Long-term efficacy of neoadjuvant-adjuvant targeted therapy in borderline resectable stage IIIB-D and IV melanoma.

BACKGROUND: Neoadjuvant-adjuvant therapy for locally advanced or potentially resectable metastatic melanoma was expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment only. METHODS: Forty-seven consecutive patients were treated with neoadjuvant-adjuvant BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi) and surgery. RESULTS: Twelve (26%) patients achieved a pathological complete response and 10 (21%) patients achieved a near-complete response. In the whole group, median recurrence-free survival was 19.4 months and median distant metastasis-free survival (mDMFS) was 21.9 months. In patients with a pathological complete response (pCR)/near-pCR median recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were significantly longer than in patients with minor pathological response with hazard ratio (HR) = 0.37 (p = .005) for RFS and HR = 0.33 (p = .002) for DMFS. After median follow-up of 52.5 months, median progression-free survival since BRAFi/MEKi therapy initiation was 25.1 months. The median time-to-treatment-failure since initiation of neoadjuvant therapy was 22.2 months and was significantly longer in patients with pCR/near-pCR (HR = 0.45; p = .022). Neoadjuvant therapy did not result in any new specific complications of surgery. After 48 months, RFS and overall survival were 36.3% and 64.8% or 20% and 37.4% in patients with pCR/near-pCR and pathological partial response/pathological nonresponse, respectively. CONCLUSIONS: The authors confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of stage III/IV melanoma. Major pathological response to neoadjuvant treatment is a surrogate marker of recurrence including DMFS in these patients. PLAIN LANGUAGE SUMMARY: Our study presents a large comprehensive analysis of neoadjuvant-adjuvant systemic therapy in patients diagnosed with marginally resectable stage III or IV melanoma. Neoadjuvant therapy effectively reduced the volume of the disease, which facilitated subsequent surgical resection. After median follow-up of 52.5 months, median progression-free survival since therapy initiation was 25.1 months. Twelve patients had complete pathological response and 10 patients had a near-complete pathological response-and together they had median recurrence-free survival and distant metastasis-free survival significantly longer than in patients with pathological partial response or nonresponse. Complete/near-complete pathological response to neoadjuvant treatment is a surrogate marker of recurrence-free, including distant metastasis-free, survival in these patients.

Efficacy of immunotherapy beyond RECIST progression in advanced melanoma: a real-world evidence.

Immunotherapy (ITH) holds the possibility of tumor burden decrease after initial RECIST 1.1 defined progression. The clinical concept of treating selected patients (pts) beyond disease progression (PD) is supported by so-called pseudoprogression phenomenon. The aim of this study was to evaluate real-life practice and outcomes related to treatment beyond (RECIST) progression (TBP) in advanced melanoma patients. Of 584 subsequent melanoma pts analyzed 77 (13.2%) received TBP. In this cohort, the median time to first PD (TTFP) was 5.29 months (m), while time to second PD (TTSP)-8.02 m. On TBP 23.4% pts achieved an objective response (OR), and next 42.9%-stabilization of the disease (SD). 1st PD was reported most often as the development of a new lesion or increase (> 20%) of the diameter of three or more targets. In about 50% second PD was observed as an increase in the diameter of different targets that in 1st PD. Multimodal treatment resulted in 9.82 m TTSP, while ITH alone-4.93 m (p = 0.128). An oligoprogressive pattern of first PD was associated with longer TTSP (HR 0.55, 95% CI: 0.32-0.94). Median OS after first PD was 28.75 months and correlated with OR during TBP (HR 0.18, 95% CI: 0.004-0.76). Selected clinically fit melanoma patients, despite evidence of first radiographic progression, may benefit from continued treatment with PD-1 checkpoint inhibitors, but the findings should be validated in larger prospective trials. Multidisciplinary treatment should be offered to advanced melanoma patients, including radiosurgery or stereotactic radiotherapy of single loci progressing during immunotherapy.

Association of adverse childhood experiences (ACEs) with obesity and underweight in children.

