-40.3%) at 6 weeks and 12.5% (95% CI:1.6-38.3%) at 12 weeks. Treatment utility rates at 6 and 12 weeks were, respectively, 88.6% and 69.8% for bevacizumab, compared to 49% and 19.1% for cetuximab (p = 0.004), a difference confirmed in subset analyses.
CONCLUSIONS: In patients with mCRC, cetuximab-containing regimens led to a progressive negative impact on PROs and global HRQoL, when compared to baseline and bevacizumab. Future research is needed to confirm these results. Our findings demonstrate the value of PROs when assessing comparative effectiveness of different treatment regimens.

Tsilimigras DI, Hyer JM, Moris D, et al.
Prognostic utility of albumin-bilirubin grade for short- and long-term outcomes following hepatic resection for intrahepatic cholangiocarcinoma: A multi-institutional analysis of 706 patients.
J Surg Oncol. 2019; 120(2):206-213 [PubMed] Related Publications
BACKGROUND: The objective of the current study was to define the impact of albumin-bilirubin (ALBI) grade on short- as well as long-term outcomes among patients with intrahepatic cholangiocarcinoma (ICC).
METHODS: Patients who underwent hepatectomy for ICC between 1990 and 2016 were identified using an international multi-institutional database. Clinicopathologic factors including ALBI score were assessed using bivariate and multivariable analyses, as well as standard survival analyses.
RESULTS: Among 706 patients, 453 (64.2%) patients had ALBI grade 1, 231 (32.7%) ALBI grade 2, and 22 (3.1%) had ALBI grade 3. After adjusting for all competing factors, patients with ALBI grade 2/3 had higher odds of a prolonged length-of-stay (>10 days, odds ratio [OR] = 2.37, 95% confidence interval [CI]:1.47-3.80), perioperative transfusion (OR = 2.15, 95% CI:1.45-3.18) and 90-day mortality (OR = 2.50, 95% CI:1.16-5.38). Median and 5-year overall survival (OS) for the entire cohort was 41.5 months (IQR:15.7-107.8) and 39.8%, respectively. Of note, median OS incrementally worsened with increased ALBI grade: grade 1, 49.6 months (IQR:18.3-NR) vs grade 2, 29.6 months (IQR:12.6-98.4) vs grade 3, 16.9 months (IQR:6.5-32.4; P < 0.001). On multivariable analysis, higher ALBI grade remained associated with higher hazards of death (grade 2/3: hazard ratio = 1.36, 95% CI:1.04-1.78).
CONCLUSION: The ALBI score was associated with both short- and long-term outcomes following resection for ICC and could prove a useful surrogate marker to identify patients at risk for adverse outcomes.

Teixeira S, Branco L, Fernandes MH, Costa-Rodrigues J
Bisphosphonates and Cancer: A Relationship Beyond the Antiresorptive Effects.
Mini Rev Med Chem. 2019; 19(12):988-998 [PubMed] Related Publications
Bisphosphonates (BPs) are stable analogues of the Inorganic Pyrophosphate (PPi), an endogenous regulator of bone mineralization, which can resist the hydrolysis in the gastrointestinal tract. Their conformation allows targeting the bone as a result of their three-dimensional structure, which makes them primary agents against osteoclast-mediated bone loss. They are used in many bone pathological conditions, like bone metastasis, because of its ability to modulate bone metabolism into a less favorable place to cancer cell growth, through the inhibition of osteoclastogenesis and bone resorption. This review is focused on the mechanisms of action through which BPs affect the cellular activity and survival, mainly on their antitumoral effects. In conclusion, BPs are considered the primary therapy for skeletal disorders due to its high affinity for bone, but now they are also considered as potential antitumor agents due to its ability to induce tumor cell apoptosis, inhibition of cell adhesion, invasion and proliferation, modulation of the immune system to target and eliminate cancer cells as well as affect the angiogenic mechanisms. Like any other drug, they also have some adverse effects, but the most common, the acute phase reaction, can be minimized with the intake of calcium and vitamin D.

