CD19-CD28: an affinity-optimized CD28 agonist for combination with glofitamab (CD20-TCB) as off-the-shelf immunotherapy.

ABSTRACT: Effective T-cell responses not only require the engagement of T-cell receptors (TCRs; "signal 1"), but also the availability of costimulatory signals ("signal 2"). T-cell bispecific antibodies (TCBs) deliver a robust signal 1 by engaging the TCR signaling component CD3ε, while simultaneously binding to tumor antigens. The CD20-TCB glofitamab redirects T cells to CD20-expressing malignant B cells. Although glofitamab exhibits strong single-agent efficacy, adding costimulatory signaling may enhance the depth and durability of T-cell-mediated tumor cell killing. We developed a bispecific CD19-targeted CD28 agonist (CD19-CD28), RG6333, to enhance the efficacy of glofitamab and similar TCBs by delivering signal 2 to tumor-infiltrating T cells. CD19-CD28 distinguishes itself from the superagonistic antibody TGN1412, because its activity requires the simultaneous presence of a TCR signal and CD19 target binding. This is achieved through its engineered format incorporating a mutated Fc region with abolished FcγR and C1q binding, CD28 monovalency, and a moderate CD28 binding affinity. In combination with glofitamab, CD19-CD28 strongly increased T-cell effector functions in ex vivo assays using peripheral blood mononuclear cells and spleen samples derived from patients with lymphoma and enhanced glofitamab-mediated regression of aggressive lymphomas in humanized mice. Notably, the triple combination of glofitamab with CD19-CD28 with the costimulatory 4-1BB agonist, CD19-4-1BBL, offered substantially improved long-term tumor control over glofitamab monotherapy and respective duplet combinations. Our findings highlight CD19-CD28 as a safe and highly efficacious off-the-shelf combination partner for glofitamab, similar TCBs, and other costimulatory agonists. CD19-CD28 is currently in a phase 1 clinical trial in combination with glofitamab. This trial was registered at www.clinicaltrials.gov as #NCT05219513.

Off-label use of a vena caval filter in the SVC in an adolescent with upper deep vein thrombosis.

Vena caval filters remain as a useful tool in patients with deep vein thrombosis and contraindications to anticoagulation. Although they are rarely used in paediatric patients, they have been shown to be safe and effective when used in the inferior vena cava.In this case report, we describe the off-label use of a retrievable vena caval filter in the superior vena cava in an adolescent with acute lymphoblastic leukaemia with extensive thrombosis of the right upper neck veins as a means to reduce the risk of pulmonary embolism.

Repositioning an embolised stent during a percutaneous pulmonary valve implantation.

Percutaneous pulmonary valve implantation is a less invasive procedure to treat right outflow tract dysfunction related to surgical procedures such as repair of Tetralogy of Fallot. Despite the lower risks, complications have been reported, namely embolisation of the pre-stent. We report a case of a 16-year-old boy, whose procedure was complicated by embolisation of the pre-stents and the strategy used to reimplant them, prior to the successful implantation of a pulmonary valve.

The nucleolar protein Viriato/Nol12 is required for the growth and differentiation progression activities of the Dpp pathway during Drosophila eye development.

Drosophila Decapentaplegic (Dpp), a member of the BMP2/4 class of the TGF-ßs, is required for organ growth, patterning and differentiation. However, much remains to be understood about the mechanisms acting downstream of these multiple roles. Here we investigate this issue during the development of the Drosophila eye. We have previously identified viriato (vito) as a dMyc-target gene encoding a nucleolar protein that is required for proper tissue growth in the developing eye. By carrying out a targeted in vivo double-RNAi screen to identify genes and pathways functioning with Vito during eye development, we found a strong genetic interaction between vito and members of the Dpp signaling pathway including the TGF-ß receptors tkv (type I), put (type II), and the co-Smad medea (med). Analyzing the expression of the Dpp receptor Tkv and the activation pattern of the pathway's transducer, p-Mad, we found that vito is required for a correct signal transduction in Dpp-receiving cells. Overall, we validate the use of double RNAi to find specific genetic interactions and, in particular, we uncover a link between the Dpp pathway and Vito, a nucleolar component. vito would act genetically downstream of Dpp, playing an important role in maintaining a sufficient level of Dpp activity for the promotion of eye disc growth and regulation of photoreceptor differentiation in eye development.

The Drosophila Nol12 homologue viriato is a dMyc target that regulates nucleolar architecture and is required for dMyc-stimulated cell growth.

