Development and Validation of a Scoring System to Predict Response to Obeticholic Acid in Primary Biliary Cholangitis.

BACKGROUND & AIMS: Obeticholic acid (OCA) is the only licensed second-line therapy for primary biliary cholangitis (PBC). With novel therapeutics in advanced development, clinical tools are needed to tailor the treatment algorithm. We aimed to derive and externally validate the OCA response score (ORS) for predicting the response probability of individuals with PBC to OCA. METHODS: We used data from the Italian RECAPITULATE (N = 441) and the IBER-PBC (N = 244) OCA real-world prospective cohorts to derive/validate a score including widely available variables obtained either pre-treatment (ORS) or also after 6 months of treatment (ORS+). Multivariable Cox regressions with backward selection were applied to obtain parsimonious predictive models. The predicted outcomes were biochemical response according to POISE (alkaline phosphatase [ALP]/upper limit of normal [ULN]<1.67 with a reduction of at least 15%, and normal bilirubin), or ALP/ULN<1.67, or normal range criteria (NR: normal ALP, alanine aminotransferase [ALT], and bilirubin) up to 24 months. RESULTS: Depending on the response criteria, ORS included age, pruritus, cirrhosis, ALP/ULN, ALT/ULN, GGT/ULN, and bilirubin. ORS+ also included ALP/ULN and bilirubin after 6 months of OCA therapy. Internally validated c-statistics for ORS were 0.75, 0.78, and 0.72 for POISE, ALP/ULN<1.67, and NR response, which raised to 0.83, 0.88, and 0.81 with ORS+, respectively. The respective performances in validation were 0.70, 0.72, and 0.71 for ORS and 0.80, 0.84, and 0.78 for ORS+. Results were consistent across groups with mild/severe disease. CONCLUSIONS: We developed and externally validated a scoring system capable to predict OCA response according to different criteria. This tool will enhance a stratified second-line therapy model to streamline standard care and trial delivery in PBC.

Characterizing Hepatitis Delta in Spain and the gaps in its management.

BACKGROUND AND AIMS: Chronic hepatitis D (CHD) is a severe form of chronic viral hepatitis. The estimated hepatitis delta prevalence in Spain is around 5% of patients with hepatitis B. Reimbursement of new antiviral therapies (Bulevirtide, BLV) was delayed in our country until February 2024. We aimed to characterize the clinical profile of patients with HDV/HBV infection in Spain and current barriers in their management at the time of BLV approval. METHOD: Multicenter registry including patients with positive anti-HDV serology actively monitored in 30 Spanish centers. Epidemiological, clinical and virological variables were recorded at the start of follow-up and at the last visit. RESULTS: We identified 329 anti-HDV patients, 41% were female with median age 51 years. The most common geographical origin was Spain (53%) and East Europe (24%). Patients from Spain were older and had HCV and HIV coinfection probably associated to past drug injection (p<0.01). HDV-RNA was positive in 138 of 221 assessed (62%). Liver cirrhosis was present at diagnosis in 33% and it was more frequent among viremic patients (58% vs 25%, p<0.01). After a median follow-up of 6 (3-12) years, 44 (16%) resolved infection (18 spontaneously and 26 after Peg-INF). An additional 10% of patients developed cirrhosis (n=137) during follow-up (45% had portal hypertension and 14% liver decompensation). Liver disease progression was associated to persisting viremia. CONCLUSION: One-third of the patients with CHD already have cirrhosis at diagnosis. Persistence of positive viremia is associated to rapid liver disease progression. Importantly, barriers to locally determine/quantify HDV-RNA were present.

ProFUSO: Business process and ontology-based framework to develop ubiquitous computing support systems for chronic patients' management.

