Practical management of disease-related manifestations and drug toxicities in patients with multiple myeloma.

Multiple myeloma (MM) is a very heterogeneous disease with multiple symptoms and clinical manifestations. MM affects mainly elderly patients and is difficult to manage in the presence of comorbidities, polypharmacy, frailty and adverse events of disease-targeted drugs. The rapid changes in MM treatment resulting from constant innovations in this area, together with the introduction of numerous new drugs with distinct mechanisms of action and toxicity profiles, have led to an increased complexity in the therapeutic decision-making and patient management processes. The prolonged exposure to novel agents, sometimes in combination with conventional therapies, makes this management even more challenging. A careful balance between treatment efficacy and its tolerability should be considered for every patient. During treatment, a close monitoring of comorbidities, disease-related manifestations and treatment side effects is recommended, as well as a proactive approach, with reinforcement of information and patient awareness for the early recognition of adverse events, allowing prompt therapeutic adjustments. In this review, we discuss various issues that must be considered in the treatment of MM patients, while giving practical guidance for monitoring, prevention and management of myeloma-related manifestations and treatment-related toxicities.

Intraoperative Angle Measurement of Anatomical Structures: A Systematic Review.

Ensuring precise angle measurement during surgical correction of orientation-related deformities is crucial for optimal postoperative outcomes, yet there is a lack of an ideal commercial solution. Current measurement sensors and instrumentation have limitations that make their use context-specific, demanding a methodical evaluation of the field. A systematic review was carried out in March 2023. Studies reporting technologies and validation methods for intraoperative angular measurement of anatomical structures were analyzed. A total of 32 studies were included, 17 focused on image-based technologies (6 fluoroscopy, 4 camera-based tracking, and 7 CT-based), while 15 explored non-image-based technologies (6 manual instruments and 9 inertial sensor-based instruments). Image-based technologies offer better accuracy and 3D capabilities but pose challenges like additional equipment, increased radiation exposure, time, and cost. Non-image-based technologies are cost-effective but may be influenced by the surgeon's perception and require careful calibration. Nevertheless, the choice of the proper technology should take into consideration the influence of the expected error in the surgery, surgery type, and radiation dose limit. This comprehensive review serves as a valuable guide for surgeons seeking precise angle measurements intraoperatively. It not only explores the performance and application of existing technologies but also aids in the future development of innovative solutions.

[Multiple Myeloma Treatment Guidelines by the Portuguese Group of Multiple Myeloma]. / Recomendações do Grupo Português do Mieloma Múltiplo para Tratamento do Mieloma Múltiplo.

The treatment of multiple myeloma has profoundly changed with the introduction of several innovative therapies. The optimization of therapeutic sequencing through the combined use of the various drugs developed in recent years and the attention given to the characteristics of patients have allowed the reduction of toxicities and increased survival and quality of life of patients with multiple myeloma. These treatment recommendations from the Portuguese Multiple Myeloma Group offer guidance for first-line treatment and progression/relapse situations. These recommendations are given highlighting the data that justify each choice and referring to the respective levels of evidence that support these options. Whenever possible, the respective national regulatory framework is presented. These recommendations constitute an advance towards the best treatment of multiple myeloma in Portugal.

O tratamento do mieloma múltiplo tem sido amplamente alterado com introdução de várias terapêuticas inovadoras. A otimização da sequenciação terapêutica através do uso combinado dos vários fármacos desenvolvidos nos últimos anos e a atenção dada às características dos doentes têm permitido diminuir toxicidades e aumentar a sobrevivência dos doentes, bem como aumentar a sua qualidade de vida. As presentes recomendações terapêuticas do Grupo Português do Mieloma Múltiplo oferecem orientações para o tratamento de primeira linha e progressão/recaída. As recomendações são fundamentadas evidenciando os dados que justificam cada escolha e referindo os respetivos níveis de evidência que suportam essas opções. Sempre que possível é apresentado o respetivo enquadramento regulamentar nacional. Estas recomendações constituem um avanço para o melhor tratamento do mieloma múltiplo em Portugal.

