Not always a miracle - The case of the missing metastasis.

Spontaneous regression of malignant neoplasms is extremely rare, but renal cell carcinomas (RCC) are most often associated with this phenomenon. We report a case of a patient with personal history of RCC, who underwent nephrectomy and no other oncological treatment. One year after nephrectomy, a lung metastasis was detected and kept under follow-up for 3 years. Its size increased over time until a needle biopsy was performed, and its metastatic nature confirmed. Wedge resection of the lung nodule was performed, and no neoplastic cells were found, suggesting its spontaneous regression after biopsy. Different theories have been proposed to explain this phenomenon and, in most cases, the mechanism seems to involve the activation of the immune system. This case supports the importance of reducing tumor burden and the impact of the disturbance of the tumor microenvironment caused by instrumentation, in improving immune system activation and its essential role in neoplasm regression.

Specialized Tfh cell subsets driving type-1 and type-2 humoral responses in lymphoid tissue.

Effective antibody responses are essential to generate protective humoral immunity. Different inflammatory signals polarize T cells towards appropriate effector phenotypes during an infection or immunization. Th1 and Th2 cells have been associated with the polarization of humoral responses. However, T follicular helper cells (Tfh) have a unique ability to access the B cell follicle and support the germinal center (GC) responses by providing B cell help. We investigated the specialization of Tfh cells induced under type-1 and type-2 conditions. We first studied homogenous Tfh cell populations generated by adoptively transferred TCR-transgenic T cells in mice immunized with type-1 and type-2 adjuvants. Using a machine learning approach, we established a gene expression signature that discriminates Tfh cells polarized towards type-1 and type-2 response, defined as Tfh1 and Tfh2 cells. The distinct signatures of Tfh1 and Tfh2 cells were validated against datasets of Tfh cells induced following lymphocytic choriomeningitis virus (LCMV) or helminth infection. We generated single-cell and spatial transcriptomics datasets to dissect the heterogeneity of Tfh cells and their localization under the two immunizing conditions. Besides a distinct specialization of GC Tfh cells under the two immunizations and in different regions of the lymph nodes, we found a population of Gzmk+ Tfh cells specific for type-1 conditions. In human individuals, we could equally identify CMV-specific Tfh cells that expressed Gzmk. Our results show that Tfh cells acquire a specialized function under distinct types of immune responses and with particular properties within the B cell follicle and the GC.

Parental Perceptions of the Impact of a Child's Complex Chronic Condition: A Validation Study of the Impact on Family Scale.

The diagnosis of a child's complex chronic illness may impact family relationships and cohesion. The Impact on Family Scale (IFS) is an instrument used to assess the parental perception of the effects of children's chronic illness on family life. With a sample of 110 mothers and fathers between the ages of 29 and 50 who have a child with a complex chronic illness, we examine evidence of the validity of the IFS for use in Portugal within this specific family configuration, (1) comparing its factor structure with the original one; (2) assessing its reliability; and (3) evaluating its relationship with life satisfaction and family cohesion/acceptance. As expected, CFA analysis showed that IFS is a one-factor reliable instrument with 12 items (Cronbach's alpha = 0.910), which are negatively correlated with satisfaction with life (r = -0.229, p = 0.016) and positively correlated with family acceptance and cohesion (r = 0.363; p < 0.001). The results support the validity of the IFS in families with children and adolescents with a complex chronic illness. The implications of the use of this instrument for research and professional practice is analyzed.

The Impact Of Thymectomy In Thymomatous And Nonthymomatous Myasthenia Gravis - The Experience Of A Tertiary Center.