New advances in telemedicine, ubiquitous computing, and artificial intelligence have supported the emergence of more advanced applications and support systems for chronic patients. This trend addresses the important problem of chronic illnesses, highlighted by multiple international organizations as a core issue in future healthcare. Despite the myriad of exciting new developments, each application and system is designed and implemented for specific purposes and lacks the flexibility to support different healthcare concerns. Some of the known problems of such developments are the integration issues between applications and existing healthcare systems, the reusability of technical knowledge in the creation of new and more sophisticated systems and the usage of data gathered from multiple sources in the generation of new knowledge. This paper proposes a framework for the development of chronic disease support systems and applications as an answer to these shortcomings. Through this framework our pursuit is to create a common ground methodology upon which new developments can be created and easily integrated to provide better support to chronic patients, medical staff and other relevant participants. General requirements are inferred for any support system from the primary attention process of chronic patients by the Business Process Management Notation. Numerous technical approaches are proposed to design a general architecture that considers the medical organizational requirements in the treatment of a patient. A framework is presented for any application in support of chronic patients and evaluated by a case study to test the applicability and pertinence of the solution.

Interferon-Free Therapy in Elderly Patients With Advanced Liver Disease.

OBJECTIVES: Interferon-free therapies have an improved safety and efficacy profile. However, data in elderly patients, who have frequently advanced liver disease, associated comorbidities, and use concomitant medications are scarce. The im of this study was to assess the effectiveness and tolerability of all-oral regimens in elderly patients in real-life clinical practice. METHODS: Retrospective analysis of hepatitis C virus (HCV) patients aged ≥65 years receiving interferon-free regimens within the Spanish National Registry (Hepa-C). RESULTS: Data of 1,252 patients were recorded. Of these, 955 (76%) were aged 65-74 years, 211 (17%) were aged 75-79 years, and 86 (7%) were aged ≥80 years at the start of antiviral therapy. HCV genotype-1b was predominant (88%) and 48% were previous non-responders. A significant proportion of patients had cirrhosis (922; 74%), of whom 11% presented decompensated liver disease. The most used regimens were SOF/LDV (33%), 3D (28%), and SOF/SMV (26%). Ribavirin was added in 49% of patients. Overall, the sustained virological response (SVR12) rate was 94% without differences among the three age categories. Albumin ≤3.5 g/dl was the only independent negative predictor of response (0.25 (0.15-0.41); P<0.01). Regarding tolerability, the rate of severe adverse events increased with age category (8.8, 13, and 14%; P=0.04). In addition, the main predictors of mortality (2.3%) were age ≥75 years (2.59 (1.16-5.83); P =0.02) and albumin ≤3.5 (17 (6.3-47); P <0.01). CONCLUSIONS: SVR rates with interferon-free regimens in elderly patients are high and comparable to the general population. Baseline low albumin levels (≤3.5 g/dl) was the only predictor of treatment failure. Importantly, the rate of severe adverse events and death increased with age. Elderly patients (≥75 years) or those with advanced liver disease (albumin ≤3.5) presented higher mortality. Thus a careful selection of patients for antiviral treatment is recommended.

Achieving complete metabolic response in stage IV lung adenocarcinoma with chemotherapy, nivolumab, ipilimumab, and salvage SBRT: A case report.

Oncogene-negative, PDL1-negative metastatic non-small cell lung cancer (NSCLC) presents significant treatment challenges due to its complexity and resistance to conventional therapies. The case report presented addresses a 55-year-old male patient with oncogene-negative, PDL1-negative stage IV lung adenocarcinoma, showcasing an exceptional complete metabolic response to a multimodality treatment combining double immune checkpoint inhibition (ICI) and chemotherapy, followed by salvage stereotactic body radiotherapy (SBRT). The patient underwent a treatment regimen incorporating two cycles of carboplatin, pemetrexed, nivolumab, and ipilimumab followed by nivolumab, and ipilimumab maintenance. After a partial response, SBRT was applied to persistent lesions, achieving a complete metabolic response. This case highlights the potential of combining dual ICI with chemotherapy and SBRT in treating oncogene-negative, PDL1-negative NSCLC underscoring the importance of multimodality treatment strategies.

High-grade neuroendocrine head and neck cancer: Case series and review of the literature.