Case Report of an Osteochondral Lesion of the First Metatarsal Head in an Adolescent Patient Treated by Autograft Mosaicplasty: Surgical Technique and Decision-Making Rationale.

Introduction: First metatarsophalangeal (MTP) joint mobility is critical to a normal gait pattern; therefore, osteochondral defects (OCDs) of the first metatarsal head should be treated promptly to avoid functional limitation and progression to hallux rigidus. <15 cases of OCDs of the first MTP joint in the pediatric population, predominantly adolescents, have been published so far. The purpose of this article is to present a rare case of an adolescent first MTP joint OCD treated by the technique of autograft osteochondral mosaicplasty, which has been commonly used for OCDs of the knee and talus but scarcely described for the first MTP joint. Case Report: The case of a 13-year-old male futsal player with a post-traumatic 50 mm2 OCD of the first metatarsal head is presented. The Osteochondral Autograft Transfer System® (Arthrex Inc™, Naples, FL) was used to harvest a 10-mm diameter donor plug from the medial ipsilateral femoral condyle, then delivered to the first metatarsal head. At the 6-month follow-up, physical activity had been resumed with no pain or significant mobility limitation and an improvement of the American Orthopedic Foot and Ankle Society hallux score of 54-95 points. At the same time, a follow-up magnetic resonance showed complete incorporation of the osteochondral graft without bone edema or subchondral osteonecrosis. Conclusion: Treatment for osteochondral lesions, regardless of their location, aims to restore function by recreating the articular congruity reducing the potential for a progressive degenerative process. Multiple surgical treatment options exist for OCDs of the first metatarsal head. The treatment decision must take into consideration both patient factors and lesion factors. Based on this, a literature revision and treatment decision rationale are presented. This case demonstrated that an osteochondral transplant could be a reasonable treatment option for a traumatic, full-thickness OCD of the first metatarsal head in adolescent patients.

Evaluation of Semiautomatic and Deep Learning-Based Fully Automatic Segmentation Methods on [18F]FDG PET/CT Images from Patients with Lymphoma: Influence on Tumor Characterization.

The objective is to assess the performance of seven semiautomatic and two fully automatic segmentation methods on [18F]FDG PET/CT lymphoma images and evaluate their influence on tumor quantification. All lymphoma lesions identified in 65 whole-body [18F]FDG PET/CT staging images were segmented by two experienced observers using manual and semiautomatic methods. Semiautomatic segmentation using absolute and relative thresholds, k-means and Bayesian clustering, and a self-adaptive configuration (SAC) of k-means and Bayesian was applied. Three state-of-the-art deep learning-based segmentations methods using a 3D U-Net architecture were also applied. One was semiautomatic and two were fully automatic, of which one is publicly available. Dice coefficient (DC) measured segmentation overlap, considering manual segmentation the ground truth. Lymphoma lesions were characterized by 31 features. Intraclass correlation coefficient (ICC) assessed features agreement between different segmentation methods. Nine hundred twenty [18F]FDG-avid lesions were identified. The SAC Bayesian method achieved the highest median intra-observer DC (0.87). Inter-observers' DC was higher for SAC Bayesian than manual segmentation (0.94 vs 0.84, p < 0.001). Semiautomatic deep learning-based median DC was promising (0.83 (Obs1), 0.79 (Obs2)). Threshold-based methods and publicly available 3D U-Net gave poorer results (0.56 ≤ DC ≤ 0.68). Maximum, mean, and peak standardized uptake values, metabolic tumor volume, and total lesion glycolysis showed excellent agreement (ICC ≥ 0.92) between manual and SAC Bayesian segmentation methods. The SAC Bayesian classifier is more reproducible and produces similar lesion features compared to manual segmentation, giving the best concordant results of all other methods. Deep learning-based segmentation can achieve overall good segmentation results but failed in few patients impacting patients' clinical evaluation.

Patient-Derived Extracellular Vesicles Proteins as New Biomarkers in Multiple Myeloma - A Real-World Study.