The nucleolus is a subnuclear factory, the activity of which is required beyond ribosome biogenesis for the regulation of cell growth, death and proliferation. In both Drosophila and mammalian cells, the activity of the nucleolus is regulated by the proto-oncogene Myc. Myc induces the transcription of genes required for ribosome biogenesis and the synthesis of rRNA by RNA polymerase I, a nucleolar event that is rate limiting for cell growth. Here, we show that the fruit fly Nol12 homologue Viriato is a key determinant of nucleolar architecture that is required for tissue growth and cell survival during Drosophila development. We further show that viriato expression is controlled by Drosophila Myc (dMyc), and that the ability of dMyc to stimulate nucleolar and cellular growth depends on viriato expression. Therefore, viriato acts downstream of dMyc to ensure a coordinated nucleolar response to dMyc-induced growth and, thereby, normal organ development.

Accidental finding of a giant right coronary artery aneurysm associated with a fistula to the right atrium.

Coronary artery fistulae are uncommon but may be haemodynamically significant, being an incidental finding in 0.1-0.2% of coronary angiograms. Even rarer is the association between fistulae and non-atherosclerotic coronary artery aneurysms. They most frequently originate in the right coronary artery, and the right cardiac chambers are the most common draining chambers. Most children are asymptomatic, whereas those older than 20 years may present with signs of congestive heart failure, infective endocarditis, myocardial ischaemia, or aneurysm rupture. Management is either surgical or via percutaneous means. We report the case of a 5-year-old child referred for assessment of an asymptomatic cardiac murmur. The echocardiographic evaluation showed an enlarged right atrium, a fenestrated atrial septal defect, and a giant right coronary artery aneurysm with a fistulous tract that appeared to drain directly into the right atrium. Computed angiocardiac tomography and cardiac catherisation confirmed the presence of a large right coronary fistula originating from the right coronary aneurysm draining into the right atrium. The patient underwent surgical ligation of the fistula and the post-operative course has been uneventful. He is currently on double antiaggregation therapy.

Retrospective study of cisplatin plus radiotherapy toxicities in locally advanced squamous cell carcinoma of the head and neck - ReCisTT study.

Introduction: Squamous cell carcinoma of the head and neck (SCCHN) is a multifactorial disease involving genetic and environmental factors representing one of the most frequent cancer-related deaths worldwide. Tobacco and alcohol use account for most SCCHN, while a growing subset of oropharyngeal cancers is causally associated with human papillomavirus (HPV) infection. Despite improvements in overall survival, patients with HPV-negative locally advanced (LA) SCCHN continue to have a poor prognosis. For these patients, the standard of care is radiotherapy with concurrent chemotherapy (RCT). Methods: This retrospective, multicenter, and observational study analyzed the treatment compliance of 326 patients with LA-SCCHN who underwent RCT between January 1st, 2014, and June 30th, 2017. This study also evaluated the potential factors associated with treatment compliance, the compliance impact on clinical response, and the main toxicities experienced by patients. Results: A total of 274 (84%) patients were compliant and received the planned dose of cisplatin. Overall, 957 adverse events were reported in 98.2% of patients during the study. The overall response rate was 80.2%, with 60.4% of patients achieving a complete response. Discussion: Despite the high treatment compliance, 62.6% of adverse events reported were related to cisplatin. Identifying risk factors associated with non-compliance could enable physicians to identify ineligible patients for cisplatin-based RCT and prevent patients from receiving inadequate treatment leading to severe adverse events..

Epidemiological and Clinical Aspects of Cutaneous and Mucosal Leishmaniases in Portugal: Retrospective Analysis of Cases Diagnosed in Public Hospitals and Reported in the Literature between 2010 and 2020.

Leishmania infantum, a zoonotic vector-born parasite, is endemic in the Mediterranean region, presenting mostly as visceral (VL), but also as cutaneous (CL) and mucosal leishmaniasis (ML). This study aimed to describe the epidemiological and clinical aspects of the CL and ML cases diagnosed in mainland Portugal between 2010 and 2020. Collaboration was requested from every hospital of the Portuguese National Health System. Cases were screened through a search of diagnostic discharge codes or positive laboratory results for Leishmania infection. Simultaneously, a comprehensive literature search was performed. Descriptive statistics and hypothesis testing were performed using IBM® SPSS® Statistics. A total of 43 CL and 7 ML cases were identified, with a predominance of autochthonous cases (86%). In CL, immunosuppressed individuals constituted a significant proportion of patients (48%), and in this group, disseminated CL (22%) and simultaneous VL (54%) were common. In autochthonous cases, lesions, mostly papules/nodules (62%), were frequently observed on the head (48%). The approach to treatment was very heterogeneous. ML cases were all autochthonous, were diagnosed primarily in older immunosuppressed individuals, and were generally treated with liposomal amphotericin B. The findings suggest a need for enhanced surveillance and reporting, clinical awareness, and diagnostic capacity of these forms of leishmaniasis to mitigate underdiagnosis and improve patient outcomes. A holistic One Health approach is advocated to address the multifaceted challenges posed by leishmaniases in Portugal and beyond.