PURPOSE: The aim of the study was to test the hypothesis that adverse childhood experiences (ACEs) are related to both obesity and underweight from childhood, and that the association of ACEs with weight abnormalities is modulated by type of ACEs, sex and socioeconomic status (SES) indices. METHODS: The relations between ACEs (0 vs ≥ 1), ACE accumulation and ACE type with weight status and z scores BMI were assessed in 503 children aged 6-12 years from Poznan, Poland. The effects of interaction of ACEs with sex and SES on z scores BMI were included in the analyses. RESULTS: ACEs were significantly related to both obesity and underweight, in unadjusted analysis, and when sex and SES indices, such as size of place of residence, people per room in household, and parental education were controlled. The relation of ACEs with z scores BMI was modulated by ACE type, parental subjective assessment of economic situation of a family and parental education. ACE accumulation was not related to an increase of obesity or underweight rate, or z scores BMI. CONCLUSION: The study implicates the need for both obesity and underweight prevention in individuals with adverse experiences as early as in childhood. LEVEL OF EVIDENCE: III: evidence obtained from well-designed cohort study.

Pragmatic aspects of verbal communication in elderly people: A study of Polish seniors.

BACKGROUND: Behavioural and neuropsychological studies on elderly populations concentrate on many aspects of cognitive functioning, but significantly less research concerns communication processes, including aspects of verbal communication skills, pragmatic issues that are important for performing social tasks at every age. AIMS: To characterize the variability in changes that occur with age in the domain of pragmatic aspects of verbal communication skills in a group of individuals aged > 65 years and to define their determinants. METHODS & PROCEDURES: A group of 109 normally ageing individuals (aged 64.9-90 years) participated in the study (62 women and 47 men). Participants were divided into two age groups: < 70 and > 71 years old. The verbal communication skills were examined using the Polish version of the Right Hemisphere Language Battery (RHLB-PL), and cognitive skills using the Mini Mental State Examination (MMSE). OUTCOMES & RESULTS: Comparison between the subgroups showed that there was a significant decline in the older group in all the subtests except for the Discourse Analysis. Age did not differentiate discursive abilities in seniors. These data apparently confirm the hypothesis that discursive competences are stable throughout one's lifespan. In order to compare younger and older seniors in terms of the 11 aspects of pragmatic communication, two performance profiles were prepared for the groups and subjected to comparative analyses. The shape of the two profiles of all communication competences was similar. The biggest differences were identified between the groups in the Comments, Humour and Metaphor comprehension and explanation subtests. Analysis of the determinants of changes in pragmatic aspects of verbal communication skills in elderly individuals revealed that the important factors include age, overall level of cognitive function, higher education and female sex. CONCLUSION & IMPLICATIONS: The relationship between age and pragmatic aspects of verbal communication skills is complex. The results indicate that treating seniors as a homogenous group in terms of pragmatic aspects of verbal communication functioning is incorrect. Age differentially affects the various aspects of communication functions. The level of cognitive functioning mediates the relationship between age and pragmatic aspects of verbal communication skills. What this paper adds What is already known on the subject? Behavioural and neuropsychological studies on elderly populations concentrate on many aspects of mnestic functions, executive functions, cognitive flexibility, fluency, cognitive control, working memory, semantic processing, arithmetic competences and perception speed. Significantly less research concerns communication processes, including verbal communication. Older and younger people have usually been compared in particular areas of communication: discourse, understanding of metaphors or prosody. At present there is a paucity of research regarding changes in communication functions at different stages of ageing and profiles of various aspects of verbal communication in old age. What this paper adds to existing knowledge The study indicates that normally ageing individuals are a non-homogeneous group in terms of pragmatic aspects of verbal communication. Various communication functions change at different rate at various stages of ageing. The study clarified the determinants of changes in pragmatic aspects of verbal communication skills in elderly individuals. These aspects are cognitive abilities, age, a high education level and sex. What are the potential or actual clinical implications of this work? The research shows that diagnosis of communication competencies in elderly individuals is necessary. Furthermore, the kind of abilities is very important for social relationships and quality of life. It is essential to inform a senior's family about communication changes that occur in normal ageing. Understanding potential verbal communication difficulties in seniors and their determinants are fundamental issues.

NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial.

