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- Chemoradiotherapy completion and neutropenia risk in HIV patients with cervical cancerPublication . Vendrell, Ines; Ferreira, Arlindo; Abrunhosa-Branquinho, André; Semedo, Patrícia Miguel; Pulido, Catarina F.; Jorge, Marília; Pina, Maria Filomena; Pinto, Conceição; Costa, LuisCervical cancer (CC) is one of the acquired immunodeficiency syndrome (AIDS) defining diseases and the human immunodeficiency virus (HIV) infection is thought to relate with increased acute toxicity of chemoradiotherapy (CRT). We investigated the effect of HIV status in the incidence of neutropenia associated with cisplatin-based CRT for CC and its impact in treatment completion. This is a single-center retrospective cohort study. Data collection was performed for all the consecutive stage Ib-IV CC women treated with cisplatin-based CRT from 2012 to 2016, and with known HIV status. Sixty-one patients were included, 6 were HIV+. HIV+ patients had a higher risk of neutropenia at any cycle during cisplatin CRT [adjusted odds ratio (OR) 7.3, 95% confidence interval (95% CI) 1.02–52.3; P = .05]. Despite the absolute differences, mean neutrophil count was nonsignificantly lower in HIV+ women, both at baseline [4455/μL (interquartile range, IQR: 1830–6689) vs 6340 (IQR: 1720–18,970) for HIV−, P = .98] and at the end of treatment [1752/μL (IQR: 1100–2930) vs 3147/μL (IQR: 920–18,390) in HIV−; P = .06]. Moreover, when considering the effect of time, CRT seems to induce a consistent drop of neutrophils in both groups (P = .229). No febrile neutropenia events occurred. In HIV+ women, there were more CT cycle delays (P = .013), patients were more prone to use granulocyte colony-stimulating factor (G-CSF; HIV+ 40.0% vs HIV− 4.0%; P = .04) and less likely to complete at least 5 cycles of cisplatin (P = .02). All patients received adequate dose of pelvic RT, regardless of HIV status. HIV+ patients have a significantly increased risk of neutropenia during CRT treatment for CC and are less likely to complete chemotherapy with cisplatin.
- Collagen biology making inroads into prognosis and treatment of cancer progression and metastasisPublication . Martins Cavaco, Ana C.; Dâmaso, Sara; Casimiro, Sandra; Costa, LuisProgression through dissemination to tumor-surrounding tissues and metastasis development is a hallmark of cancer that requires continuous cell-to-cell interactions and tissue remodeling. In fact, metastization can be regarded as a tissue disease orchestrated by cancer cells, leading to neoplastic colonization of new organs. Collagen is a major component of the extracellular matrix (ECM), and increasing evidence suggests that it has an important role in cancer progression and metastasis. Desmoplasia and collagen biomarkers have been associated with relapse and death in cancer patients. Despite the increasing interest in ECM and in the desmoplastic process in tumor microenvironment as prognostic factors and therapeutic targets in cancer, further research is required for a better understanding of these aspects of cancer biology. In this review, published evidence correlating collagen with cancer prognosis is retrieved and analyzed, and the role of collagen and its fragments in cancer pathophysiology is discussed.
- Oncobiology and treatment of breast cancer in young womenPublication . Kumar, Rakesh; Marques, Catarina; Toi, Masakazu; Saini, Sunil; Casimiro, Sandra; Arora, Anshika; Paul, Aswathy Mary; Velaga, Ravi; Rameshwar, Pranela; Lipton, Allan; Gupta, Sudeep; Costa, LuisFemale breast cancer emerged as the leading cancer type in terms of incidence globally in 2020. Although mortality due to breast cancer has improved during the past three decades in many countries, this trend has reversed in women less than 40 years since the past decade. From the biological standpoint, there is consensus among experts regarding the clinically relevant definition of breast cancer in young women (BCYW), with an age cut-off of 40 years. The idea that breast cancer is an aging disease has apparently broken in the case of BCYW due to the young onset and an overall poor outcome of BCYW patients. In general, younger patients exhibit a worse prognosis than older pre- and postmenopausal patients due to the aggressive nature of cancer subtypes, a high percentage of cases with advanced stages at diagnosis, and a high risk of relapse and death in younger patients. Because of clinically and biologically unique features of BCYW, it is suspected to represent a distinct biologic entity. It is unclear why BCYW is more aggressive and has an inferior prognosis with factors that contribute to increased incidence. However, unique developmental features, adiposity and immune components of the mammary gland, hormonal interplay and crosstalk with growth factors, and a host of intrinsic and extrinsic risk factors and cellular regulatory interactions are considered to be the major contributing factors. In the present article, we discuss the status of BCYW oncobiology, therapeutic interventions and considerations, current limitations in fully understanding the basis and underlying cause(s) of BCYW, understudied areas of BCYW research, and postulated advances in the coming years for the field.
