Instituto Português de Oncologia de Lisboa - IPO

Sclerosing mucoepidermoid carcinoma (SMEC) of the salivary glands is a rare variant of low-grade mucoepidermoid carcinoma with scanty cellular atypia characterized by marked fibrosis/sclerosis and a rich inflammatory infiltrate. Herein, we report 25 unpublished cases of SMEC, two of them with prominent eosinophilia (2/25; 8%) and three with abundant IgG4-positive plasma cells (3/25; 12%). In our series of salivary SMEC, molecular analysis using fluorescence in situ hybridization (FISH) and/or next-generation sequencing (NGS) provided evidence of MAML2 gene rearrangement in 18 cases of the 21 analyzable cases tested (86%), while this gene locus was intact in 3 cases (14%). This study focuses on the diagnostic criteria of salivary SMEC given its challenge of abundant collagenous stroma, minimal residual neoplastic areas, and inconspicuous mucous cells. Follow-up data of our cases indicate that salivary SMECs have favorable outcomes. Molecular analysis for MAML2 gene rearrangement suggests that SMECs of salivary glands represent a rare variant of conventional low-grade MECs of salivary glands. In contrast, SMECs of the thyroid gland are genetically distinct from salivary-type thyroid MECs.

Background/Objectives: Surgical procedures carry inherent risks, including injuries from surgical positioning, which impact patient safety and healthcare quality. An instrument to assess and prevent these injuries is essential. This study aimed to validate and culturally adapt the ELPO-PT for the Portuguese population to ensure its applicability and effectiveness in assessing the risk of injury from surgical positioning. Methods: A validation study was conducted with 126 adult patients undergoing surgical procedures at a central hospital in northern Portugal. Statistical analyses, including the calculation of Cronbach’s alpha coefficient, assessed the internal reliability of the scale. Additionally, sensitivity and specificity analyses evaluated the ELPO-PT’s diagnostic accuracy in identifying patients at risk of developing positioning-related injuries. Results: The validation showed a Cronbach’s alpha coefficient of 0.782, indicating reasonable internal reliability. Sensitivity analysis revealed an 85% accuracy rate in identifying patients at risk of positioning injuries, while specificity analysis demonstrated a 90% accuracy rate for patients not at risk. Conclusions: The ELPO-PT is a valid and reliable instrument for aiding nurses in clinical decision-making, with significant sensitivity and specificity in identifying the risk of positioning-related injuries, including pressure ulcers, in adult patients during the intraoperative period. Its implementation is expected to be beneficial in healthcare settings, contributing to the prevention of complications associated with surgical positioning.

Background Neurofibromatosis type 1 (NF1) is a common genetic disorder of phenotypic variability with age-dependent penetrance. This study describes the diagnosis, clinical characterization, management, and outcomes of a large patient cohort with plexiform neurofibroma (PN) treated with selumetinib in a real-world clinical setting. Methods This single-center observational study consecutively enrolled patients with NF1-PN treated with selumetinib from April 2018 to 2023. Data on clinical features, tumor types and locations, and results from genetic tests were recorded at baseline; details of disease management with selumetinib and surgical intervention and disease evolution including imaging data and evaluations of pain and function were documented. Results Overall, 54 patients with a median age (range) of 16.4 (4.5–58.0) years were enrolled. Most had cutaneous manifestations (88.9%), including cutaneous neurofibromas and PN. Patients underwent [18F]fluorodeoxyglucose (FDG)-PET/CT imaging before treatment to rule out malignant lesions. Initial evaluations included directed magnetic resonance imaging (MRI), which facilitated future comparisons and allowed for the assessment of PN resectability. Pharmacological treatment with selumetinib (with surgery, without surgery) resulted in the following proportion of patients achieving stable disease (58.8%, 54.3%), partial response (29.4%, 28.6%), and improved pain (58.8%, 37.1%), deformity (17.6%, 20.0%), and functional (17.6%, 20.0%) outcomes, respectively. Conclusions Results from this study demonstrate that NF1-PN can be managed effectively with selumetinib with surgical intervention in some patients. Most patients achieved tumor stability and improved symptom control, and the majority of patients continue under treatment. Effective diagnosis and management were achieved through individualized utility of FDG-PET/CT and MRI imaging and targeted resource allocation.