BACKGROUND: High-grade neuroendocrine cancers (NEC) of the head and neck (HN) are rare and aggressive, accounting for ≤1 % of all HN cancers, with a 5-year overall survival (OS) of ≤20 %. This case series examines clinical characteristics, treatments, and outcomes of patients diagnosed at a regional UK HN cancer centre over the last 23 years. METHODS: A retrospective review of medical records was conducted for all patients diagnosed with NEC HN from 1st January 2000 until 1st March 2023 at Velindre Cancer Centre. RESULTS: During the study period, 19 cases of NEC HN were identified, primarily affecting males (n = 15, 79 %). Median age of 67 years (range: 44-86). At diagnosis, 32 % of patients (n = 6) were smokers. The most common primary tumour sites were larynx (n = 5, 26.3 %) and sinonasal (n = 5, 26.3 %). Most patients presented with advanced loco-regional disease or distant metastasis, with stage IVA (n = 6, 32 %) and stage IVC (n = 6, 32 %) being the most common. The key pathology marker was synaptophysin, present in 100 % of the tested patients (n = 15). In the study, of the 12 patients with non-metastatic disease, 10 received a combination of treatments that included radiotherapy (RT). Some of these patients also received chemotherapy (CT) at the same time as their radiotherapy. Surgery alone was used in two patients with stage II disease. Seven subjects had complete responses, and one achieved a partial response. Among the seven metastatic patients, three received CT, and one underwent palliative RT, all achieving a partial response. In all cases, the CT used was carboplatin and etoposide. After a median follow-up of 11 months (range: 1-96), the median OS was 27 months for the overall population, 51 months for those treated radically, and three months for metastatic patients with palliative treatment. The 1-year OS for all patients was 54.3 %, the 2-year OS was 46.5 %, and the 5-year OS was 23.3 %. Among patients treated radically, these rates were 65.3 %, 52.2 %, and 26.1 %, respectively. For patients treated palliatively, the 1-year OS was 33.3 %. CONCLUSION: This case series contributes preliminary observations on the characteristics and management of non-metastatic NEC HN, suggesting potential benefits from multimodality treatment strategies. Given the small cohort size, these observations should be interpreted cautiously and seen as a foundation for further research.

Global Stage Distribution of Breast Cancer at Diagnosis: A Systematic Review and Meta-Analysis.

Importance: Stage at diagnosis is a key prognostic factor for cancer survival. Objective: To assess the global distribution of breast cancer stage by country, age group, calendar period, and socioeconomic status using population-based data. Data Sources: A systematic search of MEDLINE and Web of Science databases and registry websites and gray literature was conducted for articles or reports published between January 1, 2000, and June 20, 2022. Study Selection: Reports on stage at diagnosis for individuals with primary breast cancer (C50) from a population-based cancer registry were included. Data Extraction and Synthesis: Study characteristics and results of eligible studies were independently extracted by 2 pairs of reviewers (J.D.B.F., A.D.A., A.M., R.S., and F.G.). Stage-specific proportions were extracted and cancer registry data quality and risk of bias were assessed. National pooled estimates were calculated for subnational or annual data sets using a hierarchical rule of the most relevant and high-quality data to avoid duplicates. Main Outcomes and Measures: The proportion of women with breast cancer by (TNM Classification of Malignant Tumors or the Surveillance, Epidemiology, and End Results Program [SEER]) stage group. Results: Data were available for 2.4 million women with breast cancer from 81 countries. Globally, the proportion of cases with distant metastatic breast cancer at diagnosis was high in sub-Saharan Africa, ranging from 5.6% to 30.6% and low in North America ranging from 0.0% to 6.0%. The proportion of patients diagnosed with distant metastatic disease decreased over the past 2 decades from around 3.8% to 35.8% (early 2000s) to 3.2% to 11.6% (2015 onwards), yet stabilization or slight increases were also observed. Older age and lower socioeconomic status had the largest proportion of cases diagnosed with distant metastatic stage ranging from 2.0% to 15.7% among the younger to 4.1% to 33.9% among the oldest age group, and from 1.7% to 8.3% in the least disadvantaged groups to 2.8% to 11.4% in the most disadvantaged groups. Conclusions and Relevance: Effective policy and interventions have resulted in decreased proportions of women diagnosed with metastatic breast cancer at diagnosis in high-income countries, yet inequality persists, which needs to be addressed through increased awareness of breast cancer symptoms and early detection. Improving global coverage and quality of population-based cancer registries, including the collection of standardized stage data, is key to monitoring progress.

