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The accurate assessment of malignancy and the precise characterization of cancer type are pivotal in guiding clinical decisions and ensuring optimal patient outcomes. The challenging task of identifying the primary site of carcinoma, especially during a surgical procedure, is not always possible and necessitates the exploration of novel, innovative diagnostic techniques. In this report, we detail a unique case of carcinoma of unknown primary origin encountered during an orthopedic surgical procedure. We introduce a novel intraoperative flow cytometry (iFC) methodology, distinctly different from traditional flow cytometry, which is tailored for real-time assessment during surgeries. This iFC technique, applied in a bone metastasis case of unknown primary origin, enabled DNA content analysis and the quantification of cytokeratin for rapid malignancy characterization, presenting an avenue for immediate surgical guidance and decision making. The case was distinctively characterized using iFC, shedding light on the potential of this emerging technique. iFC has been gaining traction because of its ability to facilitate cancer cell assessment and margin evaluation. It has been successfully applied across a wide spectrum of neoplastic conditions. Our innovative, two-step approach using iFC encompasses (1) DNA content analysis, which serves as a reliable indicator for the detection of cancer cells, and (2) the quantification of cytokeratin, a pivotal marker, which aids in the characterization and classification of a malignancy. In this case, the malignancy was classified as a carcinoma. The findings obtained from iFC were subsequently validated through pathology assessment, confirming the accuracy and reliability of our approach. This noteworthy case strengthens the potential of iFC as a novel tool in malignancy assessment, which is not just limited to cell cycle analysis but instead extends beyond this application. The promising results obtained from this case study serve as a testament to the need for more extensive research in clinical studies.

Background: Dose-dense sequential (dds) chemotherapy has changed the clinical outcome of patients with early breast cancer (BC). To investigate the impact of dose intensity (DI) in the adjuvant setting of BC, this observational trial (HE 10/10) was conducted assessing the long-term survival outcome, safety and toxicity of a currently widely used chemotherapeutic regimen. In addition, the prognostic significance of tumor infiltrating lymphocytes (TILs) and infiltrating CD8+ lymphocytes were also evaluated in the same cohort. Patients and methods: Totally, 1054 patients were prospectively enrolled in the current study with 1024 patients being eligible, while adequate tissue was available for 596 of them. TILs, CD8+ lymphocytes in intratumoral areas in contact with malignant cells (iCD8), CD8+ lymphocytes in tumor stroma (sCD8) as well as the total number of CD8+ lymphocytes within the tumor area (total CD8) were assessed by immunohistochemistry. Results: Within a median follow-up of 125.18 months, a total of 200 disease-free survival (DFS) events (19.5%) were reported. Importantly, the 10-year DFS and OS rates were 78.4% (95% CI 75.0–81.5) and 81.7% (95% CI 79.0–84.1), respectively. Interestingly, higher CD8+ T cells as well as TILs in the tumor microenvironment were associated with an improved long-term survival outcome. Conclusions: In conclusion, this study confirms the significance of dds adjuvant chemotherapeutic regimen in terms of long-term survival outcome, safety and toxicity as well as the prognostic significance of TILs and infiltrating CD8+ lymphocytes in BC patients with early-stage disease.