Lérias JR, Paraschoudi G, Silva I, et al.
Clinically Relevant Immune Responses against Cytomegalovirus: Implications for Precision Medicine.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
Immune responses to human cytomegalovirus (CMV) can be used to assess immune fitness in an individual. Further to its clinical significance in posttransplantation settings, emerging clinical and translational studies provide examples of immune correlates of protection pertaining to anti-CMV immune responses in the context of cancer or infectious diseases, e.g., tuberculosis. In this viewpoint, we provide a brief overview about CMV-directed immune reactivity and immune fitness in a clinical context and incorporate some of our own findings obtained from peripheral blood or tumour-infiltrating lymphocytes (TIL) from patients with advanced cancer. Observations in patients with solid cancers whose lesions contain both CMV and tumour antigen-specific T-cell subsets are highlighted, due to a possible CMV-associated "bystander" effect in amplifying local inflammation and subsequent tumour rejection. The role of tumour-associated antibodies recognising diverse CMV-derived epitopes is also discussed in light of anti-cancer immune responses. We discuss here the use of anti-CMV immune responses as a theranostic tool-combining immunodiagnostics with a personalised therapeutic potential-to improve treatment outcomes in oncological indications.

Sousa B, Pereira J, Paredes J
The Crosstalk Between Cell Adhesion and Cancer Metabolism.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
Cancer cells preferentially use aerobic glycolysis over mitochondria oxidative phosphorylation for energy production, and this metabolic reprogramming is currently recognized as a hallmark of cancer. Oncogenic signaling frequently converges with this metabolic shift, increasing cancer cells' ability to produce building blocks and energy, as well as to maintain redox homeostasis. Alterations in cell-cell and cell-extracellular matrix (ECM) adhesion promote cancer cell invasion, intravasation, anchorage-independent survival in circulation, and extravasation, as well as homing in a distant organ. Importantly, during this multi-step metastatic process, cells need to induce metabolic rewiring, in order to produce the energy needed, as well as to impair oxidative stress. Although the individual implications of adhesion molecules and metabolic reprogramming in cancer have been widely explored over the years, the crosstalk between cell adhesion molecular machinery and metabolic pathways is far from being clearly understood, in both normal and cancer contexts. This review summarizes our understanding about the influence of cell-cell and cell-matrix adhesion in the metabolic behavior of cancer cells, with a special focus concerning the role of classical cadherins, such as Epithelial (E)-cadherin and Placental (P)-cadherin.

Sahara K, Tsilimigras DI, Mehta R, et al.
A novel online prognostic tool to predict long-term survival after liver resection for intrahepatic cholangiocarcinoma: The "metro-ticket" paradigm.
J Surg Oncol. 2019; 120(2):223-230 [PubMed] Related Publications
BACKGROUND: The aim of the current study was to develop an online calculator to predict survival after liver resection for intrahepatic cholangiocarcinoma (ICC) based on the "metro-ticket" paradigm.
METHODS: Between 1990 and 2016, patients who underwent liver resection for ICC were identified in an international multi-institutional database. The final multivariable model of survival was used to develop an online prognostic calculator of survival.
RESULTS: Among 643 patients, actual 5-year overall survival (OS) after resection for ICC was 42.7%. On multivariable analysis, CA19-9 > 200 (hazard ratio (HR), 2.62; 95% CI, 2.01-3.42), sum of the number and largest tumor size >7 (HR, 1.88; 95% CI, 1.46-2.42), N1 disease (HR, 2.87; 95% CI, 1.98-4.16), R1 resection (HR, 1.72; 95% CI, 1.21-2.46), poor/undifferentiated tumor grade (HR, 1.74; 95% CI, 1.25-2.44), major vascular invasion (HR, 1.47; 95% CI, 1.03-2.10), and adjuvant chemotherapy (HR, 0.64; 95% CI, 0.45-0.89) were significantly associated with survival and were included in the online calculator. The predictive accuracy of the model was good to very good as the C-statistics to predict 5-year OS was 0.696 in the training dataset and 0.672 with bootstrapping resamples (n = 5000) in the test dataset.
CONCLUSION: A novel, online calculator was developed to estimate the 5-year survival probability for patients undergoing resection for ICC. This tool could help provide useful information to guide treatment decision-making and inform conversations about prognosis.

Pezzani R, Salehi B, Vitalini S, et al.
Synergistic Effects of Plant Derivatives and Conventional Chemotherapeutic Agents: An Update on the Cancer Perspective.
Medicina (Kaunas). 2019; 55(4) [PubMed] Free Access to Full Article Related Publications
Synergy is a process in which some substances cooperate to reach a combined effect that is greater than the sum of their separate effects. It can be considered a natural "straight" strategy which has evolved by nature to obtain more efficacy at low cost. In this regard, synergistic effects may be observed in the interaction between herbal products and conventional drugs or biochemical compounds. It is important to identify and exploit these interactions since any improvement brought by such kind of process can be advantageously used to treat human disorders. Even in a complex disease such as cancer, positive synergistic plant-drug interactions should be investigated to achieve the best outcomes, including providing a greater benefit to patients or avoiding adverse side effects. This review analyzes and summarizes the current knowledge on the synergistic effects of plant-drug interactions with a focus on anticancer strategies.

