Predicting neutropenia dynamics after radiation therapy in multiple myeloma patients receiving first-line bortezomib-based chemotherapy – a pilot study

Introduction.Radiation therapy (RT) is a useful modality for achieving local control and symptom relief in patients with multiple myeloma (MM), but its use can result in adverse effects such as neutropenia, which may be aggravated by prior chemotherapy. Material and methods.In this retrospective study, we analyzed 530 complete blood count results of 32 MM patients who underwent RT for symptomatic bone pain between cycles or after completing first-line bortezomib-based che­motherapy (VCD). To evaluate the dynamics of neutrophil count (ANC) changes, we developed a generalized additive model (GAM) using initial ANC, dosage (BED10), and treatment volume (PTV) as predictors. Results.Our GAM model demonstrated that ANC nadir after RT can be expected approximately 16 days after treatment initiation. The delivery of 8 Gy in 1 fraction resulted in the lowest ANC nadir, while a dose of 30 Gy in 10–15 fractions was deemed the safest. For PTV = 1000 cm3, an initial ANC level of at least 1.42 × 103/μl was associated with no incidence of severe neutropenia irrespective of the fractionation scheme. Longer courses allowed for treatment delivery without significant neutropenia even with an initial ANC of 1.23 × 103/μl on the day of RT initiation. Conclusions.Our model could aid in optimizing treatment strategies for MM patients receiving RT and chemotherapy. Further research is needed to validate our findings and evaluate the feasibility of implementing this model in clinical practice.

Predicting neutropenia dynamics after radiation therapy in multiple myeloma patients receiving first-line bortezomib-based chemotherapy – a pilot study

Introduction. Radiation therapy (RT) is a useful modality for achieving local control and symptom relief in patients with multiple myeloma (MM), but its use can result in adverse effects such as neutropenia, which may be aggravated by prior chemotherapy. Material and methods. In this retrospective study, we analyzed 530 complete blood count results of 32 MM patients who underwent RT for symptomatic bone pain between cycles or after completing first-line bortezomib-based chemotherapy (VCD). To evaluate the dynamics of neutrophil count (ANC) changes, we developed a generalized additive model (GAM) using initial ANC, dosage (BED10), and treatment volume (PTV) as predictors. Results. Our GAM model demonstrated that ANC nadir after RT can be expected approximately 16 days after treatment initiation. The delivery of 8 Gy in 1 fraction resulted in the lowest ANC nadir, while a dose of 30 Gy in 10–15 fractions was deemed the safest. For PTV = 1000cm3, an initial ANC level of at least 1.42 × 103/µl was associated with no incidence of severe neutropenia irrespective of the fractionation scheme. Longer courses allowed for treatment delivery without significant neutropenia even with an initial ANC of 1.23 × 103/µl on the day of RT initiation. Conclusions. Our model could aid in optimizing treatment strategies for MM patients receiving RT and chemotherapy. Further research is needed to validate our findings and evaluate the feasibility of implementing this model in clinical practice

Short Clinically-Based Prediction Model to Forecast Transition to Psychosis in Individuals at Clinical High Risk State

AbstractObjective:The predictive accuracy of the Clinical High Risk criteria for Psychosis (CHR-P) regarding the future development of the disorder remains suboptimal. It is therefore necessary to incorporate refined risk estimation tools which can be applied at the individual subject level. The aim of the study was to develop an easy-to use, short refined risk estimation tool to predict the development of psychosis in a new CHR-P cohort recruited in European country with less established early detection services.Methods:A cohort of 105 CHR-P individuals was assessed with the Comprehensive Assessment of At Risk Mental States12/2006, and then followed for a median period of 36 months (25th-75th percentile:10–59 months) for transition to psychosis. A multivariate Cox regression model predicting transition was generated with preselected clinical predictors and was internally validated with 1000 bootstrap resamples.Results:Speech disorganization and unusual thought content were selected as potential predictors of conversion on the basis of published literature. The prediction model was significant (p < 0.0001) and confirmed that both speech disorganization (HR = 1.69; 95%CI: 1.39–2.05) and unusual thought content (HR = 1.51; 95%CI: 1.27–1.80) were significantly associated with transition. The prognostic accuracy of the model was adequate (Harrell's c- index = 0.79), even after optimism correction through internal validation procedures (Harrell's c-index = 0.78).Conclusions:The clinical prediction model developed, and internally validated, herein to predict transition from a CHR-P to psychosis may be a promising tool for use in clinical settings. It has been incorporated into an online tool available at:https://link.konsta.com.pl/psychosis. Future external replication studies are needed