Abstract Background The vast majority of patients with HER2-positive metastatic breast cancer (MBC) treated with trastuzumab eventually develop resistance to this agent. There is an unmet need therefore, for identifying biological markers with possible prognostic/predictive value in such patients. The aim of this study was to investigate the prognostic role of topoisomerase II alpha gene (TOP2A) amplification and protein (TopoIIa) expression in patients treated with trastuzumab-containing regimens. Methods Formalin-fixed paraffin-embedded tumor tissue samples were retrospectively collected from 225 eligible patients treated with trastuzumab. Protein expression of ER, PgR, Ki67, PTEN, HER2 and TopoIIa were centrally assessed by immunohistochemistry. HER2 and TOP2A gene amplification was evaluated by fluorescence in situ hybridization. PIK3CA mutations were identified by single nucleotide polymorphism genotyping. Survival was evaluated from the initiation of trastuzumab as 1st line treatment to the date of last follow-up or death. Results Among the 225 samples analyzed, only 137 (61%) were found to be HER2-positive. TOP2A was amplified in 41% and deleted in 16% of such tumors. TOP2A gene amplification was more frequent in ER-negative tumors. TopoIIa protein expression was observed in the majority (65%) of the samples and was associated with ER-positive status, high Ki67 expression, presence of PTEN protein and PIK3CA mutations. Median follow-up for patients treated in the 1st line was 51 months. Survival was more prolonged with trastuzumab-containing treatment in HER2-positive patients (50 months, log-rank, p=0.007). TOP2A non-amplified or deleted tumors were associated with increased risk for death compared to TOP2A amplified tumors (HR=2.16, Wald’s p=0.010 and HR=2.67, p=0.009, respectively). In multivariate analysis, a significant interaction of TOP2A with anthracycline treatment (either in the adjuvant or the 1st line setting) was observed for survival (Wald’s p=0.015). Among the TOP2A amplified subgroup, anthracycline-treated patients were associated with decreased risk for death. Conclusions TOP2A gene amplification was shown to be a favorable prognostic marker in HER2-positive MBC patients treated with trastuzumab, such an effect however, appears to rather be related to treatment with anthracyclines (predictive marker for benefit from anthracyclines). The results of the present retrospective study warrant validation in larger cohorts of patients treated in the context of randomized trials.

Abstract Background To investigate the expression of E-cadherin, beta-catenin and topoisomerase-II alpha and examine their clinical relevance in liposarcomas. Materials and methods The expression of E-cadherin, beta-catenin and topoisomerase II alpha was examined immunohistochemically on formalin-fixed paraffin-embedded tissue specimens from 71 patients who underwent surgical treatment for liposarcomas of the extremities or the retroperitoneum in two major cancer reference centres between 1990 and 2000. Detailed medical notes were available for all patients who were followed for median 82 months (range 5 to 215 months). Obtained expression data were weighted against clinical and pathology parameters of clinical relevance. Results Patients were mostly male (59%), median age was 56 years for the liposarcomas of the extremities and 60 years for the retroperitoneal liposarcomas. The tumours were of diverse histology, grade and size (median diameters 7 and 17 cm for tumours of the extremities and retroperitoneum respectively). Expression of β-catenin protein was weakly detected in 15 cases (21.1%). Similarly weak expression of topoisomerase II-alpha was detected in 14 (19.7%) cases of which only two had more than 20% of tumor cells stained positive. E-cadherin was not detected in the studied cohort of liposarcomas. We did not detect associations between the expression of the above proteins by liposarcoma cells and clinical outcome. Conclusions Liposarcomas do not express E-cadherin, which matches the absence of epithelioid differentiation in this sarcoma subtype, and have low topoisomerase II-alpha expression, which justifies to some extend their resistance to anthracycline-based chemotherapy.