Multiple myeloma (MM) is a hematological malignancy of clonal antibody-secreting plasma cells (PCs). MM diagnosis and risk stratification rely on bone marrow (BM) biopsy, an invasive procedure prone to sample bias. Liquid biopsies, such as extracellular vesicles (EV) in peripheral blood (PB), hold promise as new minimally invasive tools. Real-world studies analyzing patient-derived EV proteome are rare. Here, we characterized a small EV protein content from PB and BM samples in a cohort of 102 monoclonal gammopathies patients routinely followed in the clinic and 223 PB and 111 BM samples were included. We investigated whether EV protein and particle concentration could predict an MM patient prognosis. We found that a high EV protein/particle ratio, or EV cargo >0.6 µg/108 particles, is related to poorer survival and immune dysfunction. These results were supported at the protein level by mass spectrometry. We report a set of PB EV-proteins (PDIA3, C4BPA, BTN1A1, and TNFSF13) with a new biomarker potential for myeloma patient outcomes. The high proteomic similarity between PB and BM matched pairs supports the use of circulating EV as a counterpart of the BM EV proteome. Overall, we found that the EV protein content is related to patient outcomes, such as survival, immune dysfunction, and possibly treatment response.

Multiple Myeloma in Portugal: Burden of Disease and Cost of Illness.

BACKGROUND: Multiple myeloma (MM) is the second most common hematological cancer worldwide and has significant morbidity and mortality and is increasing in incidence. While MM management costs are considerable, specific economic data at the country level remain scarce. OBJECTIVE: This study assesses the burden and cost of MM in Portugal from the perspective of the National Health Service (NHS) to support the definition of health policies, resource allocation and patient care. METHODS: Developed by the Portuguese Multiple Myeloma Group, this study considers the most recent available data. Burden of disease was measured using disability-adjusted life-years (DALYs). The cost of MM was estimated using a prevalence-based model that estimated direct costs for the NHS considering all costs associated with diagnosis, hospitalizations, surgeries, emergency visits, medical appointments, drugs and transportation. Costs were quantified based on the diagnosis-related group funding price, except for drug usage, which was calculated using the average hospital product stock price. RESULTS: The burden of disease attributable to MM for 2018 was estimated at 8931 DALYs: 8570 resulting from premature deaths and 361 from disability. Average yearly direct costs per patients with MM amounted to €31,449 (year 2018 values). Total direct costs are estimated at €61 million per year. CONCLUSIONS: The mortality rate in MM means that most DALYs are due to years of life lost rather than years lost due to disability. This study generates comprehensive data on the burden and cost of MM in Portugal and provides updated insights into the costs associated with the management of MM.

Practical Considerations for the Daratumumab Management in Portuguese Routine Clinical Practice: Recommendations From an Expert Panel of Hematologists.

The recent therapeutic progress in multiple myeloma (MM) has led to the introduction of novel and highly potent drug classes. Daratumumab was the first CD38-targeting antibody showing to be effective and safe in MM patients as monotherapy and in combination regimens, which led to its rapid implementation in clinical practice. Considering that treatment discontinuation for drug-related adverse events can impact patients' quality of life and outcomes, the treatment decision should consider different factors and be weighted for each patient individually. Here, we aimed to guide clinicians using daratumumab treatment for MM by addressing practical real-world considerations based on an expert panel of Portuguese hematologists. Carefully following the recommendations mentioned in daratumumab's SmPC, and of those from other drugs used in combination regimens, along with ensuring a good communication with all healthcare professionals involved, is critical to prevent any complications arising from treatment. The risk of infection should be assessed for all patients under treatment with daratumumab and patients should be educated on the potential adverse events. Recommendations on prophylaxis and vaccination should be considered to avoid infections, and delays in the planned therapeutic schedule may be required to prevent adverse consequences of hematological toxicity. Daratumumab treatment is effective and feasible in patients with renal impairment, although careful patient monitoring and a frequent communication with the Nephrology department are of the utmost importance. Sharing clinical practice plays an important role in medical education by allowing to maximize treatment efficacy and minimize its safety risks.