INTRODUCTION: Thymectomy remains a mainstay of treatment in Thymomatous (T) and Nonthymomatous (nT) Myasthenia Gravis (MG), with improved clinical outcomes and reduced need for medical treatment, however, there is little research regarding long-term follow-up. We aim to assess the impact of surgery on the long-term outcome of patients with MG at our center. METHODS: Retrospective analyses of MG patients submitted to thymectomy between 2007 and 2017 at the thoracic surgery department of CHUC. Clinical assessment was performed according to the MG Foundation of America (MGFA) Clinical Classification (cMGFA). The follow-up was categorized according to the MGFA Post-intervention Status (MGFA-PIS) and cMGFA. Statistical analysis was performed with SPSS, to a significance level of 5%. RESULTS: Thirty-seven patients underwent extended thymectomy and 67.6% were female. Median age at diagnosis was 46.68±19.2 years. Most patients (83.8%) had anti-acetylcholine receptor antibodies and 81.1% had generalized forms of MG. Many patients (67.6%) had surgery less than 12 months after the clinical diagnosis. TMG was present in 19 (51.4%) patients. Compared to nTMG, these patients were older (54.06±17.9 vs 40.17±19.4 years) and most were men (52.9% vs 16.7%). We obtained a good outcome in most patients in the first (81.1%), second (86.1%), and fifth (84.8%) year of follow-up. There was a shift towards better prognosis categories in the good outcome group: 9.1% CSR, 3.0% PR, and 66,7% MM in the fifth year. Preoperative medical treatment did not influence the long-term follow-up outcome. A shorter time to surgery (< 12 months) correlated with better outcomes at year 5 (p=0.016). CONCLUSION: Thymectomy led to a sustained clinical improvement in our cohort, allowing for a reduced need for medication. A shorter time to surgery seems to have a positive influence on long-term prognosis. We expect that an extended follow-up would improve our results.

Giant Intrathoracic Desmoid Tumor - a Case Report.

Desmoid tumors are soft tissue neoplasms arising from fascial and muscle-aponeurotic structure. These tumors are locally aggressive and have a high recurrence rate, even after complete resection. We present the case of a female with a giant intrathoracic desmoid tumor. She underwent complete surgical resection with no disease recurrence. Desmoid tumors' natural history is not well defined and is often enigmatic, making these tumors difficult to manage. Currently, for intrathoracic desmoid tumors, medical treatment is the recommended approach, nevertheless, surgery can be considered in selected patients.

Single-cell transcriptomics of Treg reveals hallmarks and trajectories of immunological aging.

Age-related immunosenescence is characterized by progressive dysfunction of adaptive immune response and increased autoimmunity. Nevertheless, the impact of aging on CD4+ regulatory T cells that are master regulators of the immune system remains largely unclear. Here, we report cellular and molecular hallmarks of regulatory T cells derived from murine lymphoid and adipose tissues at 3, 18, and 24 mo of age, respectively, by analyzing their heterogeneity that displays dynamic changes in transcriptomic effector signatures at a single-cell resolution. Although the proportion of regulatory T cells among total Cd4+ T cells, as well as their expression levels of Foxp3, did not show any global change with time, we have identified 6 transcriptomically distinct clusters of regulatory T cells with cross-tissue conserved hallmarks of aging, including increased numbers of proinflammatory regulatory T cells, reduced precursor cells, increased immature and mature T follicular regulatory cells potentially supported by a metabolic switch from oxidative phosphorylation to glycolysis, a gradual loss of CD150hi regulatory T cells that support hematopoiesis, and increased adipose tissue-specific regulatory T cells that are associated with metabolic disease. To dissect the impact of immunosenescence on humoral immunity, we propose some potential mechanisms underlying T follicular regulatory cell-mediated dysfunction by interactome analysis on T follicular regulatory cells, T follicular helper cells, and B cells during aging. Lastly, spatiotemporal analysis further revealed trajectories of regulatory T-cell aging that demonstrate the most significant changes in marrow and adipose tissues that might contribute to the development of age-related immunosenescence and type 2 diabetes. Taken together, our findings could provide a better understanding of age-associated regulatory T-cell heterogeneity in lymphoid and adipose tissues, as well as regulatory T-cell hallmarks during progressive adaptation to aging that could be therapeutically targeted for rejuvenating the aging immune system in the future.

Multimodal treatment of oligometastatic non-small cell lung cancer.

The management of patients with oligometastatic non-small cell lung cancer has undergone significant improvement in recent years. The combination of increase in sensitivity of diagnostic tests, development in systemic therapies, surgical techniques and radiotherapy allowing radical ablative treatment of metastases have significantly influenced the treatment of advanced lung cancer, mainly in the patients in which these treatment modalities converge.We report a rare case of a young patient with an oligometastatic lung adenocarcinoma with a single synchronous brain metastasis, who underwent aggressive locoregional and systemic therapies and is still in annual follow-up with excellent quality of life and progression-free survival of 164 months.

