Nivolumab serum concentration in metastatic melanoma patients could be related to outcome and enhanced immune activity: a gene profiling retrospective analysis.

BACKGROUND: Nivolumab is an anti-PD-1 antibody approved for treating metastatic melanoma (MM), for which still limited evidence is available on the correlation between drug exposure and patient outcomes. METHODS: In this observational retrospective study, we assessed whether nivolumab concentration is associated with treatment response in 88 patients with MM and if the patient's genetic profile plays a role in this association. RESULTS: We observed a statistically significant correlation between nivolumab serum concentration and clinical outcomes, measured as overall and progression-free survival. Moreover, patients who achieved a clinical or partial response tended to have higher levels of nivolumab than those who reached stable disease or had disease progression. However, the difference was not statistically significant. In particular, patients who reached a clinical response had a significantly higher concentration of nivolumab and presented a distinct genetic signature, with more marked activation of ICOS and other genes involved in effector T-cells mediated proinflammatory pathways. CONCLUSIONS: In conclusion, these preliminary results show that in patients with MM, nivolumab concentration correlates with clinical outcomes and is associated with an increased expression of ICOS and other genes involved in the activation of T effectors cells.

Bimodal antibody-titer decline following BNT162b2 mRNA anti-SARS-CoV-2 vaccination in healthcare workers of the INT - IRCCS "Fondazione Pascale" Cancer Center (Naples, Italy).

BACKGROUND: Both SARS-CoV-2 mRNA-based vaccines [BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)] have shown high efficacy, with very modest side effects in limiting transmission of SARS-CoV-2 and in preventing the severe COVID-19 disease, characterized by a worrying high occupation of intensive care units (ICU), high frequency of intubation and ultimately high mortality rate. At the INT, in Naples, only the BNT162b2/Pfizer vaccine has been administered to cancer patients and healthcare professionals aged 16 and over. In the present study, the antibody response levels and their decline were monitored in an interval of 6-9 months after vaccine administration in the two different cohorts of workers of the INT - IRCCS "Fondazione Pascale" Cancer Center (Naples, Italy): the group of individuals previously infected with SARS-CoV-2 and vaccinated with a single dose; and that of individuals negative for previous exposure to SARS-CoV-2 vaccinated with two doses 21 days apart. METHODS: Specific anti-RBD (receptor-binding domain) titers against trimeric spike glycoprotein (S) of SARS-CoV-2 by Roche Elecsys Anti-SARS-CoV-2 S ECLIA immunoassay were determined in serum samples of 27 healthcare workers with a previously documented history of SARS-CoV-2 infection and 123 healthcare workers without, during antibody titers' monitoring. Moreover, geometric mean titers (GMT) and relative fold changes (FC) were calculated. RESULTS: Bimodal titer decline was observed in both previously infected and uninfected SARS-CoV-2 subjects. A first rapid decline was followed by a progressive slow decline in the 6/9 month-period before the further vaccine boost. The trend was explained by 2 different mathematical models, exponential and power function, the latter revealing as predictive of antibody titer decline either in infected or in not previously infected ones. The value of the prolonged lower vaccine titer was about 1 log below in the 6/9-month interval after the single dose for previously infected individuals with SARS-CoV-2 and the two doses for those not previously infected. The titer change, after the boost dose administration, on the other hand, was ≥ 1.5 FC higher than the titers at the 6/9-month time-points in both cohorts. A similar quantitative immune titer was observed in both cohorts 8 days after the last boost dose. The subsequent immunoresponse trend remains to be verified. DISCUSSION: The results show that a very rapid first decline, from the highest antibody peak, was followed by a very slow decline which ensured immune protection lasting more than 6 months. The apparent absence of adverse effects of the rapid decline on the vaccine's immune protective role has been related to a large majority of low avidity antibodies induced by current vaccines. High avidity antibodies with prolonged anti-transmission efficacy show a longer half-life and are lost over a longer interval period. The cellular immunity, capable of preventing severe clinical diseases, lasts much longer. The unbalanced dual activity (cellular vs humoral) while effective in limiting ICU pressure and overall mortality, does not protect against transmission of SARS-CoV-2, resulting in high circulation of the virus among unvaccinated subjects, including the younger population, and the continuous production of variants characterized by changes in transmissibility and pathogenicity. The high mutation rate, peculiar to the RNA virus, can however lead to a dual opposite results: selection of defective and less efficient viruses up to extinction; risk of more efficiently transmitted variants as the current omicron pandemic. CONCLUSIONS: In conclusion the current bimodal antibody-titer decline, following BNT162b2 mRNA anti-SARS-CoV-2 vaccination, needs a further extended analysis to verify the protective borderline levels of immunity and the optimal administration schedule of vaccine boosters. Our current results can contribute to such goal, besides a direct comparison of other FDA-approved and candidate vaccines.

