An expression signature of the angiogenic response in gastrointestinal neuroendocrine tumours: correlation with tumour phenotype and survival outcomes.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are heterogeneous with respect to biological behaviour and prognosis. As angiogenesis is a renowned pathogenic hallmark as well as a therapeutic target, we aimed to investigate the prognostic and clinico-pathological role of tissue markers of hypoxia and angiogenesis in GEP-NETs. METHODS: Tissue microarray (TMA) blocks were constructed with 86 tumours diagnosed from 1988 to 2010. Tissue microarray sections were immunostained for hypoxia inducible factor 1α (Hif-1α), vascular endothelial growth factor-A (VEGF-A), carbonic anhydrase IX (Ca-IX) and somatostatin receptors (SSTR) 1–5, Ki-67 and CD31. Biomarker expression was correlated with clinico-pathological variables and tested for survival prediction using Kaplan–Meier and Cox regression methods. RESULTS: Eighty-six consecutive cases were included: 51% male, median age 51 (range 16–82), 68% presenting with a pancreatic primary, 95% well differentiated, 51% metastatic. Higher grading (P=0.03), advanced stage (P<0.001), high Hif-1α and low SSTR-2 expression (P=0.03) predicted for shorter overall survival (OS) on univariate analyses. Stage, SSTR-2 and Hif-1α expression were confirmed as multivariate predictors of OS. Median OS for patients with SSTR-2+/Hif-1α-tumours was not reached after median follow up of 8.8 years, whereas SSTR-2-/Hif-1α+ GEP-NETs had a median survival of only 4.2 years (P=0.006). CONCLUSION: We have identified a coherent expression signature by immunohistochemistry that can be used for patient stratification and to optimise treatment decisions in GEP-NETs independently from stage and grading. Tumours with preserved SSTR-2 and low Hif-1α expression have an indolent phenotype and may be offered less aggressive management and less stringent follow up

Italian Oncological Pain Survey (IOPS) A Multicentre Italian Study of Breakthrough Pain Performed in Different Settings

Objective: A survey of breakthrough pain (BTP) was performed in five palliative care units (PCU), seven oncology departments (ONC), and nine pain clinics (OPC). Methods: A standard algorithm was used to confirm the diagnosis of BTP of patients refereed to different settings. Results: 1,412 evaluable cancer patients were enrolled. 53.9% were males and the mean age was 63.7±13.1 years. The mean intensity of background pain was 2.8±0.73. Patients reported 2.4±1.1 BTP episodes/day with a mean intensity of 7.37±1.28. 80.6% patients reported that the BTP had a significant negative impact in everyday life. The majority of patients reported a fast onset of BTP, which was predictable in 50.7% of cases, while BTP with a gradual onset (>10 min) was less predictable (29%) (P=0.001). PCU patients were older, had lower Karnofsky levels, a lower number of BTP episodes/day, a slow onset of BTP onset, and a less predictable BTP. Cancer diagnosis was performed a mean of 23.5 months (SD±32.8) before the assessment. The mean duration of background pain was 3.5 months (SD±3.5), and the mean duration of any analgesic treatment was 2.5 months (SD±3). BTP started a mean of 2.2 months (SD±1.9) before the assessment. Characteristics of BTP were influenced by the course of disease, as well as the duration of background pain and initiation of BTP. Most patients took rapid onset opioids and were satisfied with the treatment. BTP diagnosis was prevalently made by ONC and OPC physicians, and rarely by GPs. Conclusion: This survey performed by an Italian observatory expert review group, has confirmed that the BTP represents a clinically relevant condition with a negative impact on the patient’s quality of life. BTP was detected in all settings involved. A number of factors are associated with the BTP. Also factors regarding the course of disease and setting of care have been assessed. This information may help in stratifying patients or predicting the risk of development of BTP with specific characteristics

Insights on surface analysis techniques to study glass primary packaging

During the forming process of a vial by tubing glass, temperatures of up to 1200◦C are applied to adjust the glass viscosity. This process causes the release of volatile components such as alkali borates. Consequently, the percentage of sodium and boron measured on the inner surface of the vial can be higher than that measured on the corresponding glass tube. This study aimed to characterize the inner surface of two different borosilicate glass tubes of type I before and after the vial forming process at the nanoscale level. Quantitative elemental analysis of the surface along the vertical axis of glass tubes and vials was performed by X-ray photoelectron spectroscopy, whereas the topographical investigation was carried out by scanning electron microscopy (SEM). In the near-bottom region of a vial, which is usually the area most prone to corrosion, the SEM micrographs showed the appearance of bulges on the surface. The latter were then analyzed by time-of-flight secondary ion mass spectrometry to characterize their molecular composition. The purpose of this work is to identify possible new strategies for faster identification of factors that eventually influence chemical resistance of pharmaceutical glasses and to provide useful information needed to improve industrial processes