Children with extended oligoarticular and polyarticular juvenile idiopathic arthritis have alterations in B and T follicular cell subsets in peripheral blood and a cytokine profile sustaining B cell activation.

OBJECTIVES: The main goal of this study was to characterise the frequency and phenotype of B, T follicular helper (Tfh) and T follicular regulatory (Tfr) cells in peripheral blood and the cytokine environment present in circulation in children with extended oligoarticular juvenile idiopathic arthritis (extended oligo JIA) and polyarticular JIA (poly JIA) when compared with healthy controls, children with persistent oligoarticular JIA (persistent oligo JIA) and adult JIA patients. METHODS: Blood samples were collected from 105 JIA patients (children and adults) and 50 age-matched healthy individuals. The frequency and phenotype of B, Tfh and Tfr cells were evaluated by flow cytometry. Serum levels of APRIL, BAFF, IL-1ß, IL-2, IL-4, IL-6, IL-10, IL-17A, IL-21, IL-22, IFN-γ, PD-1, PD-L1, sCD40L, CXCL13 and TNF were measured by multiplex bead-based immunoassay and/or ELISA in all groups included. RESULTS: The frequency of B, Tfh and Tfr cells was similar between JIA patients and controls. Children with extended oligo JIA and poly JIA, but not persistent oligo JIA, had significantly lower frequencies of plasmablasts, regulatory T cells and higher levels of Th17-like Tfh cells in circulation when compared with controls. Furthermore, APRIL, BAFF, IL-6 and IL-17A serum levels were significantly higher in paediatric extended oligo JIA and poly JIA patients when compared with controls. These immunological alterations were not found in adult JIA patients in comparison to controls. CONCLUSIONS: Our results suggest a potential role and/or activation profile of B and Th17-like Tfh cells in the pathogenesis of extended oligo JIA and poly JIA, but not persistent oligo JIA.

Molecular reshaping of phage-displayed Interleukin-2 at beta chain receptor interface to obtain potent super-agonists with improved developability profiles.

Interleukin-2 (IL-2) engineered versions, with biased immunological functions, have emerged from yeast display and rational design. Here we reshaped the human IL-2 interface with the IL-2 receptor beta chain through the screening of phage-displayed libraries. Multiple beta super-binders were obtained, having increased receptor binding ability and improved developability profiles. Selected variants exhibit an accumulation of negatively charged residues at the interface, which provides a better electrostatic complementarity to the beta chain, and faster association kinetics. These findings point to mechanistic differences with the already reported superkines, characterized by a conformational switch due to the rearrangement of the hydrophobic core. The molecular bases of the favourable developability profile were tracked to a single residue: L92. Recombinant Fc-fusion proteins including our variants are superior to those based on H9 superkine in terms of expression levels in mammalian cells, aggregation resistance, stability, in vivo enhancement of immune effector responses, and anti-tumour effect.

Hepatocellular Neoplasm of Uncertain Potential of Malignancy or Well-Differentiated Hepatocellular Carcinoma Arising within Hepatocellular Adenoma.

Background: Hepatocellular adenoma (HCA) is an uncommon solid, solitary, benign liver lesion that develops in an otherwise normal-appearing liver. Hemorrhage and malignant transformation are the most important complications. Risk factors for malignant transformation include advanced age, male gender, use of anabolic steroids, metabolic syndrome, larger lesions, and beta-catenin activation subtype. The identification of higher risk adenomas enables the selection of patients most suitable for aggressive treatment and those who benefit with surveillance, minimizing the risks for these predominantly young patients. Case Presentation. We present the case of a 29-year-old woman with a history of oral contraceptive intake for 13 years, which was sent to evaluation in our Hepato-Bilio-Pancreatic and Splenic Unit because of a large nodular lesion in segment 5 of the liver, compatible with HCA, and was proposed to surgical resection. Histological and immunohistochemical investigation revealed an area with atypical characteristics, suggesting malignant transformation. Conclusions: HCAs share similar imaging characteristics and histopathological features with hepatocellular carcinomas; therefore, immunohistochemical and genetic studies assumes great importance to discriminate adenomas with malignant transformation. Beta-catenin, glutamine synthetase, glypican-3, and heat-shock protein 70 are promising markers to identify higher risk adenomas.