CSF1R inhibition with PLX5622 affects multiple immune cell compartments and induces tissue-specific metabolic effects in lean mice

AIMS/HYPOTHESIS Colony stimulating factor 1 (CSF1) promotes the proliferation, differentiation and survival of macrophages, which have been implicated in both beneficial and detrimental effects on glucose metabolism. However, the physiological role of CSF1 signalling in glucose homeostasis and the potential therapeutic implications of modulating this pathway are not known. We aimed to study the composition of tissue macrophages (and other immune cells) following CSF1 receptor (CSF1R) inhibition and elucidate the metabolic consequences of CSF1R inhibition. METHODS We assessed immune cell populations in various organs by flow cytometry, and tissue-specific metabolic effects by hyperinsulinaemic-euglycaemic clamps and insulin secretion assays in mice fed a chow diet containing PLX5622 (a CSF1R inhibitor) or a control diet. RESULTS CSF1R inhibition depleted macrophages in multiple tissues while simultaneously increasing eosinophils and group 2 innate lymphoid cells. These immunological changes were consistent across different organs and were sex independent and reversible after cessation of the PLX5622. CSF1R inhibition improved hepatic insulin sensitivity but concomitantly impaired insulin secretion. In healthy islets, we found a high frequency of IL-1β$^{+}$ islet macrophages. Their depletion by CSF1R inhibition led to downregulation of macrophage-related pathways and mediators of cytokine activity, including Nlrp3, suggesting IL-1β as a candidate insulin secretagogue. Partial restoration of physiological insulin secretion was achieved by injecting recombinant IL-1β prior to glucose stimulation in mice lacking macrophages. CONCLUSIONS/INTERPRETATION Macrophages and macrophage-derived factors, such as IL-1β, play an important role in physiological insulin secretion. A better understanding of the tissue-specific effects of CSF1R inhibition on immune cells and glucose homeostasis is crucial for the development of targeted immune-modulatory treatments in metabolic disease. DATA AVAILABILITY The RNA-Seq dataset is available in the Gene Expression Omnibus (GEO) under the accession number GSE189434 ( http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE189434 )

Extracellular miRNAs as Biomarkers of Head and Neck Cancer Progression and Metastasis

Head and neck squamous cell carcinomas (HNSCCs) contribute to over 300,000 deaths every year worldwide. Although the survival rates have improved in some groups of patients, mostly due to new treatment options and the increasing percentage of human papillomavirus (HPV)-related cancers, local recurrences and second primary tumors remain a great challenge for the clinicians. Presently, there is no biomarker for patient surveillance that could help identify patients with HNSCC that are more likely to experience a relapse or early progression, potentially requiring closer follow-up or salvage treatment. MicoRNAs (miRNAs) are non-coding RNA molecules that posttranscriptionally modulate gene expression. They are highly stable and their level can be measured in biofluids including serum, plasma, and saliva, enabling quick results and allowing for repeated analysis during and after the completion of therapy. This has cemented the role of miRNAs as biomarkers with a huge potential in oncology. Since altered miRNA expression was described in HNSCC and many miRNAs play a role in radio- and chemotherapy resistance, cancer progression, and metastasis, they can be utilized as biomarkers of these phenomena. This review outlines recent discoveries in the field of extracellular miRNA-based biomarkers of HNSCC progression and metastasis, with a special focus on HPV-related cancers and radioresistance

Patients’ awareness of the prevention and treatment of colorectal cancer

The aim of the study was to assess patients’ awareness of the prevention and treatment of colorectal cancer. Material and methods. Patients diagnosed with colorectal cancer, hospitalised at the Department of General and Colorectal Surgery of the Medical University in Łódź during the period from January 2015 to April 2015, were asked to complete a questionnaire concerning their families’ medical case record, factors predisposing them to the development of colorectal cancer, the tests applied in diagnostics, and the treatment process. The questionnaire comprised 42 closed-ended questions with one correct answer. A statistical analysis of all answers was carried out. Results. The study group consisted of 30 men and 20 women aged 27–94 years old. A strong, statistically significant negative correlation between a patient’s age and his/her awareness of the prevention and treatment of colorectal cancer was noted (p<0.001; r= -0.51). The study demonstrated a statistically significant relationship between the occurrence of neoplasms in a patient’s family (p=0.009) or, more specifically, the occurrence of colorectal cancer (p=0.008), and the awareness of the prevention programme. The women’s group was characterised by statistically significantly greater awareness of colonoscopy as a screening examination (p=0.004). Conclusions. Patients need more information on colorectal cancer, its risk factors, prevention, the treatment process, and postoperative care. Lack of awareness of the colorectal cancer issue can be one of the major factors contributing to the high incidence of this disease