Abstract Background HER2 and TOP2A parameters (gene status, mRNA and protein expression) have individually been associated with the outcome of patients treated with anthracyclines. The aim of this study was to comprehensively evaluate the prognostic/predictive significance of the above parameters in early, high-risk breast cancer patients treated with epirubicin-based, dose-dense sequential adjuvant chemotherapy. Methods In a series of 352 breast carcinoma tissues from patients that had been post-operatively treated with epirubicin-CMF with or without paclitaxel, we assessed HER2 and TOP2A gene status (chromogenic in situ hybridization), mRNA expression (quantitative reverse transcription PCR), as well as HER2 and TopoIIa protein expression (immunohistochemistry). Results HER2 and TOP2A amplification did not share the same effects on their downstream molecules, with consistent patterns observed in HER2 mRNA and protein expression according to HER2 amplification (all parameters strongly inter-related, p values < 0.001), but inconsistent patterns in the case of TOP2A. TOP2A gene amplification (7% of all cases) was not related to TOP2A mRNA and TopoIIa protein expression, while TOP2A mRNA and TopoIIa protein were strongly related to each other (p < 0.001). Hence, TOP2A amplified tumors did not correspond to tumors with high TOP2A mRNA or TopoIIa protein expression, while the latter were characterized by high Ki67 scores (p = 0.003 and p < 0.001, respectively). Multivariate analysis adjusted for nodal involvement, hormone receptor status, Ki67 score and HER2/TOP2A parameters revealed HER2/TOP2A co-amplification (21.2% of HER2 amplified tumors) as an independent favorable prognostic factor for DFS (HR = 0.13, 95% CI: 0.02-0.96, p = 0.046); in contrast, increased HER2/TOP2A mRNA co-expression was identified as an independent adverse prognostic factor for both DFS (HR = 2.41, 95% CI: 1.31-4.42, p = 0.005) and OS (HR = 2.83, 95% CI: 1.42-5.63, p = 0.003), while high TOP2A mRNA expression was an independent adverse prognostic factor for OS (HR = 2.06, 95% CI: 1.23-3.46, p = 0.006). None of the parameters tested was associated with response to paclitaxel. Conclusions This study confirms the favorable prognostic value of HER2/TOP2A co-amplification and the adverse prognostic value of high TOP2A mRNA expression extending it to the adjuvant treatment setting in early high-risk breast cancer. The strong adverse prognostic impact of high HER2/TOP2A mRNA co-expression needs further validation in studies designed to evaluate markers predictive for anthracyclines. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12611000506998.

Abstract Low grade fibromyxoid sarcoma (LGFMS) is a distinctive variant of fibrosarcoma with a high metastasizing potential and sometimes long interval between tumour presentation and metastasis. We present the case of a 50-year-old male who developed a large mass in the posterior aspect of his lower left thigh. The tumor was excised with preservation of the neurovascular structures surrounded by the mass. The tumour measured 11 × 10 × 9 cm and on pathology evaluation was diagnosed as LGFMS. Due to the relative rarity of LGFMS, there is no dedicated protocol regarding follow-up recommendations. In order to early diagnose possible metastasis it is important to inform the patients about the longstanding metastatic potential of the disease.

Abstract Background This study aimed to investigate the efficacy of prophylactic amifostine in reducing the risk of severe radiation colitis in cancer patients receiving radical radiotherapy to the pelvis. Methods Patients with pelvic tumours referred for radical radiotherapy who consented participation in this trial, were randomly assigned to receive daily amifostine (A) (subcutaneously, 500 mg flat dose) before radiotherapy or radiotherapy alone (R). Sigmoidoscopy and blinded biopsies were scheduled to conduct prior to initiation and following completion of radiotherapy and again 6 to 9 months later. Radiation colitis was assessed by clinical, endoscopic and histolopathological criteria. Results A total 44 patients were enrolled in this trial, the majority with rectal (20 patients) and cervical cancer (12 patients) and were assigned 23 in R arm and 21 in the A arm. In total 119 sigmoidoscopies were performed and 18 patients (18/44, 40.9%) were diagnosed with radiation colitis (15 grade 1 and 2, and 3 grade 3 and 4). Of them, 6 patients belonged to the A group (6/21, 28.6%) and 12 to the R group (12/23, 52.2%). Acute and grade IV radiation colitis was only developed in four patients (17.4%) in the R group. Amifostine side effects were mild. Amifostine treated patients were less likely to develop histologically detectable mucosal lesions, which indicate protection from acute mucosal injury. Conclusions Amifostine given subcutaneously can lower the risk of acute severe radiation colitis in patients who receive radical radiotherapy to pelvic tumors.