Polyoxazoline-Based Nanovaccine Synergizes with Tumor-Associated Macrophage Targeting and Anti-PD-1 Immunotherapy against Solid Tumors.

Immune checkpoint blockade reaches remarkable clinical responses. However, even in the most favorable cases, half of these patients do not benefit from these therapies in the long term. It is hypothesized that the activation of host immunity by co-delivering peptide antigens, adjuvants, and regulators of the transforming growth factor (TGF)-ß expression using a polyoxazoline (POx)-poly(lactic-co-glycolic) acid (PLGA) nanovaccine, while modulating the tumor-associated macrophages (TAM) function within the tumor microenvironment (TME) and blocking the anti-programmed cell death protein 1 (PD-1) can constitute an alternative approach for cancer immunotherapy. POx-Mannose (Man) nanovaccines generate antigen-specific T-cell responses that control tumor growth to a higher extent than poly(ethylene glycol) (PEG)-Man nanovaccines. This anti-tumor effect induced by the POx-Man nanovaccines is mediated by a CD8+ -T cell-dependent mechanism, in contrast to the PEG-Man nanovaccines. POx-Man nanovaccine combines with pexidartinib, a modulator of the TAM function, restricts the MC38 tumor growth, and synergizes with PD-1 blockade, controlling MC38 and CT26 tumor growth and survival. This data is further validated in the highly aggressive and poorly immunogenic B16F10 melanoma mouse model. Therefore, the synergistic anti-tumor effect induced by the combination of nanovaccines with the inhibition of both TAM- and PD-1-inducing immunosuppression, holds great potential for improving immunotherapy outcomes in solid cancer patients.

Association analysis between symptomology and herpesvirus IgG antibody concentrations in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and multiple sclerosis.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and multiple sclerosis (MS) are two complex and multifactorial diseases whose patients experience persistent fatigue, cognitive impairment, among other shared symptoms. The onset of these diseases has also been linked to acute herpesvirus infections or their reactivations. In this work, we re-analyzed a previously-described dataset related to IgG antibody responses to 6 herpesviruses (CMV - cytomegalovirus; EBV - Epstein-Barr virus; HHV6 - human herpesvirus-6; HSV1 and HSV2 - herpes simplex virus-1 and -2, respectively; VZV - varicella-zoster virus) from the United Kingdom ME/CFS biobank. The primary goal was to report the underlying symptomology and its association with herpesvirus IgG antibodies using data from 4 disease-trigger-based subgroups of ME/CFS patients (n = 222) and patients with MS (n = 46). The secondary objective was to assess whether serological data could distinguish ME/CFS and its subgroup from MS using a SuperLearner (SL) algorithm. There was evidence for a significant negative association between temporary eye insight disturbance and CMV antibody concentrations and for a significant positive association between bladder problems and EBV antibody concentrations in the MS group. In the ME/CFS or its subgroups, the most significant antibody-symptom association was obtained for increasing HSV1 antibody concentration and brain fog, a finding in line with a negative impact of HSV1 exposure on cognitive outcomes in both healthy and disease conditions. There was also evidence for a higher number of significant antibody-symptom associations in the MS group than in the ME/CFS group. When we combined all the serological data in an SL algorithm, we could distinguish three ME/CFS subgroups (unknown disease trigger, non-infection trigger, and an infection disease trigger confirmed in the lab at the time of the event) from the MS group. However, we could not find the same for the remaining ME/CFS group (related to an unconfirmed infection disease). In conclusion, IgG antibody data explains more the symptomology of MS patients than the one of ME/CFS patients. Given the fluctuating nature of symptoms in ME/CFS patients, the clinical implication of these findings remains to be determined with a longitudinal study. This study is likely to ascertain the robustness of the associations during natural disease course.

The expanding family of T follicular regulatory cells.

The coevolution of multiple specialized T follicular regulatory cell subsets has led to fine-tuning of human germinal center responses in providing optimal antibody production and preventing events leading to autoimmunity (see the related Research Article by Le Coz et al.).