- The roadmap of RANKL/RANK pathway in cancerPublication . Casimiro, Sandra; Vilhais, Guilherme; Fernandes Gomes, Inês; Costa, LuisThe receptor activator of the nuclear factor-κB ligand (RANKL)/RANK signaling pathway was identified in the late 1990s and is the key mediator of bone remodeling. Targeting RANKL with the antibody denosumab is part of the standard of care for bone loss diseases, including bone metastases (BM). Over the last decade, evidence has implicated RANKL/RANK pathway in hormone and HER2-driven breast carcinogenesis and in the acquisition of molecular and phenotypic traits associated with breast cancer (BCa) aggressiveness and poor prognosis. This marked a new era in the research of the therapeutic use of RANKL inhibition in BCa. RANKL/RANK pathway is also an important immune mediator, with anti-RANKL therapy recently linked to improved response to immunotherapy in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). This review summarizes and discusses the pre-clinical and clinical evidence of the relevance of the RANKL/RANK pathway in cancer biology and therapeutics, focusing on bone metastatic disease, BCa onset and progression, and immune modulation.
- Immunotherapy around the clock: impact of infusion timing on stage IV melanoma outcomesPublication . Gonçalves, Lisa; Gonçalves, Duarte; Esteban-Casanelles, Teresa; Barroso, Tiago; Soares De Pinho, Inês; Lopes Brás, Raquel; Esperança Martins, Miguel; Patel, Vanessa; Torres, Sofia; Sousa, Rita Teixeira de; Mansinho, André; Costa, LuisAlthough the impact of circadian timing on immunotherapy has yet to be integrated into clinical practice, chronoimmunotherapy is an emerging and promising field as circadian oscillations are observed in immune cell numbers as well as the expression of immunotherapy targets, e.g., programmed cell death protein-1 and its ligand programmed death ligand 1. Concurrent retrospective studies suggest that morning infusions may lead to higher effectiveness of immune checkpoint inhibitors in melanoma, non-small cell lung cancer, and kidney cancer. This paper discusses the results of a retrospective study (2016-2022) exploring the impact of infusion timing on the outcomes of all 73 patients with stage IV melanoma receiving immunotherapy at a particular medical center. While the median overall survival (OS) was 24.2 months (95% confidence interval [CI] 9.04-39.8), for a median follow-up of 15.3 months, our results show that having more than 75% of infusions in the afternoon results in shorter median OS (14.9 vs. 38.1 months; hazard ratio 0.45 [CI 0.23-0.86]; p < 0.01) with more expressive impacts on particular subgroups: women, older patients, and patients with a lower tumor burden at the outset of immunotherapy. Our findings highlight the potential benefits of follow-up validation in prospective and translational randomized studies.