Objectives Patients with multiple myeloma often require multiple treatment lines. The order in which treatments are sequenced has impact on clinical outcomes. This study aimed to estimate progression‐free survival (PFS) and overall survival (OS) with common treatment sequences used in Portugal and the incremental benefit of an optimal sequence in transplant‐ineligible patients with multiple myeloma. Methods A state‐transition sequential model with a five‐health state conceptual structure was developed to simulate and compare survival outcomes between treatment sequences up to four lines of treatments. Data sources included randomized clinical trials and indirect treatment comparisons. A panel of Portuguese hematologists listed four most common treatment sequences and optimal sequence of choice in transplant‐ineligible patients. Results Our simulation estimated an OS between 6.1 and 7.8 years using the most common sequences, with VMP + DRd + Pd + Kd as the most effective (7.8 years). Optimal sequence of choice (DRd + PVd + Kd + Vd) achieved OS of 9.8 years and may extend OS in 2.0–3.7 years vs. most common sequences (26%–61% increase). This benefit was mostly explained by extended PFS in the first line of treatment. Conclusion Model results demonstrate that choosing the most effective treatment upfront is crucial in delaying disease progression thus yielding better survival outcomes in transplant‐ineligible patients. There was a clear survival benefit in using daratumumab‐based regimens in first line. This modelling exercise highlights the need to raise awareness around the impact of sequencing strategies to improve patient's outcomes.

Introduction: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Surgery is the standard of care with curative intent of localized disease; however, for large head and neck cSCCs, it is associated with high morbidity. Cemiplimab, an antibody anti programmed cell death-1 (PD-1) protein, is effective in locally advanced unresectable or metastatic cSCC. A pilot study demonstrated a high rate of pathologic complete response using cemiplimab in the neoadjuvant setting. Case Presentation: Here, we report the case of an 84-year-old man with two locally advanced unresectable cSCCs (a nasolabial lesion and a retroauricular lesion) treated with cemiplimab, for whom closer follow-up revealed a complete response of the retroauricular lesion and a partial response of the nasolabial lesion after 4 cycles. Patient will be submitted to nasolabial lesion resection. Conclusion: This illustrates the efficacy of the use of cemiplimab as preoperative therapy in advanced unresectable cSCC, facilitating a definitive surgical treatment.

Summary Background Surgical site infection preventions bundles have been used to reduce infection rate in most types of surgery. In colorectal surgery they have been used with success as well, with tailored care bundles designed for that purpose. Aim To identify and review the individual interventions that constitute each infection prevention care bundle in colorectal surgery, and the surgical site infection rate reduction related to their implementation. Methods A scoping review was conducted in PUBMED, CINAHL; Web of Science Core Collection and Scopus databases, during December 2022. Results This review analysed 48 of 164 identified studies on surgical site infection (SSI) prevention in colorectal surgery from 2011 to 2022. It revealed an average of 11 interventions per study, primarily in preoperative (mechanical bowel preparation, oral antibiotic bowel decontamination, hair removal, CHG showers, normoglycemia), intraoperative (antibiotic prophylaxis, normothermia, CHG skin preparation, antibiotic prophylaxis re-dosing, gown/glove change), and postoperative phases (normothermia, normoglycemia, dressing removal, oxygen optimization, incision cleansing). Despite these interventions, SSI rates remain high, indicating a need for further research to optimize intervention bundles and improve compliance across surgical stages. Conclusions The implementation of Surgical Site Infection prevention bundles, tailored to Colorectal surgery, have shown a reduction in surgical site infection rates and costs. Grouping intervention according to the perioperative phase, may contribute to increased compliance rates.