Impact of Misdiagnosis in Case-Control Studies of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Misdiagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) can occur when different case definitions are used by clinicians (relative misdiagnosis) or when failing the genuine diagnosis of another disease (misdiagnosis in a strict sense). This problem translates to a recurrent difficulty in reproducing research findings. To tackle this problem, we simulated data from case-control studies under misdiagnosis in a strict sense. We then estimated the power to detect a genuine association between a potential causal factor and ME/CFS. A minimum power of 80% was obtained for studies with more than 500 individuals per study group. When the simulation study was extended to the situation where the potential causal factor could not be determined perfectly (e.g., seropositive/seronegative in serological association studies), the minimum power of 80% could only be achieved in studies with more than 1000 individuals per group. In conclusion, current ME/CFS studies have suboptimal power under the assumption of misdiagnosis. This power can be improved by increasing the overall sample size using multi-centric studies, reporting the excluded illnesses and their exclusion criteria, or focusing on a homogeneous cohort of ME/CFS patients with a specific pathological mechanism where the chance of misdiagnosis is reduced.

Routine Ultrasound at 30th-33rd weeks versus 30th-33rd and 35th-37th weeks in Low-Risk Pregnancies: A Randomized Trial.

INTRODUCTION: The aim of this study was to evaluate the accuracy of 35-37 weeks' ultrasound for fetal growth restriction (FGR) detection and the impact of 30th-33rd weeks versus 30th-33rd and 35th-37th weeks' ultrasound on perinatal outcomes. METHODS: This was a randomized controlled trial that enrolled 1,061 low-risk pregnant women: 513 in the control group (routine ultrasound performed at 30th-33rd weeks) and 548 in the study group (with an additional ultrasound at 35th-37th weeks). FGR was defined as a fetus with an estimated fetal weight (EFW) below the 10th percentile. p values < 0.05 were considered statistically significant. RESULTS: The ultrasound at 35-37 weeks had an overall accuracy of FGR screening of 94%. Spearman's correlation coefficient between EFW and birthweight centile was higher for at 35-37 weeks' ultrasound (ρ = 0.75) compared with 30-33 weeks' ultrasound (ρ = 0.44). The study group had a lower rate of operative vaginal deliveries (24.4% vs. 39.3%, p = 0.005) and cesarean deliveries for nonreassuring fetal status (16.8% vs. 38.8%, p < 0.001). DISCUSSION/CONCLUSION: A later ultrasound (35-37 weeks) had a high accuracy for detection of FGR and had a higher correlation between EFW and birthweight centiles. Furthermore, it was also associated with lower adverse perinatal outcomes compared to an earlier ultrasound.

Different antibody-associated autoimmune diseases have distinct patterns of T follicular cell dysregulation.

Autoantibodies are produced within germinal centers (GC), in a process regulated by interactions between B, T follicular helper (Tfh), and T follicular regulatory (Tfr) cells. The GC dysregulation in human autoimmunity has been inferred from circulating cells, albeit with conflicting results due to diverse experimental approaches. We applied a consistent approach to compare circulating Tfr and Tfh subsets in patients with different autoimmune diseases. We recruited 97 participants, including 72 patients with Hashimoto's thyroiditis (HT, n = 18), rheumatoid arthritis (RA, n = 16), or systemic lupus erythematosus (SLE, n = 32), and 31 matched healthy donors (HD). We found that the frequency of circulating T follicular subsets differed across diseases. Patients with HT had an increased frequency of blood Tfh cells (p = 0.0215) and a reduced Tfr/Tfh ratio (p = 0.0338) when compared with HD. This was not observed in patients with systemic autoimmune rheumatic diseases (RA, SLE), who had a reduction in both Tfh (p = 0.0494 and p = 0.0392, respectively) and Tfr (p = 0.0003 and p = 0.0001, respectively) cells, resulting in an unchanged Tfr/Tfh ratio. Activated PD-1+ICOS+Tfh and CD4+PD-1+CXCR5-Tph cells were raised only in patients with SLE (p = 0.0022 and p = 0.0054), without association with disease activity. Our data suggest that GC dysregulation, assessed by T follicular subsets, is not uniform in human autoimmunity. Specific patterns of dysregulation may become potential biomarkers for disease and patient stratification.