- Predictive and therapeutic implications of a novel PLCγ1/SHP2-driven mechanism of cetuximab resistance in metastatic colorectal cancerPublication . Duarte, Raquel; Rebelo de Almeida, Cátia; Negrão, Magda; Fernandes, Afonso; Borralho, Paula; Sobral, Daniel; Gallego-Paez, Lina M.; Machado, Daniel; Gramaça, João; Vílchez, José; Xavier, Ana T.; Ferreira, Miguel Godinho; Miranda, Ana R.; Mansinho, Helder; Brito, Maria J.; Pacheco, Teresa; Marques, Catarina; Lucia Costa, Ana; Mansinho, André; Fior, Rita; Costa, Luis; Martins, MartaPurpose: Cetuximab is an EGFR-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, it is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to overcome cetuximab resistance. Experimental design: We evaluated the value of EGFR effector phospholipase C gamma 1 (PLCγ1) in predicting cetuximab responses, by analyzing progression-free survival (PFS) of a multicentric retrospective cohort of 94 treated patients with mCRC (log-rank test and Cox regression model). Furthermore, we used in vitro and zebrafish xenotransplant models to identify and target the mechanism behind PLCγ1-mediated resistance to cetuximab. Results: In this study, levels of PLCγ1 were found increased in RAS WT tumors and were able to predict cetuximab responses in clinical samples and in vitro and in vivo models. Mechanistically, PLCγ1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLCγ1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCγ1-resistant cells to cetuximab. Conclusions: Our discoveries reveal the potential of PLCγ1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCγ1-mediated resistance to cetuximab in patients with RAS WT mCRC. In this way, this work contributes to the development of novel strategies in the medical management and treatment of patients with mCRC.
- Variation in type of adjuvant chemotherapy received among patients with stage I breast cancer: a multi-institutional Portuguese cohort studyPublication . Ferreira, Arlindo; Palha, Ana; Correia, Lurdes; Filipe, Pedro; Rodrigues, Vasco; Costa, Luis; Miranda, Ana; André, Rosário; Fernandes, João; Gouveia, Joaquim; Passos-Coelho, José Luís; Moreira, António; Brito, Margarida; Ribeiro, Joana; Metzger-Filho, Otto; U. Lin, Nancy; Vaz-Luís, InêsBackground: A contemporary US study showed an increase in the use of chemotherapy in the last decade for some patients with stage-I breast cancer; with a rise in more intensive regimens, and declining use of anthracyclines. Nevertheless, there is still uncertainty on the absolute benefit of chemotherapy for these patients and the optimal regimen. In this study we compare those findings with the patterns of care among a Portuguese cohort of stage-I breast cancers. Methods: Retrospective cohort study of patients with stage-I breast cancer diagnosed from 2006 to 2008 at four Portuguese institutions. The use and type of chemotherapy was evaluated. Results: Among patients with stage I-III breast cancer 39.4% (n = 682) had stage I disease. Of the 595 eligible patients, 22.4% were treated with chemotherapy, 33.9% aged <55 years vs. 12.7% aged >65 years (p < 0.001). Thirteen percent of patients with hormone receptor (HR)+/HER2- tumors, 52.7% of patients with HER2+ and 66.0% of patients with HR-/HER2- received chemotherapy (p < 0.001). In addition, we found inter-institutional variability, with the use of chemotherapy ranging from 0.0% to 43.4% (p < 0.001). Eighty-five percent of patients treated with chemotherapy received less-intensive regimens with anthracycline-based regimens, such as doxorubicin and cyclophosphamide, being the most frequently used, while docetaxel and cyclophosphamide was only used in 1.5% of cases. Conclusions: Overall, almost one-quarter of patients received chemotherapy with institutional variability. When treated, mostly less-intensive associations including anthracyclines were used, which contrasts with contemporary US practice. This study highlights the need for health-services research to understand local practices and tailor quality improvement interventions.