BACKGROUND: Pathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2-3 trial evaluated the safety and efficacy of the hafnium oxide (HfO2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma. METHODS: Act.In.Sarc is a phase 2-3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0-2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3 g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete. FINDINGS: Between March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group. Two patients in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3-4 treatment-emergent adverse event was postoperative wound complication (eight [9%] of 89 patients in the NBTXR3 group and eight [9%] of 90 in the radiotherapy alone group). The most common grade 3-4 adverse events related to NBTXR3 administration were injection site pain (four [4%] of 89) and hypotension (four [4%]) and the most common grade 3-4 radiotherapy-related adverse event was radiation skin injury in both groups (five [6%] of 89 in the NBTXR3 group and four [4%] of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3-4 adverse event related to NBTXR3 was hypotension (six [7%] of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred. INTERPRETATION: This trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers. FUNDING: Nanobiotix SA.

Challenges and solutions in 3D printing for oncology: a narrative review.

BACKGROUND AND OBJECTIVE: Oncology is increasingly adopting three-dimensional (3D) printing, a method of creating objects through additive manufacturing using various techniques and materials. This technology, divided into conventional 3D printing (using non-biological materials like thermoplastics or titanium) and bioprinting (involving living cells and tissues), has shown potential in surgical planning, implant creation, and radiotherapy. However, despite promising preclinical and clinical applications, its clinical integration faces challenges such as a lack of strong evidence, standardized guidelines, and detailed data on costs and scalability. This study reviews the current use of 3D printing in oncology, aiming to differentiate between practical and experimental applications, thereby guiding clinicians interested in incorporating this technology. METHODS: A literature search was conducted to gather comments, reviews, and preclinical and clinical studies focusing on the use of 3D printing in oncology, with publications dated before December 1, 2023. The search for pertinent studies involved utilizing PubMed and Google Scholar Review. The selection process for articles was based on a unanimous consensus among all authors. We excluded topics related to bioprinting and the technical nuances of 3D printing. KEY CONTENT AND FINDINGS: The review comprehensively describes the utilization of 3D printing in radiation oncology, surgical oncology, orthopedic oncology, medical oncology, hyperthermia, and patients' education. However, 3D printing faces several limitations that are related to unpredictable costs, difficult scalability, very complex regulations and lack of standardization. CONCLUSIONS: 3D printing is increasingly useful in oncology for diagnostics and treatment, yet remains experimental and case-based. Despite growing literature, it focuses mostly on pre-clinical studies and case reports, with few clinical studies involving small samples. Thus, extensive research is needed to fully evaluate its efficacy and application in larger patient groups.

Preoperative-postoperative immunotherapy as treatment of borderline resectable and oligoprogressive stage III B-D and IV melanoma.

INTRODUCTION: Perioperative therapy has gained significant importance in patients with advanced melanoma. Currently, there is little data on the routine use of preoperative immunotherapy in metastatic melanoma outside clinical trials. This study aimed to evaluate the effectiveness of preoperative treatment in patients with borderline resectable stage III or IV melanoma as well as in oligoprogressing stage IV cases; the secondary aim is to describe the safety of surgery after immunotherapy. MATERIALS AND METHODS: Since 1/Jan/2016 seventeen patients were treated with curative intent neoadjuvant immunotherapy, surgery, and adjuvant immunotherapy, while nineteen patients were operated due to oligoprogression while treted with immunotherapy. Survival was analyzed using the Kaplan-Meier method and association between variables was tested using the chi-squared test. RESULTS: R0 resection was achieved in 76.5 % of cases after neoadjuvant immunotherapy. 24 % of patients achieved objective RECIST response and 35 % complete or major pathological response. At the median follow-up time of 51.4 months, 64.7 % of patients were free of PD after perioperative treatment, while 3-year RFS and OS rates were 68 % and 80.9 %, respectively. R0 resection was achieved in 73.7 % of oligo-progressing nodules. The median time to PD on immunotherapy after the first oligoprogression was 10.3 months. Immunotherapy did not result in any unexpected surgical complications. No patient died during preoperative treatment due to immunotherapy toxicity or disease progression. CONCLUSIONS: We confirmed treatment safety and long-term disease control after perioperative immunotherapy. Patients with borderline resectable melanoma should be referred to reference centers using neoadjuvant immunotherapy.