Single­nucleotide polymorphisms in the promoter of the gene encoding for C­reactive protein associated with acute coronary syndrome.

Acute coronary syndrome (ACS) is a leading cause of mortality worldwide. Several studies have shown that certain single nucleotide polymorphisms (SNPs) are linked to the development of ACS. In particular, C-reactive protein (CRP) has emerged as an important predictive biomarker for cardiovascular disease. The current study aimed to investigate four polymorphisms of the CRP gene as possible biomarkers for ACS in a sample of 252 individuals (114 patients with ACS and 138 healthy controls) from Southeastern Mexico. Multivariate analysis adjusted for clinical variables showed that the polymorphism 3872CT for the genotype CC/CT [adjusted Odds Ratio (AdOR)=3.78; 95% Confidence Interval (CI): 1.11-12.92; P=0.034] and the genotype GG/GC of the polymorphisms 2667CG (AdOR=4.82; 95% CI: 1.69-13.72; P=0.02) were associated with ACS. However, the polymorphisms 3006AC genotype AA/AC and 5237GA genotype GG/GC were not found to be associated in the multivariate analysis with ACS (P>0.05). These results suggested that 3872CC/CT and 2667CC/CG polymorphism of the CRP gene plays a significant role in the development of ACS.

The Missed Opportunity: HIV, Hepatitis C Virus (HCV), and Hepatitis B Virus (HBV) Positive Patients in Neoadjuvant and Perioperative Immunotherapy Clinical Trials for Lung Cancer.

This editorial addresses a critical oversight in recent clinical trials on neoadjuvant or perioperative immunotherapy for lung cancer, the exclusion of patients with human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV). The ethical implications of this exclusion are highlighted, demonstrating how it undermines principles of inclusivity and equity in clinical research. We emphasize the necessity to include these patients to enhance the generalizability of trial findings. We suggest that trial eligibility criteria be revised, and collaborations with patient advocacy groups be initiated to ensure more inclusive future trials. This approach aims to uphold ethical research practices, yielding robust, representative data, and ultimately improving patient care in oncology.

Prognostic value of human leukocyte antigen G expression in solid tumors: a systematic review and meta-analysis.

Introduction: Identification of modulators of the immune response with inhibitory properties that could be susceptible for therapeutic intervention is a key goal in cancer research. An example is the human leukocyte antigen G (HLA-G), a nonclassical major histocompatibility complex (MHC) class I molecule, involved in cancer progression. Methods: In this article we performed a systematic review and meta-analysis on the association between HLA-G expression and outcome in solid tumors. This study was performed in accordance with PRISMA guidelines and registered in PROSPERO. Results: A total of 25 studies met the inclusion criteria. These studies comprised data from 4871 patients reporting overall survival (OS), and 961 patients, reporting disease free survival (DFS). HLA-G expression was associated with worse OS (HR 2.09, 95% CI = 1.67 to 2.63; P < .001), that was higher in gastric (HR = 3.40; 95% CI = 1.64 to 7.03), pancreatic (HR = 1.72; 95% CI = 0.79 to 3.74) and colorectal (HR = 1.55; 95% CI = 1.16 to 2.07) cancer. No significant differences were observed between the most commonly utilized antibody (4H84) and other methods of detection. HLA-G expression was associated with DFS which approached but did not meet statistical significance. Discussion: In summary, we describe the first meta-analysis associating HLA-G expression and worse survival in a variety of solid tumors. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022311973.