Abstract Introduction Male breast cancer is rare compared to its female counterpart representing less than 1% of cancer in men. Moreover, mucinous carcinoma of the male breast is an extremely rare histological subtype of malignancy. Paget's disease of the nipple is rarely observed in males. Case report Herein, we describe a unique case of an 86 years old man with mucinous breast cancer presenting as Paget's disease of the nipple. According to the immunohistochemical evaluation the neoplastic cells were positive for estrogen (ER) and progesterone receptors (PR). Conclusion To our best knowledge this is the first case of mucinous male breast cancer presenting as Paget's disease of the nipple.

Abstract Chondrosarcoma is the third most common primary malignancy of bone, affecting primarily the pelvic and shoulder girdles and being extremely rare in the spine. Herein, we present a case of a 65-year-old woman with a rare chondrosarcoma of the spine, who presented with clinical symptoms from the lung metastasis. The neoplasm was grade II and exhibited overexpression of the p53 tumor suppressor protein. The latter has been associated with a high propensity for distant metastases.

Abstract The term melanosis in the gastrointestinal tract refers to the accumulation of pigment deposits in the mucosa. Melanosis of the colon is not uncommon and has been associated with certain conditions, however melanosis of the small intestine is extremely rare. Herein, we describe a case in which we observed melanosis not only in the colon, but in the terminal ileum as well, associated with the use of anthraceneline laxatives. The clinical significance of this condition is not clear, however Gastroenterologists and Pathologists should be aware of its existence.

Facial thermal reactions were measured to confirm individuals preferences for the colors used in moodboards as a functionof their motivation profile to leisure physical activity (PA). Forty-five individuals were recruited as primary motivated byPsychological well-being (PSY), beauty appearance (APP) or Physical strength (PHY). Participants performed two taskssitting in front of a computer screen. In the first, a SMI-eye tracking system was used to measure fixation durations (in ms)when color-patches were presented. In the second task, a thermal camera measured emotional reactions to the presentationof motivation-designed moodboards. Specific eye-tracking patterns and thermal reactions were obtained as a function ofmotivation profiles. Green, pink and red/black were the preferred colors for PSY, APP and PHY profiles, respectively.Data from the thermal camera confirmed the specificity of the profile groups by indicating that greater emotional changesin face temperature were observed when individuals viewed moodboards that corresponded to their own profile.

Abstract The kinase haspin phosphorylates histone H3 at threonine-3 (H3T3ph) during mitosis. H3T3ph provides a docking site for the Chromosomal Passenger Complex at the centromere, enabling correction of erratic microtubule-chromosome contacts. Although this mechanism is operational in all dividing cells, haspin-null mice do not exhibit developmental anomalies, apart from aberrant testis architecture. Investigating this problem, we show here that mouse embryonic stem cells that lack or overexpress haspin, albeit prone to chromosome misalignment during metaphase, can still divide, expand and differentiate. RNA sequencing reveals that haspin dosage affects severely the expression levels of several genes that are involved in male gametogenesis. Consistent with a role in testis-specific expression, H3T3ph is detected not only in mitotic spermatogonia and meiotic spermatocytes, but also in non-dividing cells, such as haploid spermatids. Similarly to somatic cells, the mark is erased in the end of meiotic divisions, but re-installed during spermatid maturation, subsequent to methylation of histone H3 at lysine-4 (H3K4me3) and arginine-8 (H3R8me2). These serial modifications are particularly enriched in chromatin domains containing histone H3 trimethylated at lysine-27 (H3K27me3), but devoid of histone H3 trimethylated at lysine-9 (H3K9me3). The unique spatio-temporal pattern of histone H3 modifications implicates haspin in the epigenetic control of spermiogenesis.