Pain control and functional improvement in patients treated by autologous conditioned serum after failure of platelet rich plasma treatments in knee osteoarthritis.

OBJECTIVE: To assess the efficacy of autologous conditioned serum (ACS) for the treatment of patients with knee osteoarthritis after failure of medical treatments and platelet rich plasma (PRP) injections. BACKGROUND: Knee osteoarthritis is the most common form of arthritis. Prior to prosthetic surgery these patients might benefit from medical treatments, physiotherapy, and in case of their ineffectiveness, from autologous blood component injections. METHODOLOGY: We have treated 30 patients with Kellgren-Lawrence I-III knee osteoarthritis with ACS after failure of standard medical treatments/physiotherapy and platelet rich plasma (PRP) injections for a full cycle, within the previous year from enrollment. RESULTS: ACS administration was performed in all patients with mild side effects and produced prompt (1 month) improvements of VAS and Lequesne scales in 67% of patients and this result persisted at 6 and 12 months. No relationship between the rate of response and Kellgren-Lawrence scale at enrollment was observed whilst responders had a significantly higher amount of interleukin-1 receptor antagonist (IL1-RA) in ACS as compared to nonresponders. CONCLUSION: The present study confirms the efficacy of ACS in pain control and functional recovery of patients with knee osteoarthritis resistant to medical and PRP treatment. These results were obtained in a well-defined cohort of resistant patients and seem to be related with IL1-RA content in injected ACS.

Vaccination strategy and anti - SARS-CoV-2 S titers in healthcare workers of the INT - IRCCS "Fondazione Pascale" Cancer Center (Naples, Italy).

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and the resulting disease, coronavirus disease 2019 (COVID-19), have spread to millions of people globally, requiring the development of billions of different vaccine doses. The SARS-CoV-2 spike mRNA vaccine (named BNT162b2/Pfizer), authorized by the FDA, has shown high efficacy in preventing SARS-CoV-2 infection after administration of two doses in individuals 16 years of age and older. In the present study, we retrospectively evaluated the differences in the SARS-CoV-2 humoral immune response after vaccine administration in the two different cohorts of workers at the INT - IRCCS "Fondazione Pascale" Cancer Center (Naples, Italy): previously infected to SARS-CoV-2 subjects and not infected to SARS-CoV-2 subjects. METHODS: We determined specific anti-RBD (receptor-binding domain) titers against trimeric spike glycoprotein (S) of SARS-CoV-2 by Roche Elecsys Anti-SARS-CoV-2 S immunoassay in serum samples of 35 healthcare workers with a previous documented history of SARS-CoV-2 infection and 158 healthcare workers without, after 1 and 2 doses of vaccine, respectively. Moreover, geometric mean titers and relative fold changes (FC) were calculated. RESULTS: Both previously infected and not infected to SARS-CoV-2 subjects developed significant immune responses to SARS-CoV-2 after the administration of 1 and 2 doses of vaccine, respectively. Anti-S antibody responses to the first dose of vaccine were significantly higher in previously SARS-CoV-2-infected subjects in comparison to titers of not infected subjects after the first as well as the second dose of vaccine. Fold changes for subjects previously infected to SARS-CoV-2 was very modest, given the high basal antibody titer, as well as the upper limit of 2500.0 BAU/mL imposed by the Roche methods. Conversely, for naïve subjects, mean fold change following the first dose was low ([Formula: see text] =1.6), reaching 3.8 FC in 72 subjects (45.6%) following the second dose. CONCLUSIONS: The results showed that, as early as the first dose, SARS-CoV-2-infected individuals developed a remarkable and statistically significant immune response in comparison to those who did not contract the virus previously, suggesting the possibility of administering only one dose in previously SARS-CoV-2-infected subjects. FC for previously infected subjects should not be taken into account for the generally high pre-vaccination values. Conversely, FC for not infected subjects, after the second dose, were = 3.8 in > 45.0% of vaccinees, and ≤ 3.1 in 19.0%, the latter showing a potential susceptibility to further SARS-CoV-2 infection.