Clinical Experience with Abemaciclib in Patients Previously Treated with Another CDK 4/6 Inhibitor in a Tertiary Hospital: A Case Series Study.

The three approved cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including abemaciclib, have shown differences in their preclinical, pharmacological, and clinical data. Abemaciclib stands out for its broader target range and more rapid and intense activity. It has demonstrated efficacy as a monotherapy or in combination with tamoxifen in endocrine-refractory metastatic breast cancer (MBC) patients with prior chemotherapy. However, the clinical data on abemaciclib after exposure to previous CDK4/6 inhibitors are limited. In this single-center retrospective case series, we identified all patients who received abemaciclib until February 2022 after experiencing documented progression on palbociclib or ribociclib. The safety profile and clinical outcomes of abemaciclib treatment in this specific patient cohort were evaluated. Eleven patients were included in this retrospective case series, nine receiving abemaciclib with tamoxifen. Eight patients had visceral involvement, and the median age was 69 (ranging from 42 to 84). The median time from the end of prior CDK4/6 inhibitor treatment to abemaciclib initiation was 17.5 months (ranging from 3 to 41 months). Patients had undergone a median of three prior therapies (ranging from 1 to 7), including chemotherapy in 54.5% of cases. The median follow-up time was six months (ranging from 1 to 22 months). The median progression-free survival (PFS) was 8 months (95% CI 3.9-12). Five patients continued abemaciclib treatment, and one patient with liver metastases achieved a complete hepatic response. The most common adverse events were diarrhea (72.7%, no grade ≥ 3) and asthenia (27.3%, no grade ≥ 3). Our preliminary findings suggest that abemaciclib could be an effective and safe treatment option for MBC patients who have previously received palbociclib or ribociclib.

Specific Cellular and Humoral Immune Responses to the Neoantigen RBD of SARS-CoV-2 in Patients with Primary and Secondary Immunodeficiency and Healthy Donors.

Patients with antibody deficiency disorders, such as primary immunodeficiency (PID) or secondary immunodeficiency (SID) to B-cell lymphoproliferative disorder (B-CLPD), are two groups vulnerable to developing the severe or chronic form of coronavirus disease caused by SARS-CoV-2 (COVID-19). The data on adaptive immune responses against SARS-CoV-2 are well described in healthy donors, but still limited in patients with antibody deficiency of a different cause. Herein, we analyzed spike-specific IFN-γ and anti-spike IgG antibody responses at 3 to 6 months after exposure to SARS-CoV-2 derived from vaccination and/or infection in two cohorts of immunodeficient patients (PID vs. SID) compared to healthy controls (HCs). Pre-vaccine anti-SARS-CoV-2 cellular responses before vaccine administration were measured in 10 PID patients. Baseline cellular responses were detectable in 4 out of 10 PID patients who had COVID-19 prior to vaccination, perceiving an increase in cellular responses after two-dose vaccination (p < 0.001). Adequate specific cellular responses were observed in 18 out of 20 (90%) PID patients, in 14 out of 20 (70%) SID patients and in 74 out of 81 (96%) HCs after vaccination (and natural infection in some cases). Specific IFN-γ response was significantly higher in HC with respect to PID (1908.5 mUI/mL vs. 1694.1 mUI/mL; p = 0.005). Whereas all SID and HC patients mounted a specific humoral immune response, only 80% of PID patients showed positive anti-SARS-CoV-2 IgG. The titer of anti-SARS-CoV-2 IgG was significantly lower in SID compared with HC patients (p = 0.040), without significant differences between PID and HC patients (p = 0.123) and between PID and SID patients (p =0.683). High proportions of PID and SID patients showed adequate specific cellular responses to receptor binding domain (RBD) neoantigen, with a divergence between the two arms of the adaptive immune response in PID and SID patients. We also focused on the correlation of protection of positive SARS-CoV-2 cellular response to omicron exposure: 27 out of 81 (33.3%) HCs referred COVID-19 detected by PCR or antigen test, 24 with a mild course, 1 with moderate symptoms and the remaining 2 with bilateral pneumonia that were treated in an outpatient basis. Our results might support the relevance of these immunological studies to determine the correlation of protection with severe disease and for deciding the need for additional boosters on a personalized basis. Follow-up studies are required to evaluate the duration and variability in the immune response to COVID-19 vaccination or infection.