Management of older and frail patients with multiple myeloma in the Portuguese routine clinical practice: Deliberations and recommendations from an expert panel of hematologists.

The management of older patients with Multiple Myeloma (MM) is particularly challenging due to the highly heterogeneous nature of this population, both in terms of physical and cognitive functioning. Older patients may be divided into fit, intermediate and frail, with variable abilities to tolerate treatments. A careful and correct assessment of the frailty status is thus paramount for the success of therapy and for improving outcomes. With the aging of the European population, the number of older patients with MM is rapidly growing. We hereby present the deliberations and recommendations from an expert panel of Portuguese hematologists conducted to discuss the management of this population, including how to stratify and treat older patients with MM according to their frailty status. The use of frailty tools is critical for the development of individualized risk-adapted treatment strategies and to minimize the risk of under or overtreatment. Aggressive therapies should be used in fitter patients to improve survival outcomes, while frail patients should generally be treated with less toxic approaches to control symptoms while minimizing toxicity. In intermediate-fit patients, low-dose triplets are recommended to achieve a balance between improving survival and maintaining quality of life. The management of older patients with MM should be performed by a multidisciplinary team in view of their advanced age and high prevalence of comorbidities. The inclusion of older and frail patients in future clinical trials investigating treatment regimens for MM is crucial to evaluate treatment feasibility and to improve clinical decision making in this population.

Tendency towards operative treatment is increasing in children's fractures: results obtained from patient databases, causes, impact of evidence-based medicine.

Results of numerous studies assessing the national or the local patient databases in several countries have indicated that the overall rate of operative treatment in fractures, as well as the rate in certain upper and lower limb fractures, has significantly increased in children. The most prominent increase in the rate of operative treatment was observed in forearm shaft fractures.Results of several survey studies have revealed that there was not a high level of agreement among paediatric orthopaedic surgeons concerning treatment preferences for several children's fractures.The reasons for the increasing tendency towards operative treatment are multifactorial and patient-, parent- and surgeon-dependent factors as well as technological, economic, social, environmental and legal factors seem to have an impact on this trend.It is obvious that evidence-based medicine is not the only factor that leads to this tendency. A high level of scientific evidence is currently lacking to support the statement that operative treatment really leads to better long-term outcomes in children's fractures. Properly designed multicentre clinical trials are needed to determine the best treatment options in many fractures in children. Cite this article: EFORT Open Rev 2020;5:347-353. DOI: 10.1302/2058-5241.5.200012.

Multiple myeloma in elderly patients-a Portuguese multicentric real-life study.

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.

Exploring sialyl-Tn expression in microfluidic-isolated circulating tumour cells: A novel biomarker and an analytical tool for precision oncology applications.

Circulating tumour cells (CTCs) originating from a primary tumour, lymph nodes and distant metastases hold great potential for liquid biopsies by providing a molecular fingerprint for disease dissemination and its temporal evolution through the course of disease management. CTC enumeration, classically defined on the basis of surface expression of Epithelial Cell Adhesion Molecule (EpCAM) and absence of the pan-leukocyte marker CD45, has been shown to correlate with clinical outcome. However, existing approaches introduce bias into the subsets of captured CTCs, which may exclude biologically and clinically relevant subpopulations. Here we explore the overexpression of the membrane protein O-glycan sialyl-Tn (STn) antigen in advanced bladder and colorectal tumours, but not in blood cells, to propose a novel CTC isolation technology. Using a size-based microfluidic device, we show that the majority (>90%) of CTCs isolated from the blood of patients with metastatic bladder and colorectal cancers express the STn antigen, supporting a link with metastasis. STn+ CTC counts were significantly higher than EpCAM-based detection in colorectal cancer, providing a more efficient cell-surface biomarker for CTC isolation. Exploring this concept, we constructed a glycan affinity-based microfluidic device for selective isolation of STn+ CTCs and propose an enzyme-based strategy for the recovery of viable cancer cells for downstream investigations. Finally, clinically relevant cancer biomarkers (transcripts and mutations) in bladder and colorectal tumours, were identified in cells isolated by microfluidics, confirming their malignant origin and highlighting the potential of this technology in the context of precision oncology.