- Clinical validation of a size-based microfluidic device for circulating tumor cell isolation and analysis in renal cell carcinomaPublication . Palmela Leitão, Tito; Corredeira, Patrícia; Kucharczak, Sandra; Rodrigues, Margarida; Piairo, Paulina; Rodrigues, Carolina; Alves, Patrícia; Martins Cavaco, Ana Cláudia; Miranda, Miguel; Antunes, Marilia; Ferreira, João; Palma Dos Reis, José Manuel; Lopes, Tomé; Diéguez, Lorena; Costa, LuisRenal cell carcinoma (RCC) presents as metastatic disease in one third of cases. Research on circulating tumor cells (CTCs) and liquid biopsies is improving the understanding of RCC biology and metastases formation. However, a standardized, sensitive, specific, and cost-effective CTC detection technique is lacking. The use of platforms solely relying on epithelial markers is inappropriate in RCC due to the frequent epithelial-mesenchymal transition that CTCs undergo. This study aimed to test and clinically validate RUBYchip™, a microfluidic label-free CTC detection platform, in RCC patients. The average CTC capture efficiency of the device was 74.9% in spiking experiments using three different RCC cell lines. Clinical validation was performed in a cohort of 18 patients, eight non-metastatic (M0), five metastatic treatment-naïve (M1TN), and five metastatic progressing-under-treatment (M1TP). An average CTC detection rate of 77.8% was found and the average (range) total CTC count was 6.4 (0-27), 101.8 (0-255), and 3.2 (0-10), and the average mesenchymal CTC count (both single and clustered cells) was zero, 97.6 (0-255), and 0.2 (0-1) for M0, M1TN, and M1TP, respectively. CTC clusters were detected in 25% and 60% of M0 and M1TN patients, respectively. These results show that RUBYchip™ is an effective CTC detection platform in RCC.
- Low doses of ionizing radiation activate endothelial cells and induce angiogenesis in peritumoral tissuesPublication . Gil Marques, Filipa; Poli, Maria Esmeralda; Malaquias, João; Carvalho, Tânia; Portêlo, Ana; Ramires, Afonso; Aldeia, Fernando; Ribeiro, Ruy M.; Vitorino, Emília; Diegues, Isabel; Costa, Luis; Coutinho, João; Pina, Maria Filomena; Mareel, Marc; Santos, Susana Constantino RosaPurpose: During radiotherapy the peritumoral tissues are daily exposed to subtherapeutic doses of ionizing radiation. Herein, the biological and molecular effects of doses lower than 0.8 Gy per fraction (LDIR), previously described as angiogenesis inducers, were assessed in human peritumoral tissues. Material and methods: Paired biopsies of preperitoneal adipose tissue were surgically collected from 16 patients diagnosed with locally advanced rectal cancer who underwent neo-adjuvant radiotherapy. One of the biopsies is located in the vicinity of the region where the tumor received the prescribed dose of radiation, and thus exposed to LDIR; the other specimen, outside all beam apertures, was used as an internal calibrator (IC). Microvessel density (MDV) was quantified by immunohistochemistry and the expression of angiogenic, pro-inflammatory, adhesion and oxidative stress genes was assessed by quantitative RT-PCR using exclusively endothelial cells (ECs) isolated by laser capture microdissection microscopy. Results: LDIR activated peritumoral ECs by significantly up-regulating the expression of several pro-angiogenic genes such as VEGFR1, VEGFR2, ANGPT2, TGFB2, VWF, FGF2, HGF and PDGFC and down-regulating the pro-inflammatory IL8 marker. Accordingly, the MVD was significantly increased in peritumoral tissues exposed to LDIR, compared to the IC. The patients that yielded a larger pro-angiogenic response, also showed the highest MVD. Conclusions: LDIR activate ECs in peritumoral tissues that are associated with increased MVD. Although the technological advances in radiotherapy have contributed to reduce the damage to healthy tissues over the past years, the anatomical regions receiving LDIR should be taken into account in the treatment plan report for patient follow-up and in future studies to correlate these doses with tumor dissemination.
- Castration-resistant prostate cancer: mechanisms, targets, and treatmentPublication . Amaral, Teresa; Macedo, Daniela; Fernandes, Isabel; Costa, LuisPatients with castration-resistant prostate cancer (CRPC), who progress after docetaxel therapy, had until very recently, only a few therapeutic options. Recent advances in this field brought about new perspectives in the treatment of this disease. Molecular, basic, and translational research has given us a better understanding on the mechanisms of CRPC. This great investment has turned into a more rational approach to the development of new drugs. Some of the new treatments are already available to our patients outside clinical trials and may include inhibitors of androgen biosynthesis; new chemotherapy agents; bone-targeted therapy; and immunotherapy. This paper aims to review the mechanisms of prostate cancer resistance, possible therapeutic targets, as well as new options to treat CRPC.