Clinical Behavior, Mutational Profile and T-Cell Repertoire of High-Grade Neuroendocrine Tumors of the Head and Neck.

Neuroendocrine carcinomas (NECs) of the head and neck (HN) account for <1% of HN cancers (HNCs), with a 5-year overall survival (OS) <20%. This is a retrospective study of HN NECs diagnosed at our institution between 2005 and 2022. Immunohistochemistry and next-generation sequencing (NGS) were used to evaluate neuroendocrine markers, tumor mutational burden (TMB), mutational profiles and T-cell receptor repertoires. Eleven patients with high-grade HN NECs were identified (male:female ratio 6:5; median age 61 (Min-Max: 31-86)): nasoethmoidal (3), parotid gland (3), submaxillary gland (1), larynx (3) and base of tongue (1). Among n = 8 stage II/IVA/B, all received (chemo)radiotherapy with/without prior surgery or induction chemotherapy, with complete response in 7/8 (87.5%). Among n = 6 recurrent/metastatic patients, three received anti-PD1 (nivolumab (2), pembrolizumab (1)): two achieved partial responses lasting 24 and 10 months. After a median follow-up of 30 and 23.5 months since diagnosis and since recurrent/metastatic, median OS was not reached. Median TMB (n = 7) was 6.72 Mut/Mb. The most common pathogenic variants were TP53, HNF1A, SMARCB1, CDKN2A, PIK3CA, RB1 and MYC. There were 224 median TCR clones (n = 5 pts). In one patient, TCR clones increased from 59 to 1446 after nivolumab. HN NECs may achieve long-lasting survival with multimodality treatment. They harbor moderate-high TMBs and large TCR repertoires, which may explain responses to anti-PD1 agents in two patients and justify the study of immunotherapy in this disease.

Perforation of the Nasal Septum in a Colorectal Cancer Patient Treated With Aflibercept: A Case Report.

Aflibercept is an antiangiogenic agent used in patients with metastatic colorectal cancer who have progressed to a first-line oxaliplatin-based regimen. The main adverse effects (AEs) of antiangiogenic agents are fatigue, asthenia, anorexia, hypertension, proteinuria, urinary tract infection, diarrhea, and neutropenia. Other AEs, such as hemorrhage, thromboembolic events, and gastrointestinal perforation, are much less frequent. Nasal septal perforation caused by antiangiogenic agents is even rarer. The published literature on this subject is scarce. Here, we report the case of a 54-year-old male with metastatic colorectal cancer undergoing treatment with leucovorin, fluorouracil (5-FU), irinotecan, and aflibercept who presented with epistaxis and nasal congestion. An otolaryngologist performed a rhinoscopy that revealed a perforation of the nasal septum. Aflibercept was withdrawn first, and local treatment was applied with lubricant and antibacterial lotions. It was considered a non-life-threatening side effect, and given the high risk of not continuing treatment in this patient with a recent recurrence, aflibercept was reintroduced in combination with leucovorin, 5-FU, and irinotecan. The patient continued local treatment and follow-up with medical oncology and otolaryngology with gradual improvement of symptoms. Follow-up was discontinued due to disease progression and death after 16 months of the event.

Case Report: Bocavirus Infection Radiologically Resembling a Congestive Heart Failure in a Patient with Metastatic Castration-Resistant Prostate Cancer.