Over forty years of bladder cancer glycobiology: Where do glycans stand facing precision oncology?

The high molecular heterogeneity of bladder tumours is responsible for significant variations in disease course, as well as elevated recurrence and progression rates, thereby hampering the introduction of more effective targeted therapeutics. The implementation of precision oncology settings supported by robust molecular models for individualization of patient management is warranted. This effort requires a comprehensive integration of large sets of panomics data that is yet to be fully achieved. Contributing to this goal, over 40 years of bladder cancer glycobiology have disclosed a plethora of cancer-specific glycans and glycoconjugates (glycoproteins, glycolipids, proteoglycans) accompanying disease progressions and dissemination. This review comprehensively addresses the main structural findings in the field and consequent biological and clinical implications. Given the cell surface and secreted nature of these molecules, we further discuss their potential for non-invasive detection and therapeutic development. Moreover, we highlight novel mass-spectrometry-based high-throughput analytical and bioinformatics tools to interrogate the glycome in the postgenomic era. Ultimately, we outline a roadmap to guide future developments in glycomics envisaging clinical implementation.

Sialyl-Tn identifies muscle-invasive bladder cancer basal and luminal subtypes facing decreased survival, being expressed by circulating tumor cells and metastases.

OBJECTIVES: To evaluate the potential of sialyl-Tn (STn), a cancer-associated glycan antigen present in membrane glycoproteins, to improve a recent molecular model for stratification and prognostication of advanced stage bladder tumors based on keratins (KRT14, 5, and 20) expression. In addition, determine the association between STn and disease dissemination based on the evaluation of circulating tumor cells (CTCs) and the metastasis, which is a critical matter to improve patient management. PATIENTS AND METHODS: A retrospective series of 80 muscle-invasive primary bladder tumors and associated metastasis were screened for KRT14, 5, and 20 and STn by real-time polymerase chain reaction and immunohistochemistry. Peripheral blood was collected in a patients' subset, CTCs were isolated through a size-based microfluidic chip and screened for KRTs and STn. RESULTS: Basal-like lesions presented worse cancer-specific and disease-free survival compared to luminal tumors. STn antigen inclusion discriminated patients with worst survival in each subgroup (P = 0.047 for luminal; P = 0.027 for basal-like tumors). STn expression in CTCs and distant metastasis was also demonstrated. CONCLUSION: This work reinforces the potential of the KRT-based model for bladder cancer management and the association of STn with aggressiveness, supporting its inclusion in predictive molecular models toward patient-tailored precision medicine. Moreover, we describe for the first time that CTCs and the metastasis present a basal phenotype and express the STn antigen, highlighting its link with disease dissemination. Future studies should focus on determining the biological and clinical significance of these observations in the context of liquid biopsies. Given the membrane nature of STn, highly specific targeted therapeutics may also be envisaged.

On the utility of 3D hand cursors to explore medical volume datasets with a touchless interface.

Analyzing medical volume datasets requires interactive visualization so that users can extract anatomo-physiological information in real-time. Conventional volume rendering systems rely on 2D input devices, such as mice and keyboards, which are known to hamper 3D analysis as users often struggle to obtain the desired orientation that is only achieved after several attempts. In this paper, we address which 3D analysis tools are better performed with 3D hand cursors operating on a touchless interface comparatively to a 2D input devices running on a conventional WIMP interface. The main goals of this paper are to explore the capabilities of (simple) hand gestures to facilitate sterile manipulation of 3D medical data on a touchless interface, without resorting on wearables, and to evaluate the surgical feasibility of the proposed interface next to senior surgeons (N=5) and interns (N=2). To this end, we developed a touchless interface controlled via hand gestures and body postures to rapidly rotate and position medical volume images in three-dimensions, where each hand acts as an interactive 3D cursor. User studies were conducted with laypeople, while informal evaluation sessions were carried with senior surgeons, radiologists and professional biomedical engineers. Results demonstrate its usability as the proposed touchless interface improves spatial awareness and a more fluent interaction with the 3D volume than with traditional 2D input devices, as it requires lesser number of attempts to achieve the desired orientation by avoiding the composition of several cumulative rotations, which is typically necessary in WIMP interfaces. However, tasks requiring precision such as clipping plane visualization and tagging are best performed with mouse-based systems due to noise, incorrect gestures detection and problems in skeleton tracking that need to be addressed before tests in real medical environments might be performed.