[Infective endocarditis as a form of late presentation of congenital heart disease]. / Endocardite infecciosa como primeira manifestação de cardiopatia congénita de apresentação tardia.

A diagnosis of congenital heart disease is usually established at an early age, so infective endocarditis is a rare form of presentation. The authors describe the case of a male adolescent with a week-long history of intermittent fever and unquantified weight loss. Physical examination detected pansystolic and diastolic murmurs, and an associated precordial thrill. Laboratory tests showed evidence of an active infection. Etiological investigation revealed a perimembranous ventricular septal defect, aortic regurgitation, and aortic and mitral valve vegetations. A diagnosis of mitral-aortic infective endocarditis was made and he was started on intravenous antibiotics and anticongestive therapy. After initial clinical improvement, he developed symptoms and signs of congestive heart failure. Repeat echocardiography showed an extensive mitral-aortic paravalvular abscess. The antibiotics were changed and anticongestive therapy was intensified, and he subsequently underwent surgery. The outcome has been generally favorable, and at present he is asymptomatic under anticongestive therapy.

Geriatric Assessment of Older Adults With Cancer During Acute Hospitalizations: Challenges and Opportunities.

Introduction Geriatrics is a discipline that covers all adult healthcare, and oncology is no exception. The global geriatric assessment process plays a crucial role, impacting research, funding, resource allocation, as well as therapeutic decision-making. Thus, greater knowledge of the epidemiology of the frailty and functionality of elderly patients with cancer will allow for the development of a global care strategy. This study aimed to assess the prevalence of geriatric conditions in elderly cancer patients admitted to a medical geriatric unit following unplanned hospitalisation. Methods A retrospective, single-centre cohort study was conducted of patients aged ≥ 75 with an active oncological disease who were admitted to a geriatric medicine unit over a two-year period. Results A total of 65 patients were included. The median age was 85 (IQR 81-88), and 86% were aged ≥ 80. A moderate-to-high functional dependence was found: 67.7% on ≥ 3 basic activities of daily living (Katz ≥ D), with the majority classified as severely dependent based on the Barthel Index (mean 49.0 ± 33.7). Frailty was found in 90.7%. A high prevalence of geriatric syndromes was observed: malnutrition (84.6%), polypharmacy (64.6%), urinary incontinence (58.5%) and pressure ulcers (33.8%). The mortality rate was 36.9% during hospitalisation and 13.8%, 30 days post-discharge. Conclusions The study revealed a high prevalence of geriatric conditions, emphasising the importance of comprehensive assessment in managing elderly patients at different stages of the disease. This multidimensional and multidisciplinary approach optimises patient care throughout admission, hospitalisation and discharge.

A model-based approach leveraging in vitro data to support dose selection from the outset: A framework for bispecific antibodies in immuno-oncology.

FAP-4-1BBL is a bispecific antibody exerting 4-1BB-associated T-cell activation only while simultaneously bound to the fibroblast activation protein (FAP) receptor, expressed on the surface of cancer-associated fibroblasts. The trimeric complex formed when FAP-4-1BBL is simultaneously bound to FAP and 4-1BB represents a promising mechanism to achieve tumor-specific 4-1BB stimulation. We integrated in vitro data with mathematical modeling to characterize the pharmacology of FAP-4-1BBL as a function of trimeric complex formation when combined with the T-cell engager cibisatamab. This relationship was used to prospectively predict a range of clinical doses where trimeric complex formation is expected to be at its maximum. Depending on the dosing schedule and FAP-4-1BBL plasma: tumor distribution, doses between 2 and 145 mg could lead to maximum trimeric complex formation in the clinic. Due to the expected variability in both pharmacokinetic and FAP expression in the patient population, we predict that detecting a clear dose-response relationship would remain difficult without a large number of patients per dose level, highlighting that mathematical modeling techniques based on in vitro data could aid dose selection.

A DARPin promotes faster onset of botulinum neurotoxin A1 action.