The role of dimensionality in neuronal network dynamics

The research leading to these results has received funding from the European Union’s Seventh Framework Programme under grant agreement FP7 ICT 2011 – 284553 (Acronym: Si-CODE), the NEUROSCAFFOLDS Project n. 604263, the National Natural Science Foundation of China (Grant number: 51361130033) and the Ministry of Science and Technology of China (973 Grant number: 2014CB965003)

Neuronal chemotaxis by optically manipulated liposomes

We probe chemotaxis of single neurons, induced by signalling molecules which were optically delivered from liposomes in the neighbourhood of the cells. We implemented an optical tweezers setup combined with a micro-dissection system on an inverted microscope platform. Molecules of Netrin-1 protein were encapsulated into micron-sized liposomes and manipulated to micrometric distances from a specific growth cone of a hippocampal neuron by the IR optical tweezers. The molecules were then released broken the liposomes with UV laser pulses. Chemotaxis induced by the delivered molecules was confirmed by the migration of the growth cone toward the liposome position. Since the delivery can be manipulated with high temporal and spatial resolution and the number of molecules released can be controlled quite precisely by tuning the liposome size and the solution concentration, this technique opens new opportunities to investigate the effect of physiological active compounds as Netrin-1 to neuronal signalling and guidance, which represents an important issue in neurobiology

COVID-19 and Cancer

Importance: The COVID-19 pandemic has had consequences for patients with cancer worldwide and has been associated with delays in diagnosis, interruption of treatment and follow-up care, and increases in overall infection rates and premature mortality. Observations: Despite the challenges experienced during the pandemic, the global oncology community has responded with an unprecedented level of investigation, collaboration, and technological innovation through the rapid development of COVID-19 registries that have allowed an increased understanding of the natural history, risk factors, and outcomes of patients with cancer who are diagnosed with COVID-19. This review describes 14 major registries comprising more than 28 500 patients with cancer and COVID-19; these ongoing registry efforts have provided an improved understanding of the impact and outcomes of COVID-19 among patients with cancer. Conclusions and Relevance: An initiative is needed to promote active collaboration between different registries to improve the quality and consistency of information. Well-designed prospective and randomized clinical trials are needed to collect high-level evidence to guide long-term epidemiologic, behavioral, and clinical decision-making for this and future pandemics

Homologous recombination deficiency, RB-loss gene signatures, intrinsic subtype and response to neoadjuvant treatment in HR+/HER2- early breast cancer: a correlative analysis of two phase II trials