Immunotherapy may protect cancer patients from SARS-CoV-2 infection: a single-center retrospective analysis.

Coronavirus disease 2019 (COVID-19) global pandemic has created unique challenges to healthcare systems throughout the world. Ensuring subjects' safety is mandatory especially in oncology, in consideration of cancer patients' particular frailty. We examined the proportion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgM and/or IgG positive subjects in three different groups from Istituto Nazionale Tumori - IRCCS "Fondazione G. Pascale" in Naples (Campania region, Italy): cancer patients treated with Innovative Immunotherapy (Immune Checkpoint Inhibitors, ICIs), cancer patients undergoing standard Chemotherapies (CHTs) and healthcare providers. 9 out of 287 (3.1%) ICIs patients resulted positive, with a significant lower percentage in respect to CHTs patients (39 positive subjects out of 598, 6.5%) (p = 0.04). There was no statistically significant difference between ICIs cohort and healthcare providers, 48 out of 1050 resulting positive (4.6%). Performing a Propensity Score Matching based on gender and tumor stage, the effect of treatment on seropositivity was analyzed through a regression logistic model and the ICIs treatment resulted to be the only protective factor significantly (p = 0.03) associated with positivity (odds ratio-OR: 0.41; 95% confidence interval-CI 0.18-0.91). According to these preliminary data, ICIs would appear to be a protective factor against the onset of COVID-19 infection.

A potential prognostic marker in primitive lung neuroendocrine tumor: A case report.

BACKGROUND: The diagnosis and monitoring of primitive lung neuroendocrine tumors (lung pNETs) are usually performed by the measurement of serum chromogranin A (CgA) and urinary 5-hydroxyindolacetic acid (5-HIAA) levels. However, imaging techniques are necessary due to the poor diagnostic efficiency of the laboratory tests. METHODS: A total-body computed tomography and bone scintigraphy scans showed multiple hepatic and bone metastases of a 55-year-old man affected by well-differentiated lung pNETs without severe initial symptoms. After diagnosis, he started therapy and was monitored with serum, urinary markers, and imaging techniques. RESULTS: During follow-up, the urinary 5-HIAA levels did not significantly increase, while serum CgA and urinary para-hydroxyphenylacetic acid (pHPAA) levels (urinary organic acid physiologically present in the urines of healthy subjects) showed significant increases related to worsening clinical condition. CONCLUSIONS: The early increase in urinary pHPAA levels-usually not dosed in pNET patient monitoring-could be a promising prognostic marker.

The epithelial-mesenchymal transition in cancer: a potential critical topic for translational proteomic research.

The epithelial-mesenchymal transition (EMT) is a morphogenetic process that results in a loss of epithelial characteristics and the acquisition of a mesenchymal phenotype. First described in embryogenesis, the EMT has been recently implicated in carcinogenesis and tumor progression. In addition, recent evidence has shown that stem-like cancer cells present the hallmarks of the EMT. Some of the molecular mechanisms related to the interrelationships between cancer pathophysiology and the EMT are well-defined. Nevertheless, the precise molecular mechanism by which epithelial cancer cells acquire the mesenchymal phenotype remains largely unknown. This review focuses on various proteomic strategies with the goal of better understanding the physiological and pathological mechanisms of the EMT process.

Neuron-Specific Enolase as a Biomarker: Biochemical and Clinical Aspects.

Neuron-specific enolase (NSE) is known to be a cell specific isoenzyme of the glycolytic enzyme enolase. In vertebrate organisms three isozymes of enolase, expressed by different genes, are present: enolase α is ubiquitous; enolase ß is muscle-specific and enolase γ is neuron-specific. The expression of NSE, which occurs as γγ- and αγ-dimer, is a late event in neural differentiation, thus making it a useful index of neural maturation.NSE is a highly specific marker for neurons and peripheral neuroendocrine cells. As a result of the findings of NSE in specific tissues under normal conditions, increased body fluids levels of NSE may occur with malignant proliferation and thus can be of value in diagnosis, staging and treatment of related neuroendocrine tumours (NETs).NSE is currently the most reliable tumour marker in diagnosis, prognosis and follow-up of small cell lung cancer (SCLC), even though increased levels of NSE have been reported also in non-small cell lung cancer (NSCLC). The level of NSE correlates with tumour burden, number of metastatic sites and response to treatment.NSE can be also useful at diagnosis of NETs and gastroenteropancreatic (GEP)-NETs.Raised serum levels of NSE have been found in all stages of neuroblastoma, although the incidence of increased concentration is greater in widespread and metastatic disease. Moreover, NSE determination in cord blood offers an early postnatal possibility of confirming the diagnosis of neuroblastoma in newborns.NSE has been demonstrated to provide quantitative measures of brain damage and/or to improve the diagnosis and the outcome evaluation in ischaemic stroke, intracerebral hemorrhage, seizures, comatose patients after cardiopulmonary resuscitation for cardiac arrest and traumatic brain injury.Increased NSE serum levels have also been found associated with melanoma, seminoma, renal cell carcinoma, Merkel cell tumour, carcinoid tumours, dysgerminomas and immature teratomas, malignant phaechromocytoma, Guillain-Barré syndrome and Creutzfeldt-Jakob disease.