In this study, we characterize Designed Ankyrin Repeat Proteins (DARPins) as investigative tools to probe botulinum neurotoxin A1 (BoNT/A1) structure and function. We identify DARPin-F5 that completely blocks SNAP25 substrate cleavage by BoNT/A1 in vitro. X-ray crystallography reveals that DARPin-F5 inhibits BoNT/A1 activity by interacting with a substrate-binding region between the α- and ß-exosite. This DARPin does not block substrate cleavage of BoNT/A3, indicating that DARPin-F5 is a subtype-specific inhibitor. BoNT/A1 Glu-171 plays a critical role in the interaction with DARPin-F5 and its mutation to Asp, the residue found in BoNT/A3, results in a loss of inhibition of substrate cleavage. In contrast to the in vitro results, DARPin-F5 promotes faster substrate cleavage of BoNT/A1 in primary neurons and muscle tissue by increasing toxin translocation. Our findings could have important implications for the application of BoNT/A1 in therapeutic areas requiring faster onset of toxin action combined with long persistence.

Digital health in geriatric oncology: A Young International Society of Geriatric Oncology review.

The integration of digital health technologies in geriatric oncology has the potential to enhance patient care and self-management. This review article discusses the applications of these technologies, including teleassessment, telemonitoring, and teleintervention, within geriatric oncology, and evaluates their potential to improve cancer care and patient outcomes. We also review challenges to the implementation of digital health technologies among populations of older patients with cancer. The article provides a perspective for clinicians, researchers, policymakers, and patients on the integration and utilisation of digital health technologies in current geriatric oncology practice.

Geriatric Oncology in Portugal: Where We Are and What Comes Next-A Survey of Healthcare Professionals.

In keeping with the trend worldwide, in Portugal, more than 60% of newly diagnosed patients with cancer are aged 65 years or older, which makes older adults the most common population seen in an oncology practice. This study's objectives were to assess geriatric oncology practices in Portugal and investigate medical professionals' current needs and perceptions on the treatment of elderly cancer patients. METHODS: A cross-sectional study was conducted using a web-based survey of healthcare providers treating elderly patients. RESULTS: There were 222 responses: 62.6% of physicians reported the absence of geriatric oncology and/or geriatrics consultations in their institutions, 14.9% had guidelines for the management of older patients with cancer and 4.5% had physicians dedicated to geriatric oncology. The reported use of geriatric assessment tools was 23.4%. Medical oncologists and physicians from medical specialties (p = 0.009) and those practicing in the south of Portugal (p = 0.054) were more likely to use geriatric assessment. Education and training in geriatric oncology was identified by 95.0% of respondents as an unmet need. The inquiries identified that geriatric assessment could be useful to define a therapeutic strategy (85.1%), detect frailty (77.5%), predict toxicity and improve quality of life (73.4%). CONCLUSIONS: There is a paucity of expertise and training in geriatric oncology in Portugal but an increasing perception of the value of geriatric assessment and the demand for education. In the next years, Portugal will progress in this area with the aid of the recently created Geriatric Oncology Working Group.

Transfusion practices in patients with advanced cancer: a retrospective study in a palliative care service.

Background: Anemia is highly prevalent in patients with advanced cancer and adversely affects the quality of life. There are limited data on the frequency, clinical utility, and effectiveness of red blood cell (RBC) transfusions, and no randomized controlled clinical trials or clinical practice guidelines are available. The aim of this study was to evaluate clinician practices on RBC transfusion in an oncologic palliative care service and its impact on patients' symptoms, adverse events, and overall survival. Methods: This is a retrospective analysis of all patients with advanced cancer who received RBC transfusions admitted for 3 years. Preblood counts, the reason for transfusion, subjective benefit, and objective outcomes were listed. Results: We identified 179 patients who underwent RBC transfusions. The mean age was 67 years, and 60% were male. We found a total of 435 RBC units in 301 transfusion episodes. Asthenia/fatigue was the most frequent symptom (68%). The mean pretransfusion hemoglobin (Hb) was 6.85 g/dL, and 48% of patients had a Hb above 7 g/dL. The symptomatic benefit was achieved in 36% of patients. Adverse events were reported in 4%, with a 30-day survival rate of 57%. A statistically significant association was found between Eastern Cooperative Oncology Group performance status (ECOG-PS) and the symptomatic benefit (P = .005). Hb level pretransfusion, ECOG-PS, and symptomatic benefits with transfusions were significantly associated with survival. Conclusion: This study suggests that patients with advanced cancer with a higher functioning level may benefit more from RBC transfusion. Post-transfusion symptomatic benefits and pretransfusion ECOG-PS and Hb levels are independent predictors of survival. Further studies are needed to develop validated measures of objective functional changes to evaluate transfusions' clinical impact and identify patients most likely to benefit from it.