Objective Family caregivers play an essential role in end-of-life care but suffer considerable impact on their own health. A better understanding of main factors related to carers’ health is important to inform interventions. The purpose of the study was to test for the first time the potential impact of a comprehensive set of observable variables on carer health during end-of-life caregiving within a population-based carer sample.Design National retrospective, cross-sectional, 4-month post-bereavement postal census survey of family carers of people who died from cancer.Setting and participants Relatives who registered a death from cancer during a 2-week period in England were identified from death certificates by the Office of National Statistics; response rate was 1504/5271 (28.5%).Outcome measures Carers’ mental health was measured through General Health Questionnaire (GHQ)-12; general health was measured through EuroQoL EQ-Visual Analogue Scale (EQ-5D VAS).Methods Survey questions to measure potential variables associated with carer health were based on past research and covered patients’ symptoms and functioning; caregiving activities and hours; informal and formal help received; work hours, other caregiving, volunteering; changes to work, income and expenditure; sleep and relaxation; and demographic variables. Bivariate analyses and ordinary least square regression were performed to investigate these variables’ relationship with outcomes.Results Patients’ psychological symptoms and functioning, caregiving hours, female gender and self-sought formal help related to worse mental health. General practitioner and social care input and relaxation related to better mental health. Patients’ psychological symptoms, caregiving hours and female gender were associated with worse general health, and older age, employment and relaxation were associated with better general health.Conclusions Improvements in carers’ health overall may be made by focusing on potential impacts of patients’ psychological symptoms on carers, facilitating respite and relaxation, and paying particular attention to factors affecting female carers.

Coronavirus-related Severe Acute Respiratory Syndrome-2 (SARS-CoV-2) initially was detected in Wuhan, Hubei, China. Since early 2021, World Health Organization (WHO) has declared Coronavirus Disease 2019 (COVID-19) a pandemic due to rapidly transformed to a globally massive catastrophic viral infection. In order to confront this emergency situation, many pharmaceutical companies focused on the design and development of efficient vaccines that are considered necessary for providing a level of normalization in totally affected human social-economical activity worldwide. A variety of vaccine types are under development, validation or even some of them have already completed these stages, initially approved as conditional marketing authorisation by Food and Drug Administration (FDA), European Medicines Agency (EMA), and other national health authorities for commercial purposes (in vivo use in general population), accelerating their production and distribution process. Innovative nucleoside-modified viral messenger RNA (v-mRNA)—based vaccines encapsulated within nanoparticles—specifically lipid ones (LNPs)—are now well recognized. Although this is a promising genetic engineering topic in the field of nanopharmacogenomics or targeted nucleic vaccines, there are limited but continuously enriched in vivo data in depth of time regarding their safety, efficacy, and immune response. In the current paper we expand the limited published data in the field of ribosome machinery and SARS-CoV-2 mRNA fragment vaccines interaction by describing their functional specialization and modifications. Additionally, alterations in post-transcriptional/translational molecules and mechanisms that could potentially affect the interaction between target cells and vaccines are also presented. Understanding these mechanisms is a crucial step for the next generation v-mRNA vaccines development.