[Selected aspects of social cognition in patient with total agenesis of the corpus callosum (ACC) and Arnold-Chiari desease--case study]. / Wybrane aspekty poznania spolecznego u pacjenta z pelna agenezja ciala modzelowatego (ACC) i zespolem Arnolda-Chiari--studium przypadku.

AIM: The goal of the research was a characteristic of emotional-social competencies and communicative abilities in a 16-years old patient with ACC and Arnold-Chiari disease and higher than average intelligence. METHOD: RHLB-PL was applied. RESULTS: Total score in RHLB-PL suggested language and communication impairment. The greatest problems were observed in the field of behavioral self-control and discourse abilities. The patient had difficulties in the topic of the discourse maintaining, resisting from production of unconnected topics and comments, interject inappropriate remarks. Problems in humor comprehension and the dissociation between relative high level of written metaphors analysis abilities and low level of Picture Metaphors perception and explanation were observed. Linguistic Prosody was average. CONCLUSION: Patient M.J. with agenesis of corpus callosum presented high number of deficits typical in right hemisphere damage patients. It is possible to explain that fact in the context of interhemispheric transfer disorders, specially when complex material was processed.

Brain metastases of sarcoma: a rare phenomenon in rare tumours.

The usual site for distant metastases of sarcoma is lungs, while brain metastasis (BM) occurs much less frequently and usually late in the disease progression. Despite the advancement in cancer treatment, the outcome for patients with brain metastasis is poor, and their lifespan is short. The frequency of BM in sarcoma seems to be affected by the location and histology of the primary tumour. Sarcoma subtypes with a high propensity for brain metastasis are ASPS, leiomyosarcoma and osteosarcoma. There are no clear guidelines for the treatment of sarcoma brain metastasis. However, therapeutic options include surgery, radiotherapy and chemotherapy, and are often combined. Targeted therapies are a promising treatment option for sarcoma but require investigation in patients with BM. The following review presents the data on sarcoma brain metastasis incidence, treatment and prognosis.

Cool executive functions and their association with body mass & fatness and the FTO gene in school-aged children.

The FTO gene rs9936909 polymorphism is one of the well-documented single nucleotide polymorphisms in the context of increased risk of obesity, including in children. Few studies have tested the association of the FTO gene with cognitive functions. Deficits of "cool" executive functions (EFs) are considered a potential risk factor for excessive weight. The aims of our study were to investigate whether cool EFs are associated with the Body Mass Index, the Fat Mass Index and the risk of excess body mass and overfatness in neurotypically school-aged children, and whether the FTO gene polymorphism is involved in development of this possible association. The sample consisted of 553 children aged 6-12 years old. A body composition analysis, a neuropsychological assessment of EFs, and FTO polymorphism genotyping were performed in the children studied. The study found a significant association of an interference effect in theStroop Color-Word Interference Task and the risk of excessive body fatness, but not excessive body mass. There were no explicit associations between the FTO genotype and EFs deficits. Environmental factors, and particularly low maternal education, appeared to be the strongest contributors to the increased risk of obesity.

Dedifferentiated Chondrosarcoma from Molecular Pathology to Current Treatment and Clinical Trials.

Dedifferentiated chondrosarcoma (DDCS) is a rare subtype of chondrosarcoma, a primary cartilaginous malignant neoplasm. It accounts for up to 1-2% of all chondrosarcomas and is generally associated with one of the poorest prognoses among all chondrosarcomas with the highest risk of metastasis. The 5-year survival rates range from 7% to 24%. DDCS may develop at any age, but the average presentation age is over 50. The most common locations are the femur, pelvis humerus, scapula, rib, and tibia. The standard treatment for localised disease is surgical resection. Most patients are diagnosed in unresectable and advanced stages, and chemotherapy for localised and metastatic dedifferentiated DDCS follows protocols used for osteosarcoma.

Mesenchymal Chondrosarcoma from Diagnosis to Clinical Trials.