Artificial intelligence (AI) has emerged as a transformative tool across several specialties, namely gastroenterology, where it has the potential to optimize both diagnosis and treatment as well as enhance patient care. Coloproctology, due to its highly prevalent pathologies and tremendous potential to cause significant mortality and morbidity, has drawn a lot of attention regarding AI applications. In fact, its application has yielded impressive outcomes in various domains, colonoscopy being one prominent example, where it aids in the detection of polyps and early signs of colorectal cancer with high accuracy and efficiency. With a less explored path but equivalent promise, AI-powered capsule endoscopy ensures accurate and time-efficient video readings, already detecting a wide spectrum of anomalies. High-resolution anoscopy is an area that has been growing in interest in recent years, with efforts being made to integrate AI. There are other areas, such as functional studies, that are currently in the early stages, but evidence is expected to emerge soon. According to the current state of research, AI is anticipated to empower gastroenterologists in the decision-making process, paving the way for a more precise approach to diagnosing and treating patients. This review aims to provide the state-of-the-art use of AI in coloproctology while also reflecting on future directions and perspectives.

This systematic review aims to explore the diagnostic criteria, epidemiology, etiology, and prognosis of Human Papillomavirus (HPV) infection in lung cancer. This PRISMA-guided review searched the PubMed® and EmbaseTM databases for “lung cancer AND HPV” on 10 June 2023, filtering human subject papers. A total of 97 studies encompassing 9098 patients worldwide, revealing varied HPV infection rates in lung cancer, ranging from 0% to 69%, were analyzed. While HPV16/18 was predominant in some regions, its association with lung cancer remained inconclusive due to conflicting findings. Studies from Asia reported lower HPV infection rates compared to Western populations. Some studies suggested a limited role of HPV in lung carcinogenesis, particularly in non-smokers. However, intriguing associations were noted, including HPV’s potential role in lung adenocarcinoma and squamous cell carcinoma. Discrepancies in HPV detection methods and sample sources highlight the need for further research with standardized methodologies to elucidate HPV’s role in lung carcinogenesis and its clinical implications. Overall, this systematic review offers insights into HPV’s role in lung cancer epidemiology and clinical characteristics. Despite inconclusive evidence, intriguing associations between HPV and lung adenocarcinoma and squamous cell carcinoma have emerged. Further research with standardized methodologies and larger cohorts is needed for clarity.

Sex Cord Tumors with Annular Tubules (SCTAT) are a very rare type of non-epithelial ovarian cancer, in one third of cases associated with Peutz-Jegher Syndrome (PJS). The diagnosis is histopathological and challenging due to their rarity. Surgery is the mainstay of treatment. Although there is a high rate of recurrence, the prognosis is relatively favorable. 34 year-old female, presenting with acute abdominal pain, increased abdominal volume and a one year long history of amenorrhea. Computed Tomography (CT) showed a voluminous left adnexal tumor and para-aortic, iliac and mediastinal lymph node enlargement. The intraoperative pathology examination was compatible with a sex cord tumor, apparently confined to the left ovary, so conservative surgery was performed with peritoneal staging. The histopathological examination of the specimen was diagnostic of SCTAT. SCTAT are a very rare ovarian neoplasm, which makes diagnosis and treatment difficult, due to the lack of evidence. Some retrospective studies, based on case reports, have been performed, but there is still a need for further investigations for optimal care.

Busulfan (Bu) is an important component of many conditioning regimens for allogeneic hematopoietic cell transplantation. The therapeutic window of Bu is well characterized, with strong associations between Bu exposure and the clinical outcome in adults (strongest evidence in myelo-ablative setting) and children (all settings). We provide an overview of the literature on Bu as well as a step-by-step guide to the implementation of Bu therapeutic drug monitoring (TDM). The guide covers the clinical, pharmacological, laboratory and administrative aspects of the procedure. Through this document, we aim to support centers in implementing TDM for Bu to further enhance the success rates of HCT and improve patient outcomes. The Pharmacist Committee of the European Society for Blood and Marrow Transplantation (EBMT) encourages all centers to perform TDM for Bu in the aforementioned indications.