Ferreira MA, Gamazon ER, Al-Ejeh F, et al.
Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.
Nat Commun. 2019; 10(1):1741 [PubMed] Free Access to Full Article Related Publications
Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

Liu J, Xiong Z, Zhang J, et al.
Zwitterionic Gadolinium(III)-Complexed Dendrimer-Entrapped Gold Nanoparticles for Enhanced Computed Tomography/Magnetic Resonance Imaging of Lung Cancer Metastasis.
ACS Appl Mater Interfaces. 2019; 11(17):15212-15221 [PubMed] Related Publications
Design of dual mode or multimode contrast agents or nanoplatforms with antifouling properties is crucial for improved cancer diagnosis since the antifouling materials are able to escape the clearance of the reticuloendothelial system with improved pharmacokinetics. Herein, we present the creation of zwitterionic gadolinium(III) (Gd(III))-complexed dendrimer-entrapped gold nanoparticles (Au DEN) for enhanced dual mode computed tomography (CT)/magnetic resonance (MR) imaging of lung cancer metastasis. In the present work, poly(amidoamine) (PAMAM) dendrimers of generation 5 were partially decorated with carboxybetanie acrylamide (CBAA), 2-methacryloyloxyethyl phosphorylcholine (MPC), and 1,3-propane sultone (1,3-PS), respectively at different degrees, then used to entrap Au NPs within their interiors, and finally acetylated to cover their remaining amine termini. Through protein resistance, macrophage cellular uptake, and pharmacokinetics assays, we show that zwitterionic Au DEN modified with 1,3-PS exhibit the best antifouling property with the longest half-decay time (37.07 h) when compared to the CBAA- and MPC-modified Au DEN. Furthermore, with the optimized zwitterion type, we then prepared zwitterionic Gd(III)-loaded Au DEN modified with arginine-glycine-aspartic acid peptide for targeted dual mode CT/MR imaging of a lung cancer metastasis model. We disclose that the designed multifunctional Au DEN having an Au core size of 2.7 nm and a surface potential of 7.6 ± 0.9 mV display a good X-ray attenuation property, relatively high r

João C, Bergantim R, Neves M, et al.
Multiple myeloma in elderly patients-a Portuguese multicentric real-life study.
Ann Hematol. 2019; 98(7):1689-1701 [PubMed] Related Publications
Patients older than 75 years old with multiple myeloma (MM) have shorter survival and are usually treated differently from what features in clinical trials. In this study, the authors characterized the Portuguese population of MM patients above 75 years old, treated between 2009 and 2016. We compared the outcomes obtained with bortezomib-based protocols (BBP), thalidomide-based protocols (TBP), and chemotherapy (CT) using univariate and multivariate controlling for age, performance status, International Staging System score, renal impairment, and number of comorbidities. We retrieved data from 386 patients, treated in 12 hospitals. Three hundred thirty-one cases were analyzed: 119 patients treated with BBP, 65 with TBP, 147 with CT. Median age was 79 years; CT-treated patients were older, had a worse performance status, and have more comorbidities. The median follow-up was 25 months. The 2-year OS was 58% and the median OS was 29.5 months. Patients treated with BBP had more frequently very good partial response (VGPR) or better response, and the subgroup of more fit patients had a significantly longer progression-free survival (PFS) and OS. The most frequently grade 3-4 toxicities were hematologic, infectious, and neurologic and were significantly lower in TBP and CT groups vs BBP. The most common second line was CT, followed by lenalidomide. Patients treated with lenalidomide had a higher probability of VGPR or better and a superior 1-year PFS. Despite the limitations of a retrospective study, our cohort represents the reality of older patients with MM in a western country. The hazard of death or progression was higher for old, fit patients treated, in first line, with CT and with TBP compared with that of BBP.

Ferraz A, Morais S, Mimoso G
Role of the cerebral ultrasound in a case of Sturge-Weber syndrome.
BMJ Case Rep. 2019; 12(4) [PubMed] Related Publications
Cerebral ultrasound (CUS) can be a valuable non-invasive diagnostic tool for brain involvement in Sturge-Weber syndrome (SWS). Literature discussing the relevance of ultrasound in SWS is, however, scarce.We report a case of a newborn with SWS and serious brain abnormalities diagnosed on the first day of life with a CUS.