The role of fluorine-18-fluorodeoxyglucose positron emission tomography in evaluating the response to tyrosine-kinase inhibitors in patients with metastatic primary renal cell carcinoma.

BACKGROUND: Positron emission tomography-computed tomography (PET-CT) using fluorodeoxyglucose (FDG) is increasingly used in the evaluation of patients with advanced renal cell carcinoma (RCC), primarily for staging purposes. The aim of this paper is to perform a systematic review about the usefulness of PET-CT using FDG in response assessment after treatment with tyrosine-kinase inhibitors (TKIs) in patients with advanced RCC. MATERIALS AND METHODS: The scientific literature about the role of PET-CT using FDG in the assessment of response to treatment with TKIs in patients affected by advanced RCC was systematically reviewed. RESULTS: Seven studies about the role of PET-CT using FDG in the response assessment after treatment with TKIs (essentially sunitinib and sorafenib) in advanced RCC were retrieved in full-text and analysed, to determine the predictive role of this morpho-functional imaging method on patient outcome. CONCLUSIONS: To date, the role of PET-CT using FDG in evaluating the response to TKIs in metastatic RCC patients is still not well defined, partly due to heterogeneity of available studies; however, PET-CT reveals potential role for the selection of patients undergoing therapy with TKIs. The use of contrast-enhanced PET-CT appears to be promising for a "multi-dimensional" evaluation of treatment response in these patients.

Positive end-expiratory pressure during laparoscopy: cardiac and respiratory effects.

STUDY OBJECTIVE: To determine the effect of positive end-expiratory pressure (PEEP) on the respiratory system and on cardiac function. DESIGN: Prospective randomized study. SETTING: Operating room. PATIENTS: 60 ASA physical status 1 women scheduled for pelvic laparoscopic surgery. INTERVENTIONS: Patients were ventilated normally during surgery; PEEP was modified depending on patient group allocation. Group A was the control group and did not receive PEEP. Group B received PEEP 5 cmH2O and Group C received PEEP 10 cmH2O. MEASUREMENTS: Respiratory parameters measured were partial pressure of arterial oxygen (PaO2), partial pressure of carbon dioxide (PaCO2), and end-tidal carbon dioxide tension (ETCO2). Cardiac parameters measured were left ventricular end-diastolic volume index (LVEDVI), ie, ratio of LVEDV/body surface area (BSA; [LVEDVI = end-diastolic volume [EDV]/BSA); left ventricular (LV) systolic function, tricuspid annular plane systolic excursion (TAPSE), right ventricular (RV) fractional area change (FAC), RV dimensions in the apical 4-chamber view, tracing basal and mid-cavity minor dimensions and longitudinal dimension, cardiac index, systolic pulmonary artery pressure (PASP), and systolic RV pressure (RVSP). Respiratory and cardiac measurements were recorded at T0 (baseline); T1 (after anesthesia induction, before pneumoperitoneum induction); at 10 (T2), 20 (T3), and 30 (T4) minutes after CO2 insufflation; and at the end of surgery (T5). MAIN RESULTS: Ventilation with PEEP at 10 cm H2O led to significant improvement in both respiratory and cardiac parameters. A reduction in pulmonary vascular resistance and enhanced washout of expiratory CO2 occurred. Ten and, to a lesser extent, 5 cm H2O of PEEP decreased LV stroke work. CONCLUSIONS: Ventilation with PEEP (up to 10 cm H2O) recruits the hypoventilated areas of the lungs and reduces cardiac afterload.