Systemic treatment for triple negative breast cancer in older patients: A Young International Society of Geriatric Oncology Review Paper.

Breast cancer is the most common type of cancer affecting women worldwide and its risk increases with age. Compared with other breast cancer subtypes, triple negative breast cancer (TNBC) behaves more aggressively, with earlier relapses and poorer survival outcomes. Although the incidence of TNBC decreases with age, it still affects about 10% of older women with breast cancer. The management of TNBC in older patients is particularly challenging as chemotherapy is the main treatment choice in both early and advanced diseases and older patients are often prone to increased treatment-related toxicities. This review highlights the specific considerations in this vulnerable group of patients and summarizes the current evidence for TNBC management in older adults from early to late stage of disease.

Anal cancer in older adults: A Young International Society of Geriatric Oncology review paper.

Anal cancer is an uncommon malignancy, however, its incidence has been increasing worldwide, including among older adults. The care of older patients with anal cancer requires a multidisciplinary and comprehensive team approach to ensure improved outcomes and maintenance of quality of life, and the geriatric assessment should be a key component in the evaluation of every older patient with anal cancer. Despite older adults representing a large proportion of patients with anal cancer, they were underrepresented in trials that defined currently accepted standard therapies, including definitive chemoradiotherapy. Nonetheless, data from retrospective studies suggest that fit older patients with anal cancer should receive standard treatment similarly to their younger counterparts. This review describes the current knowledge regarding the management of anal cancer in older adults, including geriatric assessment, localized, recurrent/persistent, and metastatic disease.

The Evolution of Geriatric Oncology and Geriatric Assessment over the Past Decade.

Cancer is predominantly a disease of aging, and older adults represent the majority of cancer diagnoses and deaths. Older adults with cancer differ significantly from younger patients, leading to important distinctions in cancer treatment planning and decision-making. As a consequence, the field of geriatric oncology has blossomed and evolved over recent decades, as the need to bring personalized cancer care to older adults has been increasingly recognized and a focus of study. The geriatric assessment (GA) has become the cornerstone of geriatric oncology research, and the past year has yielded promising results regarding the implementation of GA into routine cancer treatment decisions and outcomes for older adults. In this article, we provide an overview of the field of geriatric oncology and highlight recent breakthroughs with the use of GA in cancer care. Further work is needed to continue to provide personalized, evidence-based care for each older adult with cancer.

Gastroesophageal adenocarcinoma in older adults: A comprehensive narrative review of management by the Young International Society of Geriatric Oncology.

Gastroesophageal adenocarcinoma is a disease of older adults with very poor survival rates. Its incidence has risen dramatically across the world in recent decades. Current treatment approaches for older adults are based largely on extrapolated evidence from clinical trials conducted in younger and fitter participants than those more commonly encountered in clinical practice. Understanding how to apply available evidence to our patients in the clinic setting is essential given the high morbidity of both curative and palliative treatment. This review aims to use available data to inform the management of an older adult with gastroesophageal adenocarcinoma.

Long-term response to avelumab and management of oligoprogression in Merkel cell carcinoma: A case report.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine neoplasia, with high risk of recurrence and metastasis and poor survival. Immune checkpoint inhibitors, like the anti-programmed death-ligand 1 agent avelumab, were recently approved for the treatment of advanced MCC. We, herein, report the first case of advanced MCC with oligoprogression managed with avelumab and local radical treatment. CASE SUMMARY: A 61-year-old man was presented to the hospital with sporadic fever and an exudative malodorous mass (10 cm of diameter), located on the right gluteal region. The final diagnosis was MCC, cT4N3M1c (AJCC, TNM staging 8th edition, 2017), with invasion of adjacent muscle, in-transit metastasis, and bone lesions. Patient started chemotherapy (cisplatin and etoposide), and after six cycles, the main tumor increased, evidencing disease progression. Two months later, the patient started second line treatment with avelumab (under an early access program). After two cycles of treatment, the lesion started to decrease, achieving a major response. Local progression was documented after 16 cycles. However, as the tumor became resectable, salvage surgery was performed, while keeping the systemic treatment with avelumab. Since the patient developed bilateral pneumonia, immunotherapy was suspended. More than 2.5 years after surgery (last 19 mo without systemic therapy), the patient maintains complete local response and stable bone lesions. CONCLUSION: This report highlights the efficacy and long-term response of avelumab on the management of a chemotherapy resistant advanced MCC, with evidence of oligoprogression, in combination with local radical treatment.