The genetic basis of nonsyndromic familial nonmedullary thyroid carcinoma (FNMTC) is still poorly understood, as the susceptibility genes identified so far only account for a small percentage of the genetic burden. Recently, germline mutations in DNA repair‐related genes have been reported in cases with thyroid cancer. In order to clarify the genetic basis of FNMTC, 94 genes involved in hereditary cancer predisposition, including DNA repair genes, were analyzed in 48 probands from FNMTC families, through targeted next‐generation sequencing (NGS). Genetic variants were selected upon bioinformatics analysis and in silico studies. Structural modeling and network analysis were also performed. In silico results of NGS data unveiled likely pathogenic germline variants in 15 families with FNMTC, in genes encoding proteins involved in DNA repair (ATM, CHEK2, ERCC2, BRCA2, ERCC4, FANCA, FANCD2, FANCF, and PALB2) and in the DICER1, FLCN, PTCH1, BUB1B, and RHBDF2 genes. Structural modeling predicted that most missense variants resulted in the disruption of networks of interactions between residues, with implications for local secondary and tertiary structure elements. Functional annotation and network analyses showed that the involved DNA repair proteins functionally interact with each other, within the same DNA repair pathway and across different pathways. MAPK activation was a common event in tumor progression. This study supports that rare germline variants in DNA repair genes may be accountable for FNMTC susceptibility, with potential future utility in patients' clinical management, and reinforces the relevance of DICER1 in disease etiology.

Medication-related osteonecrosis of the jaw (MRONJ) is a rare condition, typically seen in patients receiving antiresorptive or antiangiogenic drugs. This study aims to synthesize reports and case series of MRONJ regarding sociodemographic and clinical characteristics and to evaluate the effectiveness of the treatments applied. Following PRISMA guidelines, a search for case reports and case series was carried out in the PubMed-Medline database until March 2024. A total of 88 articles were included in this review, in a total of 151 cases. The key findings reveal that females were the most affected individuals (71% of the cases) with the average age at diagnosis being 66.27 years with a standard deviation of ±13.03. Stage 2 was the most observed stage, in 43% of cases, and zoledronic acid was the most commonly used drug (32% of cases). The oral route was the most common route of administration, in 26% of cases, with an average administration duration of 60.88 months (standard deviation ± 50.92). The mandible was the most commonly affected anatomical location (in 60% of cases). Amoxicillin + clavulanic acid (875 mg + 125 mg) and chlorhexidine (0.12%) were the most used antibiotics and mouthwash, with 16% and 26% of the cases, respectively. Surgical debridement was the most common surgical procedure, in 32% of cases, while the use of an L-PRF membrane was the most prevalent unconventional treatment, in 21% of cases. This study identified a statistically significant relationship between unconventional treatments and the cure of MRONJ (p < 0.001), indicating the need for further research to confirm these results.

Purpose Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive malignancies. Our previous work revealed Chitinase 3-like 1 (CHI3L1) involvement in PDAC resistance to gemcitabine, identifying it as a promising therapeutic target. Here, we aimed to identify putative CHI3L1 inhibitors and to investigate their chemosensitizing potential in PDAC. Methods Docking analysis for CHI3L1 identified promising CHI3L1 inhibitors, including darifenacin (muscarinic receptor antagonist). PDAC cell lines (BxPC-3, PANC-1) and primary PDAC cells were used to evaluate darifenacin’s effects on cell growth (Sulforhodamine B, SRB), alone or in combination with gemcitabine or gemcitabine plus paclitaxel. Cytotoxicity against normal immortalized pancreatic ductal cells (HPNE) was assessed. Recombinant protein was used to confirm the impact of darifenacin on CHI3L1-induced PDAC cellular resistance to therapy (SRB assay). Darifenacin’s effect on Akt activation was analysed by ELISA. The association between cholinergic receptor muscarinic 3 (CHRM3) expression and therapeutic response was evaluated by immunohistochemistry of paraffin-embedded tissues from surgical resections of a 68 patients’ cohort. Results In silico screening revealed the ability of darifenacin to target CHI3L1 with high efficiency. Darifenacin inhibited PDAC cell growth, with a GI50 of 26 and 13.6 µM in BxPC-3 and PANC-1 cells, respectively. These results were confirmed in primary PDAC-3 cells, while darifenacin showed no cytotoxicity against HPNE cells. Importantly, darifenacin sensitized PDAC cells to standard chemotherapies, reverted CHI3L1-induced PDAC cellular resistance to therapy, and decreased Akt phosphorylation. Additionally, high CHMR3 expression was associated with low therapeutic response to gemcitabine. Conclusion This work highlights the potential of darifenacin as a chemosensitizer for PDAC treatment.