Coutinho R, Lobato J, Esteves S, et al.
Clinical risk scores do not accurately identify a very high risk population with diffuse large B cell lymphoma-an analysis of 386 Portuguese patients.
Ann Hematol. 2019; 98(8):1937-1946 [PubMed] Related Publications
The identification of high-risk patients deserving alternative first-line treatments to R-CHOP is a research priority in diffuse large B cell lymphoma (DLBCL). Despite the increasing recognition of biological features underlying aggressive behavior, clinical scores remain the basis for prognostic evaluation and treatment stratification in DLBCL. We performed a retrospective analysis of patients with DLBCL uniformly treated with immunochemotherapy with the aim of assessing the discriminative power of the NCCN international prognostic index (IPI) and the GELTAMO-IPI scores in risk group stratification and compared them with the IPI. Additionally, we investigated if bulky disease, gender, beta-2 microglobulin (β2m), body mass index, and B-symptoms have independent prognostic impact. We confirmed the discriminative ability of the three prognostic scores in terms of progression-free survival and overall survival and found that the NCCN-IPI performs better in the identification of a high-risk population compared to the IPI and the GELTAMO scores. In an attempt to improve the prognostic power of the NCCN-IPI we analyzed additional clinical variables. Bulky disease and elevated β2m were found to be independent predictors of prognosis when controlling for the NCCN-IPI risk groups. However, they seem to bring no incremental power to the latter in the identification of poor outcome patients. We support the use of the NCCN-IPI for the clinical identification of high-risk patients in DLBCL. Future studies to unravel the biological heterogeneity within NCCN-IPI groups are needed to improve risk prediction and design targeted therapies for poor prognosis patients.

Kundu B, Bastos ARF, Brancato V, et al.
Mechanical Property of Hydrogels and the Presence of Adipose Stem Cells in Tumor Stroma Affect Spheroid Formation in the 3D Osteosarcoma Model.
ACS Appl Mater Interfaces. 2019; 11(16):14548-14559 [PubMed] Related Publications
Osteosarcoma is one of the most common metastatic bone cancers, which results in significant morbidity and mortality. Unfolding of effectual therapeutic strategies against osteosarcoma is impeded because of the absence of adequate animal models, which can truly recapitulate disease biology of humans. Tissue engineering provides an opportunity to develop physiologically relevant, reproducible, and tunable in vitro platforms to investigate the interactions of osteosarcoma cells with its microenvironment. Adipose-derived stem cells (ASCs) are detected adjacent to osteosarcoma masses and are considered to have protumor effects. Hence, the present study focuses on investigating the role of reactive ASCs in formation of spheroids of osteosarcoma cells (Saos 2) within a three-dimensional (3D) niche, which is created using gellan gum (GG)-silk fibroin. By modifying the blending ratio of GG-silk, the optimum stiffness of the resultant hydrogels such as GG and GG75: S25 is obtained for cancer spheroid formation. This work indicates that the co-existence of cancer and stem cells can form a spheroid, the hallmark of cancer, only in particular microenvironment stiffness. The incorporation of fibrillar silk fibroin within the hydrophilic network of GG in GG75: S25 spongy-like hydrogels closely mimics the stiffness of commercially established cancer biomaterials (e.g., Matrigel, HyStem). The GG75: S25 hydrogel maintains the metabolically active construct for a longer time with elevated expression of osteopontin, osteocalcin, RUNX 2, and bone sialoprotein genes, the biomarkers of osteosarcoma, compared to GG. The GG75: S25 construct also exhibits intense alkaline phosphatase expression in immunohistochemistry compared to GG, indicating itspotentiality to serve as biomimetic niche to model osteosarcoma. Taken together, the GG-silk fibroin-blended spongy-like hydrogel is envisioned as an alternative low-cost platform for 3D cancer modeling.

Braga C, Vaz AR, Oliveira MC, et al.
Targeting gliomas with triazene-based hybrids: Structure-activity relationship, mechanistic study and stability.
Eur J Med Chem. 2019; 172:16-25 [PubMed] Related Publications
Herein we report novel hybrid compounds based on valproic acid and DNA-alkylating triazene moieties, 1, with therapeutic potential for glioblastoma multiforme chemotherapy. We identified hybrid compounds 1d and 1e to be remarkably more potent against glioma and more efficient in decreasing invasive cell properties than temozolomide and endowed with chemical and plasma stability. In contrast to temozolomide, which undergoes hydrolysis to release an alkylating metabolite, the valproate hybrids showed a low potential to alkylate DNA. Key physicochemical properties align for optimal CNS penetration, highlighting the potential of these effective triazene based-hybrids for enhanced anticancer chemotherapy.