Mesenchymal chondrosarcoma (MCS) is a rare subtype of chondrosarcoma with a poor prognosis. Although these tumors are sensitive to radiotherapy/chemotherapy, the standard treatment for localized MCS is only surgical resection, and there are no established treatment guidelines for patients with advanced and metastatic MCS. Due to the low incidence of MCS, the pathology of these tumors is still unknown, and other therapeutic options are lacking. Some studies show the potential role of the PDGF/PPI3K/AKT, PKC/RAF/MEK/ERK, and pRB pathways, and BCL2 overexpression in the pathogenesis of MCS. These findings provide an opportunity to use protein kinases and BCL2 inhibitors as potential therapy in MCS. In this review, we summarize the current knowledge about MCS diagnosis and treatment options. We show the immunological and molecular biomarkers used in the diagnosis of MCS. In addition, we discuss the known prognostic and predictive factors in MCS. Finally, we present the novel trends, including targeted therapies and ongoing clinical trials using protein kinase inhibitors and the death receptor 5 (DR5) agonist, which may be the focus of future MCS treatment studies.

Modern Approach to Melanoma Adjuvant Treatment with Anti-PD1 Immune Check Point Inhibitors or BRAF/MEK Targeted Therapy: Multicenter Real-World Report.

BACKGROUND: The landscape of melanoma management changed as randomized trials have launched adjuvant treatment. MATERIALS AND METHODS: An analysis of data on 248 consecutive melanoma stage III and IV patients given adjuvant therapy in eight centers (February 2019 to January 2021) was conducted. RESULTS: The analyzed cohort comprised 147 melanoma patients given anti-PD1 (33% nivolumab, 26% pembrolizumab), and 101 (41%) were given dabrafenib plus trametinib (DT). The 2-year overall survival (OS), relapse-free survival (RFS), and distant-metastases-free survival (DMFS) rates were 86.7%, 61.4%, and 70.2%, respectively. The disease stage affected only the RFS rate; for stage IV, it was 52.2% (95% CI: 33.4-81.5%) vs. 62.5% (95% CI: 52.3-74.8%) for IIIA-D, p = 0.0033. The type of lymph node surgery before adjuvant therapy did not influence the outcomes. Completion of lymph node dissection cessation after positive SLNB did not affect the results in terms of RFS or OS. Treatment-related adverse events (TRAE) were associated with longer 24-month RFS, with a rate of 68.7% (55.5-84.9%) for TRAE vs. 56.6% (45.8-70%) without TRAE, p = 0.0031. For TRAE of grade ≥ 3, a significant decline in OS to 60.6% (26.9-100%; p = 0.004) was observed. CONCLUSIONS: Melanoma adjuvant therapy with anti-PD1 or DT outside clinical trials appears to be effective and comparable with the results of registration studies. Our data support a de-escalating surgery approach in melanoma treatment.

Stereotactic radiotherapy for soft tissue and bone sarcomas: real-world evidence.

INTRODUCTION: Selected patients with locally advanced or metastatic soft tissue and bone sarcomas (STBS) may benefit from intensive local treatment, such as stereotactic radiotherapy (SRT). This study aimed to summarize the utilization and outcomes of SRT in STBS and to identify predictive factors for progression and survival. MATERIALS AND METHODS: Consecutive patients with advanced STBS who underwent STBS in a sarcoma tertiary center were identified. We collected tumor- and treatment-related factors. Endpoints comprised time to local progression (TTLP), local progression-free survival (LPFS), time to progression, progression-free survival, and overall survival (OS). The Cox proportional-hazards model was used to identify prognostic factors. RESULTS: We identified 141 patients who underwent 233 SRTs. Median follow-up was 21 months. Local and distant progression occurred after 19 and 163 SRTs, respectively. SRT for lung metastases was predictive for better TTLP and LPFS (hazard ratio, HR = 0.12, p = 0.007 and HR = 0.42, p = 0.002, respectively). Bone sarcoma (HR for TTLP = 3.18, p = 0.043; HR for LPFS = 1.99, p = 0.028) and lower administered dose (HR for TTLP = 0.98, p = 0.007; HR for LPFS = 0.99, p = 0.012) were predictive for worse TTLP and LPFS. SRT for oligometastases (HR = 0.46, p = 0.021) and lung metastases (HR = 0.55, p = 0.046) was predictive for better OS, whereas diagnosis of bone sarcoma (HR = 2.05, p = 0.029) was predictive for worse OS. CONCLUSION: SRT provides excellent local control in STBS patients without significant toxicity. Patients with oligometastatic disease, lung metastases, and soft tissue sarcomas benefit the most from SRT. The dose escalation moderately enhances local control; however, it does not translate into better survival.