Clinical significance of CD34, podoplanin and Ki-67 expression in patients with locally advanced squamous cell cervical carcinoma

The aim of the study was to assess immunohistochemical CD34, podoplanin and Ki-67 expression in cervical tumour of patients with cervical squamous cell carcinoma (SCC) staged IIB and IIIB, a relationship with selected clinical and histological parameters and its prognostic significance. This prospective study included 52 patients. Microvessel density (MVD) by CD34, lymphatic vessel density (LVD) by podoplanin and the Ki-67 index in specimens from paraffin blocks with cervical SCC tissues were examined. The relationship between these data and selected clinical and histological parameters was analysed. Positive correlation of MVD and the Ki-67 index was observed. No correlation was observed for MVD, LVD and the Ki-67 index in the tumour with staging, grading, length of treatment and squamous cell carcinoma antigen (SCC-Ag) concentration before and after treatment. The expression of MVD, LVD and the Ki-67 index in cervical SCC did not contribute to the risk of relapse and cancer-related death. No relationship was found for MVD, LVD and the Ki-67 index in cervical tumour of patients with locally advanced cervical SCC with staging, grading and serum SCC-Ag level. MVD, LVD and the Ki-67 index in the tumour did not contribute to the risk of relapse or cervical SCC-related death.Impact Statement What is already known on this subject? In many patients, invasive cervical squamous cell carcinoma (SCC) is diagnosed in a locally advanced stage, when the prognosis depends on many well-known factors connected with tumour biology, staging and general condition of the patient. Despite numerous studies, the value of immunohistochemical CD34, podoplanin and Ki-67 expression in cervical tumour of these patients is still not well defined. What do the results of this study add? In our prospective study, no relationship for microvessel density (MVD), lymphatic vessel density (LVD) and the Ki-67 index in cervical tumour of patients with locally advanced cervical SCC with staging, grading and serum squamous cell carcinoma antigen (SCC-Ag) level was found. Additionally, MVD, LVD and the Ki-67 index in the tumour did not contribute to the risk of relapse or cervical SCC-related death. What are the implications of these findings for clinical practice and/or further research? Our study underlines the limited value of immunohistochemical CD34, podoplanin and Ki-67 expression in cervical tumour of patients with locally advanced cervical SCC. Further research should be focussed on identifying and validating novel prognostic and predictive factors

Hormonal Receptor Status Determines Prognostic Significance of FGFR2 in Invasive Breast Carcinoma

Interaction between fibroblast growth factor receptor 2 (FGFR2) and estrogen/progesterone receptors (ER/PR) affects resistance to anti-ER therapies, however the prognostic value of FGFR2 in breast cancer (BCa) remains largely unexplored. We have recently showed in vitro that FGFR2-mediated signaling alters PR activity and response to anti-ER treatment. Herein, prognostic significance of FGFR2 in BCa was evaluated in relation to both ER/PR protein status and a molecular signature designed to reflect PR transcriptional activity. FGFR2 was examined in 353 BCa cases using immunohistochemistry and Nanostring-based RNA quantification. FGFR2 expression was higher in ER+PR+ and ER+PR- compared to ER&minus;PR&minus; cases (p &lt; 0.001). Low FGFR2 was associated with higher grade (p &lt; 0.001), higher Ki67 proliferation index (p &lt; 0.001), and worse overall and disease-free survival (HR = 2.34 (95% CI: 1.26&ndash;4.34), p = 0.007 and HR = 2.22 (95% CI: 1.25&ndash;3.93), p = 0.006, respectively). The poor prognostic value of low FGFR2 was apparent in ER+PR+, but not in ER+PR&minus; patients, and it did not depend on the expression level of PR-dependent genes. Despite the functional link between FGFR2 and ER/PR revealed by preclinical studies, the data showed a link between FGFR2 expression and poor prognosis in BCa patients