Targeted O-glycoproteomics explored increased sialylation and identified MUC16 as a poor prognosis biomarker in advanced-stage bladder tumours.

Bladder carcinogenesis and tumour progression is accompanied by profound alterations in protein glycosylation on the cell surface, which may be explored for improving disease management. In a search for prognosis biomarkers and novel therapeutic targets we have screened, using immunohistochemistry, a series of bladder tumours with differing clinicopathology for short-chain O-glycans commonly found in glycoproteins of human solid tumours. These included the Tn and T antigens and their sialylated counterparts sialyl-Tn(STn) and sialyl-T(ST), which are generally associated with poor prognosis. We have also explored the nature of T antigen sialylation, namely the sialyl-3-T(S3T) and sialyl-6-T(S6T) sialoforms, based on combinations of enzymatic treatments. We observed a predominance of sialoglycans over neutral glycoforms (Tn and T antigens) in bladder tumours. In particular, the STn antigen was associated with high-grade disease and muscle invasion, in accordance with our previous observations. The S3T and S6T antigens were detected for the first time in bladder tumours, but not in healthy urothelia, highlighting their cancer-specific nature. These glycans were also overexpressed in advanced lesions, especially in cases showing muscle invasion. Glycoproteomic analyses of advanced bladder tumours based on enzymatic treatments, Vicia villosa lectin-affinity chromatography enrichment and nanoLC-ESI-MS/MS analysis resulted in the identification of several key cancer-associated glycoproteins (MUC16, CD44, integrins) carrying altered glycosylation. Of particular interest were MUC16 STn+ -glycoforms, characteristic of ovarian cancers, which were found in a subset of advanced-stage bladder tumours facing the worst prognosis. In summary, significant alterations in the O-glycome and O-glycoproteome of bladder tumours hold promise for the development of novel noninvasive diagnostic tools and targeted therapeutics. Furthermore, abnormal MUC16 glycoforms hold potential as surrogate biomarkers of poor prognosis and unique molecular signatures for designing highly specific targeted therapeutics.

Reference Genes for Addressing Gene Expression of Bladder Cancer Cell Models under Hypoxia: A Step Towards Transcriptomic Studies.

Highly aggressive, rapidly growing tumors contain significant areas of hypoxia or anoxia as a consequence of inadequate and/or irregular blood supply. During oxygen deprivation, tumor cells withstand a panoply of adaptive responses, including a shift towards anaerobic metabolism and the reprogramming of the transcriptome. One of the major mediators of the transcriptional hypoxic response is the hypoxia-inducible factor 1 (HIF-1), whose stabilization under hypoxia acts as an oncogenic stimulus contributing to chemotherapy resistance, invasion and metastasis. Gene expression analysis by qRT-PCR is a powerful tool for cancer cells phenotypic characterization. Nevertheless, as cells undergo a severe transcriptome remodeling.in response to oxygen deficit, the precise identification of reference genes poses a significant challenge for hypoxic studies. Herein, we aim to establish the best reference genes for studying the effects of hypoxia on bladder cancer cells. Accordingly, three bladder cancer cell lines (T24, 5637, and HT1376) representative of two distinct carcinogenesis pathways to invasive cancer (FGFR3/CCND1 and E2F3/RB1) were used. Additionally, we have explored the most suitable control gene when addressing the influence of Deferoxamine Mesilate salt (DFX), an iron chelator often used to avoid the proteasomal degradation of HIF-1α, acting as an hypoxia-mimetic agent. Using bioinformatics tools (GeNorm and NormFinder), we have elected B2M and HPRT as the most stable genes for all cell lines and experimental conditions out of a panel of seven putative candidates (HPRT, ACTB, 18S, GAPDH, TBP, B2M, and SDHA). These observations set the molecular basis for future studies addressing the effect of hypoxia and particularly HIF-1α in bladder cancer cells.