Ribeiro B, Silva R, Dias R, Patrício V
Carcinosarcoma of the uterine cervix: a rare pathological finding originating from mesonephric remnants.
BMJ Case Rep. 2019; 12(3) [PubMed] Related Publications
Carcinosarcoma of the uterine cervix is a very rare tumour that has been described in less than 70 cases in the literature. It is less common compared with carcinosarcoma of the uterine corpus and it can have two origins: the Müllerian ducts and the mesonephric duct remnants. The association of mesonephric carcinoma with a sarcomatous component was reported in only 11 cases, including the following. We describe a case of a 64-year-old woman, presenting with vaginal bleeding and a cervical lesion reported as a sarcoma of endometrial stroma in the first biopsy. After exclusion of distant disease, she was submitted to radical surgery and the final histopathological examination showed a carcinosarcoma of the cervix with mesonephric origin.

Carvalho TM, Cardoso HJ, Figueira MI, et al.
The peculiarities of cancer cell metabolism: A route to metastasization and a target for therapy.
Eur J Med Chem. 2019; 171:343-363 [PubMed] Related Publications
The last decade has witnessed the peculiarities of metabolic reprogramming in tumour onset and progression, and their relevance in cancer therapy. Also, it has been indicated that the metastatic process may depend on the metabolic rewiring and adaptation of cancer cells to the pressure of tumour microenvironment and limiting nutrient availability. The present review gatherers the existent knowledge on the influence of tumour microenvironment and metabolic routes driving metastasis. A focus will be given to glycolysis, fatty acid metabolism, glutaminolysis, and amino acid handling. In addition, the role of metabolic waste driving metastasization will be explored. Finally, we discuss the status of cancer treatment approaches targeting metabolism. This knowledge revision will highlight the critical metabolic targets in metastasis and the chemicals already used in preclinical studies and clinical trials, providing clues that would be further exploited in medicinal chemistry research.

de Azevedo JM, Gaspar C, Andresen C, et al.
Negative pressure wound therapy for skin graft closure in complex pilonidal disease.
Br J Nurs. 2019; 28(6):S24-S28 [PubMed] Related Publications
Pilonidal disease occurs in 26 in 100 000 people, affecting mainly men aged 20-30 years. It is treated by a variety of surgical techniques; however, there is a lack of consensus on the optimal choice of treatment for complex pilonidal disease. In addition, there is no consensus regarding care of the wound after surgery. Negative pressure wound therapy applied to open wounds following pilonidal disease surgery has been suggested as a way to decrease healing times and costs and is an emerging option for complex and or recurrent pilonidal disease. This study describes a case of complex pilonidal disease managed with local excision and negative pressure wound therapy followed by a split-thickness skin graft.

Roque V, Jessop M, Pereira L, et al.
Bone scan index as metastatic bone disease quantifier and predictor of radium-223-dichloride biochemical response.
Nucl Med Commun. 2019; 40(6):588-596 [PubMed] Related Publications
OBJECTIVES: This work aims to assess whether the biochemical response of radium-223-dichloride treatment can be predicted based on the pretherapy bone scan, and consequently if bone scan index (BSI) and maximum lesion intensity have a place as alternatives or as complements to extent of bone disease (EOBD) scoring in predicting biochemical response to treatment. Many cases of advanced prostate cancer have evidence of bone metastasis. Accurate EOBD quantification could help predict the response to radium-223-dichloride therapy. Current EOBD score is simple to use but does not consider size, intensity or localisation of lesion BSI might be more suitable for stratification of bone metastases.
PATIENTS AND METHODS: Bone scans (n=20) preceding radium-223-dichloride treatment for prostate cancer were assessed retrospectively using automated BSI software (EXINI) and by assessing maximum counts per lesion. Results were then compared to total alkaline phosphatase (ALP) as a measure of biochemical response to therapy using linear regressions and to their EOBD scores using box plot analysis.
RESULTS: Moderate correlation was found between ALP response and maximum lesion intensity (R=0.41) and BSI (R=0.46). Strong correlation (R=0.71) was found between baseline ALP and BSI and between lesion number and BSI (R=0.60). Visual assessment of EOBD score was found to correlate well with baseline ALP and maximum ALP response.
CONCLUSION: BSI is a useful asset in stratification of patients with metastatic bone disease. It may also have a place in prediction of biochemical response.

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