Denosumab in Giant Cell Tumor of Bone: Multidisciplinary Medical Management Based on Pathophysiological Mechanisms and Real-World Evidence.

(1) Despite the benign nature of the giant cell tumor of bone (GCTB), it shows a local recurrence rate of up to 50% and a chance of malignant transformation. The widely accepted local therapy in extremity GCTB is surgery, in the form of extended intralesional curettage with adequate disease clearance and retention of the limb, wherever possible. Denosumab, a human monoclonal antibody directed against the RANKL and associated inhibition of the RANKL pathway, is a relevant therapy option for advanced GCTB, to benefit tumor response and surgical down-staging. (2) The literature review of patients with GCTB treated with denosumab is performed via PubMed, using suitable keywords from January 2009 to January 2021. (3) Current indications for denosumab use are not definitively clear and unambiguous. Most GCTB patients with localized disease can be successfully treated with surgical curettage, and the role of denosumab in preoperative therapy in this patient population remains unclear. (4) However, patients with primary unresectable lesions or metastases may experience long-term clinical and radiological remission and pain control with denosumab treatment, and in this clinical situation, denosumab is currently the treatment of choice.

The Role of Pathology-Based Methods in Qualitative and Quantitative Approaches to Cancer Immunotherapy.

Immune checkpoint inhibitors, including those concerning programmed cell death 1 (PD-1) and its ligand (PD-L1), have revolutionised the cancer therapy approach in the past decade. However, not all patients benefit from immunotherapy equally. The prediction of patient response to this type of therapy is mainly based on conventional immunohistochemistry, which is limited by intraobserver variability, semiquantitative assessment, or single-marker-per-slide evaluation. Multiplex imaging techniques and digital image analysis are powerful tools that could overcome some issues concerning tumour-microenvironment studies. This novel approach to biomarker assessment offers a better understanding of the complicated interactions between tumour cells and their environment. Multiplex labelling enables the detection of multiple markers simultaneously and the exploration of their spatial organisation. Evaluating a variety of immune cell phenotypes and differentiating their subpopulations is possible while preserving tissue histology in most cases. Multiplexing supported by digital pathology could allow pathologists to visualise and understand every cell in a single tissue slide and provide meaning in a complex tumour-microenvironment contexture. This review aims to provide an overview of the different multiplex imaging methods and their application in PD-L1 biomarker assessment. Moreover, we discuss digital imaging techniques, with a focus on slide scanners and software.

The Analysis of Trends in Survival for Patients with Melanoma Brain Metastases with Introduction of Novel Therapeutic Options before the Era of Combined Immunotherapy-Multicenter Italian-Polish Report.

Stage IV melanoma patients develop melanoma brain metastases (MBM) in 50% of cases. Their prognosis is improving, and its understanding outside the context of clinical trials is relevant. We have retrospectively analyzed the clinical data, course of treatment, and outcomes of 531 subsequent stage IV melanoma patients with BM treated in five reference Italian and Polish melanoma centers between 2014 and 2021. Patients with MBM after 2017 had a better prognosis, with a significantly improved median of overall survival (OS) after 2017 in the worst mol-GPA prognostic groups (mol-GPA ≤ 2): a median OS >6 months and HR 0.76 vs. those treated before 2017 (CI: 0.60−0.97, p = 0.027). In our prognostic model, mol-GPA was highly predictive for survival, and symptoms without steroid use did not have prognostic significance. Local therapy significantly improved survival regardless of the year of diagnosis (treated before or after 2017), with median survival >12 months. Systemic therapy improved outcomes when it was combined with local therapy. Local surgery was associated with improved OS regardless of the timing related to treatment start (i.e., before or after 30 days from MBM diagnosis). Local and systemic treatment significantly prolong survival for the poorest mol-GPA prognosis. Use of modern treatment modalities is justified in all mol-GPA prognostic groups.