Background: Human bocavirus (HBoV) is a viral pathogen from the genus Bocaparvovirus (family Parvoviridae, subfamily Parvovirinae) discovered in 2005. Most of available literature is about HBoV in children and adults with hematological malignancies and in otherwise healthy children with respiratory infections. Information regarding infection in the adult population with solid tumors is scarce. Case Report: We report the case of a 51-year-old male with metastatic castration resistant prostate cancer undergoing chemotherapy treatment who presented with fever, dyspnea, dry cough, and pleuritic pain. Imaging techniques showed signs of congestive heart failure. Symptoms, laboratory tests and echocardiography revealed a more probable infectious etiology. Antibiotic therapy was started. A polymerase chain reaction (PCR) test of nasopharyngeal exudate for respiratory viruses was positive for HBoV. The rest of the microbiological tests were negative. Bronchoalveolar lavage (BAL) was performed. Bacterial culture of BAL was negative while respiratory virus PCR confirmed positivity for HBoV. Antibiotic therapy was discontinued. The patient gradually recovered. Conclusions: Emerging infectious diseases are a notorious threat for immunocompromised populations such as solid tumor patients. This case is unique because to our knowledge this is the first case report article of HBoV in a solid tumor patient and because imaging techniques exhibited signs of congestive heart failure that did not correlate with the rest of the tests. It shows that unusual pathogens should be considered when managing serious clinical complications with uncommon presentations in cancer patients. Notable diagnostic efforts should be made to reach a diagnosis in these cases.

Tele-Rheumatology during the COVID-19 pandemic.

INTRODUCTION: During the Covid-19 pandemic strategies to prevent transmission of the viral infection obliged our hospital to promote virtual consultations. OBJETIVE: The objective of this study is to describe the results obtained with the previous strategy of transferring activity to teleconsultation during the period of maximum impact of the pandemic. MATERIAL AND METHODS: Between 16/03 and 10/05/2020 all successive consultations in our unit were performed in virtual rheumatology teleconference (RTC) format. The socio-demographic, geo-functional and clinical characteristics of all patients were collected; a numeric verbal scale (NVS) (where 0 = very dissatisfied to 10 = fully satisfied) was applied to assess the degree of satisfaction of the doctor/patient with the RTC. RESULTS: 469 TC were included. Most patients seen by RTC were women, mean age: 60,83 years. Only 16% had university education. The mean distance travelled for face-to face consultation is 33 Km with a mean total time of 2 h. Most individuals were diagnosed with osteoarthritis/soft tissue rheumatic diseases and/or osteoporosis; 21% had rheumatoid arthritis. The mean length of the TC was 9.64 min. We find more patient satisfaction with the TC when their level of education is higher (OR = 4.12); doctor satisfaction was higher when the individual was better able to manage the Internet (OR = 3.01). CONCLUSION: It is possible to transfer rheumatological care activity to TC with a considerable degree of satisfaction for both the patient and the doctor.

Adverse drug reactions to the three doses of the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) mRNA-1273 vaccine in a cohort of cancer patients under active treatment of a tertiary hospital in Madrid, Spain.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines efficacy and safety have been tested in phase 3 studies in which cancer patients were not included or were underrepresented. Methods: The objective of this study is to evaluate the safety profile of the mRNA-1273 vaccine across cancer patients and its relationship to patients' demographics. This retrospective cohort study included patients 18-years or older with solid malignancies receiving active treatment in our hospital who had received the three-dose schedule of the mRNA9 1273 vaccine and whose side effects after each dose were recorded. Patient electronic medical records were reviewed retrospectively to collect data between April 19, 2021, and December 31, 2021. Patients with documented previous infection by SARS-Cov-2 were excluded from the study. Results: A total of 93 patients met the inclusion criteria. Local adverse drug reactions (ADRs) were reported more frequently after the first and second dose than after the third (41.9%, 43% and 31.1% of the patients respectively), while systemic ADRs followed the opposite pattern (16.1%, 34.4% and 52.6% of the patients respectively). We found a statistically significant association between sex and systemic ADRs after the third dose. Cochran-Armitage test showed a statistically significant linear trend, p = 0.012, with a higher Eastern Cooperative Oncology Group (ECOG) score associated with a lower proportion of patients suffering from systemic side effects. A logistic regression showed that women had 5.79 times higher odds to exhibit systemic ADRs after the third dose (p=0.01) compared to males. Increasing age was associated with a decreased likelihood of exhibiting ADRs (p=0.016). Conclusion: The mRNA-1273 vaccine shows a tolerable safety profile. The likelihood of ADRs appears to be associated with gender and age. Its association with ECOG scores is less evident. Further studies are needed to elucidate this data in cancer patients.