Diagnostic performance of positron emission tomography using ¹¹C-methionine in patients with suspected parathyroid adenoma: a meta-analysis.

The diagnostic performance of positron emission tomography using ¹¹C-methionine (MET-PET) in detecting parathyroid adenoma has been investigated by several studies with conflicting results. Aim of our study is to meta-analyze published data about this topic. A comprehensive computer literature search of studies published in PubMed/MEDLINE, Scopus and Embase databases through May 2012 and regarding the diagnostic performance of MET-PET in patients with parathyroid adenoma was carried out. No language restriction was used. Only articles in which at least five patients with parathyroid adenoma underwent MET-PET were included in the meta-analysis. Pooled sensitivity and detection rate (DR) on a per patient-based analysis were calculated to assess the diagnostic performance of MET-PET. Nine studies comprising 258 patients with suspected parathyroid adenoma were included in this meta-analysis. Pooled sensitivity and DR values of MET-PET in patients with suspected parathyroid adenoma were 81 % (95 % confidence interval [95 %CI] 74-86 %) and 70 % (95 %CI 62-77 %), respectively, on a per patient-based analysis. The included studies were heterogeneous in their estimate of sensitivity and DR. Our meta-analysis demonstrates that MET-PET is a sensitive and reliable tool in patients with suspected parathyroid adenoma. Thus, this imaging method could be helpful in patients with diagnosis of primary hyperparathyroidism when conventional imaging techniques are negative or inconclusive in localizing parathyroid adenoma.

Is fluorine-18-fluorodeoxyglucose positron emission tomography useful in monitoring the response to treatment in patients with multiple myeloma?

Fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) is a useful diagnostic tool for the staging of patients with multiple myeloma (MM). The aim of this study is to perform a systematic review of the usefulness of FDG-PET or PET/CT in monitoring response to treatment in patients with MM. A comprehensive computer literature search of the PubMed/MEDLINE, Scopus and Embase databases was carried out to identify relevant peer-reviewed articles on the use of FDG-PET or PET/CT in monitoring the response to treatment in patients with MM. Ten studies described investigations of the role of FDG-PET or PET/CT in monitoring the response to treatment in 690 patients with MM or solitary plasmacytoma: six of these were conducted prospectively, while four studies were retrospective. These articles were retrieved in full-text version and analyzed. Based on these findings from the literature, FDG-PET or PET/CT appear to be useful in the assessment of treatment response in patients with MM.

The Role of Fluorine-18-fluorodeoxyglucose Positron Emission Tomography in Assessing the Response to Neoadjuvant Treatment in Patients with Osteosarcoma.

Aim. The objective of this study is to systematically review the role of positron emission tomography (PET) and PET/computed tomography (PET/CT) with fluorine-18-fluorodeoxyglucose (FDG) in assessing the response to neoadjuvant treatment in patients with osteosarcoma (OS). Methods. A comprehensive literature search of published studies through March 2012 in PubMed/MEDLINE, Embase, and Scopus databases regarding whole-body FDG-PET and FDG-PET/CT in patients with OS was performed. Results. Twenty-two studies have investigated the role of FDG-PET and FDG-PET/CT in the evaluation of response to neoadjuvant treatment with either chemotherapy or radiation therapy in patients with OS. The main findings of these studies are presented. Conclusion. FDG-PET or PET/CT seems to be sensitive and reliable diagnostic tools in the assessment of metabolic response to treatment in patients with OS, after baseline PET evaluation has been performed in advance. However, false positive findings due to inflammation in sites of tumoral response should be considered.

The role of fluorine-18-fluorodeoxyglucose positron emission tomography in evaluating the response to treatment in patients with multiple myeloma.

Background and Aim. Fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) is well recognized as a powerful diagnostic tool in the initial staging of patients with multiple myeloma (MM). The aim of this paper is to perform a systematic review about the usefulness of FDG-PET or PET/CT in evaluating the response to treatment in patients with MM. Methods. The scientific literature about the role of FDG-PET or PET/CT in evaluating the response to treatment in patients affected by MM was systematically reviewed. Results. Ten studies about the role of FDG-PET or PET/CT in evaluating treatment response in MM were retrieved and discussed. Conclusions. FDG-PET or PET/CT seems to be helpful in assessing the response to treatment in patients with MM and in the evaluation of possible sites of recurrent or progressive disease.