[Visual-spatial functions and organisation of grapho-motor actions in ADHD children]. / Funkcje wzrokowo-przestrzenne i organizacja czynnosci ci grafomotorycznych u dzieci z ADHD.

AIM: The aim of the study was to test whether children with a diagnosis of ADHD at the age of 7-16 years have deficits in visual-spatial, visual memory, planning, and organisation of the visual-motor functions. METHODS: The study included 186 unrelated patients aged 7-16 years diagnosed with ADHD. The control group consisted of 156 healthy individuals aged 7-16 years. The methods applied were the Rey-Osterrieth Complex Figure Test (ROCF) and Matching (MFFT). RESULTS: The number of errors in the MFFT was significantly different between healthy combined subtype. There were no differences between inattentive and healthy children. In the Rey-Osterieth Complex Figure test, statistically significant differences were found between the control group and a group of combined ADHD in the number of points obtained when drawing back and reproduction from memory. In the latter index were also differences between ADHD inattentive children and the combined subtype. Children with ADHD obtained statistically significant different results than healthy children in the drawing category (which were treated as an indicator of the executive functions of planning) but only in reproduction from memory. Quality of the copy does not differentiate the groups. CONCLUSIONS: ROCF and MFFT are useful measures of visual-spatial function and visual memory of children with ADHD. They have less relevance in the assessment of executive functions. Visual-spatial disorders were found only in children with ADHD combined subtype.

Significance of the Diagnosis of Executive Functions in Patients with Relapsing-Remitting Multiple Sclerosis.

Multiple sclerosis (MS) is a progressive chronic disease of the Central Nervous System (CNS). Cognitive decline occurs rather rarely in relapsing-remitting multiple sclerosis (RRMS) compared to other types. The present study aimed to assess executive functions (EF) in relation to clinical and demographic variables in patients with RRMS. The study involved 22 individuals with RRMS (aged 23 to 49 years) and 22 matching controls. All the individuals with RRMS were in the remission phase. The assessments were carried out using MoCA, BDI-II, Halstead Category Test, Porteus Maze Test, verbal fluency tasks and Stroop Colour-Word Interference Test. The findings show that the two groups differed significantly in all the tests. All patients with RRMS in the remission phase presented at least one cognitive deficit, observed in general cognitive functioning, abstract reasoning or other executive functions, i.e., fluency, interference suppression, planning, or ability to modify activity in response to feedback. The deficits in most cases (except for those measured with the MoCA, Category Tests and phonemic fluency), are not related to intensity of depression and duration of the disease. Findings suggest that the diagnostic process in the case of patients with RRMS may include psychological assessment focusing on potentially existing cognitive, mainly executive, deficits and their severity.

Clinical Significance of Tumor Microenvironment in Acral Melanoma: A Large Single-Institution Study of Caucasians.

BACKGROUND: The presence of tumor-infiltrating lymphocytes (TILs) in many studies is associated with a better prognosis in melanoma patients. Programmed death-ligand 1 (PD-L1) expression has a significant value in predicting several cancers, but its role in melanoma remains ambiguous. The study aims to report a comprehensive analysis of TILs characteristics and their impact on survival in primary acral melanoma (AM). METHODS: Clinical and pathological features and survival outcomes were investigated in 70 patients with AM. Immunohistochemical quantitative analysis of TILs, including expression of CD4, CD8, FOXP3, PD-1, and PD-L1, on melanoma cells was performed. RESULTS: Kaplan-Meier analysis showed significant differences in overall survival (OS) for CD4+ (p = 0.021), CD8+ (p = 0.037), FOXP3+ (p = 0.007), and TILs density (p = 0.043). In univariate analysis of immunohistochemical features, FOXP3, CD4, CD8, PD-1, and Melanoma Institute of Australia (MIA) grading TILs (grade, density, and distribution) were correlated with survival. The higher density of FOXP3-positive cells was an independent factor associated with better survival. CONCLUSIONS: High TILs content (classed as brisk Clark scale and marked/diffuse TILs MIA grade) regardless of its immunophenotype was associated with better survival outcomes in AM. PD-L1 expression on tumor cells did not influence OS and was independent of clinical and pathological characteristics. We demonstrated that TILs are significant biomarkers in sentinel lymph node status prediction.