Hypoxia enhances the malignant nature of bladder cancer cells and concomitantly antagonizes protein O-glycosylation extension.

Invasive bladder tumours express the cell-surface Sialyl-Tn (STn) antigen, which stems from a premature stop in protein O-glycosylation. The STn antigen favours invasion, immune escape, and possibly chemotherapy resistance, making it attractive for target therapeutics. However, the events leading to such deregulation in protein glycosylation are mostly unknown. Since hypoxia is a salient feature of advanced stage tumours, we searched into how it influences bladder cancer cells glycophenotype, with emphasis on STn expression. Therefore, three bladder cancer cell lines with distinct genetic and molecular backgrounds (T24, 5637 and HT1376) were submitted to hypoxia. To disclose HIF-1α-mediated events, experiments were also conducted in the presence of Deferoxamine Mesilate (Dfx), an inhibitor of HIF-1α proteasomal degradation. In both conditions all cell lines overexpressed HIF-1α and its transcriptionally-regulated protein CA-IX. This was accompanied by increased lactate biosynthesis, denoting a shift toward anaerobic metabolism. Concomitantly, T24 and 5637 cells acquired a more motile phenotype, consistent with their more mesenchymal characteristics. Moreover, hypoxia promoted STn antigen overexpression in all cell lines and enhanced the migration and invasion of those presenting more mesenchymal characteristics, in an HIF-1α-dependent manner. These effects were reversed by reoxygenation, demonstrating that oxygen affects O-glycan extension. Glycoproteomics studies highlighted that STn was mainly present in integrins and cadherins, suggesting a possible role for this glycan in adhesion, cell motility and invasion. The association between HIF-1α and STn overexpressions and tumour invasion was further confirmed in bladder cancer patient samples. In conclusion, STn overexpression may, in part, result from a HIF-1α mediated cell-survival strategy to adapt to the hypoxic challenge, favouring cell invasion. In addition, targeting STn-expressing glycoproteins may offer potential to treat tumour hypoxic niches harbouring more malignant cells.

Lenalidomide is effective and safe for the treatment of patients with relapsed multiple myeloma and very severe renal impairment.

Patients with multiple myeloma (MM) and severe renal impairment (SRI) have shorter survival than MM patients without renal failure. Although lenalidomide is a highly active drug, this immunomodulatory agent is frequently neglected in this context due to its predominant renal clearance and, consequently, an increased risk of toxicity. This risk might be overcome with the proper lenalidomide dose adjustment to renal function. This study evaluates the outcomes of 23 relapsed MM patients with SRI (baseline creatinine clearance (CrCl) <30 mL/min) treated with lenalidomide-dexamethasone (LenDex), including 56 % (13 patients) under hemodialysis. The median CrCl at start of LenDex was 19 mL/min; an overall response rate (partial response or better) of 56 % was obtained, with a median follow-up from start of LenDex of 52 months (8-79). The median time until maximal response was 4 months, and in 58 % (7/12), the response was longer than 2 years. Nine percent had renal improvement, but all the 13 patients on hemodialysis remained under treatment. LenDex was interrupted in three cases because of adverse events (infections and cutaneous events); 78 % of the patients were on thromboprophylaxis with aspirin. It is important to notice that, after initial dose adjustment of therapy, there should be a continuous process of dose adjustment, taking into account variations in renal function. Furthermore, lenalidomide dose adjustment should be made according to the individual tolerance, even with stable renal function. LenDex dose adjustment, according to these principles, does not negatively impact response and improves treatment tolerance. It has a clear potential to treat this group of patients and to induce long duration of responses [event-free survival (EFS) 20.5 m and overall survival (OS) 42.6 m].