Evidence of exhausted lymphocytes after the third anti-SARS-CoV-2 vaccine dose in cancer patients.

Introduction: Evidence is scant regarding the long-term humoral and cellular responses Q7 triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines in cancer patients after repeated booster doses. The possibility of T-cell exhaustion following these booster doses in this population has not yet been fully studied and remains uncertain. Methods: In this single-center prospective observational study, we explored the specific humoral and cellular response to S1 antigen in 36 patients with solid malignancies at baseline, and after the second and third doses of the mRNA-1273 vaccine. Results: A dual behavior was observed: 24 (66.7%) patients showed partial specific IFN-γ response after the second dose that was further enhanced after the third dose; and 11 (30.5%) already showed an optimal response after the second dose and experienced a marked fall-off of specific IFN-γ production after the third (4 patients negativization), which might suggest T cell exhaustion due to repetitive priming to the same antigen. One (2.8%) patient had persistently negative responses after all three doses. Seroconversion occurred in all patients after the second dose. We then studied circulating exhausted CD8+ T-cells in 4 patients from each of the two response patterns, those with increase and those with decrease in cellular response after the third booster. The patients with decreased cellular response after the booster had a higher expression of PD1+CD8+ and CD57+PD1+CD8+ exhausted T cells compared with those with an increased cellular response both in vivo and in vitro. The proportion of PD1+CD8+ and CD57+PD1+CD8+ exhausted T cells inversely correlated with IFN-γ production. Discussion: Our preliminary data show that the two-dose SARS-CoV-2 vaccine regimen was beneficial in all cancer patients of our study. An additional booster seems to be beneficial in suboptimal vaccine seroconverters, in contrast to maximal responders that might develop exhaustion. Our data should be interpreted with caution given the small sample size and highlight the urgent need to validate our results in other independent and larger cohorts. Altogether, our data support the relevance of immunological functional studies to personalize preventive and treatment decisions in cancer patients.

Trafficking and chromatin dynamics of holocarboxylase synthetase during development of Drosophila melanogaster.

This work examines the cellular localization of holocarboxylase synthetase (HCS) and its association to chromatin during different stages of development of Drosophila melanogaster. While HCS is well known for its role in the attachment of biotin to biotin-dependent carboxylase, it also regulates the transcription of HCS and carboxylases genes by triggering a cGMP-dependent signal transduction cascade. Further, its presence in the nucleus of cells suggests additional regulatory roles, but the mechanism involved has remained elusive. In this study, we show in D. melanogaster that HCS migrates to the nucleus at the gastrulation stage. In polytene chromosomes, it is associated to heterochromatin bands where it co-localizes with histone 3 trimethylated at lysine 9 (H3K9met3) but not with the euchromatin mark histone 3 acetylated at lysine 9 (H3K9ac). Further, we demonstrate the association of HCS with the hsp70 promoter by immunofluorescence and chromatin immuno-precipitation (ChIP) of associated DNA sequences. We demonstrate the occupancy of HCS to the core promoter region of the transcriptionally inactive hsp70 gene. On heat-shock activation of the hsp70 promoter, HCS is displaced and the promoter region becomes enriched with the TFIIH subunits XPD and XPB and elongating RNA pol II, the latter also demonstrated using ChIP assays. We suggest that HCS may have a role in the repression of gene expression through a mechanism involving its trafficking to the nucleus and interaction with heterochromatic sites coincident with H3K9met3.