Objective Investigated clinical effectiveness and cost-effectiveness of a person-centred intervention for informal carers/caregivers of stroke survivors.Design Pragmatic cluster randomised controlled trial (cRCT) with economic and process evaluation.Setting Clusters were services, from a UK voluntary sector specialist provider, delivering support primarily in the homes of stroke survivors and informal carers.Participants Adult carers in participating clusters were referred to the study by cluster staff following initial support contact.Interventions Intervention was the Carer Support Needs Assessment Tool for Stroke: a staff-facilitated, carer-led approach to help identify, prioritise and address the specific support needs of carers. It required at least one face-to-face support contact dedicated to carers, with reviews as required. Control was usual care, which included carer support (unstructured and variable).Outcome measures Participants provided study entry and self-reported outcome data by postal questionnaires, 3 and 6 months after first contact by cluster staff. Primary outcome: 3-month caregiver strain (Family Appraisal of Caregiving Questionnaire, FACQ). Secondary outcomes: FACQ subscales of caregiver distress and positive appraisals of caregiving, mood (Hospital Anxiety and Depression Scale) and satisfaction with stroke services (Pound). The economic evaluation included self-reported healthcare utilisation, intervention costs and EQ-5D-5L.Randomisation and masking Clusters were recruited before randomisation to intervention or control, with stratification for size of service. Cluster staff could not be masked as training was required for participation. Carer research participants provided self-reported outcome data unaware of allocation; they consented to follow-up data collection only.Results Between 1 February 2017 and 31 July 2018, 35 randomised clusters (18 intervention; 17 control) recruited 414 cRCT carers (208 intervention; 206 control). Study entry characteristics were well balanced. Primary outcome measure: intention-to-treat analysis for 84% retained participants (175 intervention; 174 control) found mean (SD) FACQ carer strain at 3 months to be 3.11 (0.87) in the control group compared with 3.03 (0.90) in the intervention group, adjusted mean difference of −0.04 (95% CI −0.20 to 0.13). Secondary outcomes had similarly small differences and tight CIs. Sensitivity analyses suggested robust findings. Intervention fidelity was not achieved. Intervention-related group costs were marginally higher with no additional health benefit observed on EQ-5D-5L. No adverse events were related to the intervention.Conclusions The intervention was not fully implemented in this pragmatic trial. As delivered, it conferred no clinical benefits and is unlikely to be cost-effective compared with usual care from a stroke specialist provider organisation. It remains unclear how best to support carers of stroke survivors. To overcome the implementation challenges of person-centred care in carers’ research and service development, staff training and organisational support would need to be enhanced.Trial registration number ISRCTN58414120.

Simple Summary: This study aims to explore the connection between tumor-associated macrophages (TAMs) and the programmed cell death protein 1(PD-1)/programmed death ligand 1 (PD-L1) pathway in gastric cancer (GC). Immune checkpoint inhibitors (ICIs) have shown promise in cancer treatment. Here, we investigate their potential in GC. TAMs, abundant in the tumor microenvironment (TME), can express PD-1, which interacts with PD-L1 on cancer cells. This systematic review indicates that high PD-L1 expression correlates with increased TAM infiltration and may lead to worse patient outcomes. This suggests that TAMs could be crucial in regulating the PD-1/PD-L1 network in GC. Enhanced comprehension of this intricate relationship may offer opportunities for optimizing the efficacy of ICIs in this malignancy. Background: Gastric cancer (GC) is one of the most common and aggressive types of cancer. Immune checkpoint inhibitors (ICIs) have proven effective in treating various types of cancer. The use of ICIs in GC patients is currently an area of ongoing research. The tumor microenvironment (TME) also seems to play a crucial role in cancer progression. Tumor-associated macrophages (TAMs) are the most abundant population in the TME. TAMs are capable of displaying programmed cell death protein 1 (PD-1) on their surface and can form a ligand with programmed death ligand 1 (PD-L1), which is found on the surface of cancer cells. Therefore, it is expected that TAMs may significantly influence the immune response related to immune checkpoint inhibitors (ICIs). Aim of the study: Understanding the role of TAMs and PD-1/PD-L1 networking in GC. Methods: A systematic review of published data was performed using MEDLINE (PubMed), Embase, and Cochrane databases. We retrieved articles investigating the co-existence of TAMs and PD-1 in GC and the prognosis of patients expressing high levels of PD-1+ TAMs. Results: Ten articles with a total of 2277 patients were included in the systematic review. The examined data suggest that the expression of PD-L1 has a positive correlation with the infiltration of TAMs and that patients who express high levels of PD-1+ TAMs may have a worse prognosis than those who express low levels of PD-1+ TAMs. Conclusions: TAMs play a pivotal role in the regulation of PD-1/PD-L1 networking and the progression of GC cells. Nevertheless, additional studies are needed to better define the role of TAMs and PD-1/PD-L1 networking in GC. [ABSTRACT FROM AUTHOR]