Background: Hormone-receptor (HR)+/HER2- breast cancer (BC) is a biologically heterogeneous disease. Homologous recombination deficiency (HRD) and BRCA mutations have been previously reported to be associated with worse outcomes in HR+/HER2- metastatic BC patients receiving CDK4/6 inhibitors and endocrine therapy. Here, we assess the relation between HRD and RB-loss signatures, intrinsic subtyping, the PAM50-based chemo-endocrine score, and response to chemotherapy-based therapy and endocrine treatment in HR+/HER2- early BC. Methods: GIADA is a multicentric neoadjuvant phase II trial that treated premenopausal patients with Luminal B (LumB)-like BC (HR-positive, HER2-negative, with Ki67&gt;20% and/or histologic Grade 3) with a combination of chemotherapy, immunotherapy and endocrine treatment. Expression of 758 genes on baseline tumor samples from all 43 patients was quantified by nCounter platform. The LETLOB phase II trial randomized postmenopausal women with clinical stage II-IIIA HR+/HER2- BC to neoadjuvant letrozole + lapatinib or letrozole + placebo for 6 months (Guarneri, JCO 2014). Gene-expression data (Affymetrix platform) from pre-treatment frozen core-biopsies was available from 66 out of 92 pts enrolled. Intrinsic subtype was assigned using a research-based PAM50 subtype predictor. A published HRD signature (Peng, Nat Commun 2014) and a signature of RB loss (RBsig), previously reported to potentially predict resistance to CDK4/6 inhibitors in HR+/HER2- BC (Malorni, Oncotarget 2016) were computed. The PAM50 based chemo-endocrine score (CES) was calculated using published definition (Prat, CCR 2017). Higher values of CES indicate increased endocrine sensitivity, while lower values indicate chemosensitivity. Association between genomic signatures was assessed through Pearson’s correlation coefficient. Association of genomic signatures with pCR was assessed through logistic regression and association with PEPI scores was assessed through Kruskal-Wallis test. Results: HRD signature levels were significantly higher in non-luminal (Basal-like and HER2-enriched) tumors as compared to Luminal (A or B) tumors (p&gt;0.001 in the GIADA trial, p=0.021 in the LETLOB trial). Moreover, higher levels of HRD signature were associated with higher levels of RB-loss signature (Pearson correlation 0.355, p=0.020 in the GIADA trial; Pearson correlation 0.942, p&lt; 0.001 in the LETLOB trial), higher levels of Basal-like signature (Pearson correlation 0.502, p&lt; 0.001 in the GIADA trial; Pearson correlation 0.373, p=0.002 in the LETLOB trial) and lower levels of CES (Pearson correlation -0.422, p=0.005 in the GIADA trial; Pearson correlation -0.763, p&lt; 0.001 in the LETLOB trial), indicative of higher chemosensitivity. In the GIADA trial, higher levels of HRD signature (p=0.018) and RBloss signature (p=0.073) and lower levels of CES (p=0.007) were associated with higher pCR rates after chemo, endocrine and immunotherapy. In the LETLOB trial, lower levels of HRD signature (p=0.068) and RBloss signature (p=0.042) and higher levels of CES (p=0.050) were associated with higher sensitivity to endocrine treatment (lower PEPI scores, 0 vs 1-3 vs 4 or more, after neoadjuvant letrozole). Conclusions: In HR+/HER2- early BC, HRD gene signatures, RB-loss gene signatures and non-luminal (especially Basal-like) intrinsic subtyping are associated with each other and associated with higher sensitivity to chemotherapy-based therapy and lower sensitivity to endocrine treatment. These observations might help correctly tailor systemic therapy, including biologic agents, in patients with HR+/HER2- early and advanced BC

Less than 5 Netrin-1 molecules initiate attraction but 200 Sema3A molecules are necessary for repulsion

Guidance molecules, such as Sema3A or Netrin-1, induce growth cone (GC) repulsion or attraction. In order to determine the speed of action and efficiency of these guidance cues we developed an experimental procedure to deliver controlled amounts of these molecules. Lipid vesicles encapsulating 10-10 4 molecules of Sema3A or Netrin-1 were manipulated with high spatial and temporal resolution by optical tweezers and their photolysis triggered by laser pulses. Guidance molecules released from the vesicles diffused and reached the GC membrane in a few seconds. Following their arrival, GCs retracted or grew in 20-120 s. By determining the number of guidance molecules trapped inside vesicles and estimating the fraction of guidance molecules reaching the GC, we show that the arrival of less than 5 Netrin-1 molecules on the GC membrane is sufficient to induce growth. In contrast, the arrival of about 200 Sema3A molecules is necessary to induce filopodia repulsion

Delivering adjuvant and neoadjuvant treatments in the early stages of hepatocellular carcinoma

Introduction: Hepatocellular carcinoma (HCC) presents a formidable challenge in oncology, demanding innovative treatment approaches. Both adjuvant and neoadjuvant therapies, thanks to the introduction of immunotherapy, have emerged as promising strategies in the management of HCC, aiming to reduce the risk of relapse and ultimately to improve survival. Areas Covered: This review considers current evidence, ongoing clinical trials, and future strategies to elucidate the evolving landscape of neoadjuvant and adjuvant treatments in HCC. Expert Opinion: Both adjuvant and neoadjuvant regimens, notably those incorporating immune checkpoint inhibitors, demonstrated encouraging safety profiles and efficacy outcomes in HCC. While significant challenges persist, including optimizing patient selection and endpoint definition, the evolving landscape of neoadjuvant and adjuvant therapy holds promise for maximizing the therapeutic potential of immunotherapy across all stages of HCC. Further insights into tumor biology and host immunity will shape the role of these approaches which are close to becoming reality in clinical practice