Transcanal transpromontorial approach for vestibular schwannoma: experience of a single center.

BACKGROUND: The expanded transpromontorial transcanal approach (ExpTTA) represents a recent addition to the surgical approaches available for the treatment of vestibular schwannoma. An initial purely endoscopic version has been complemented by the use of the microscope and it is now one of the possible surgical options for small to medium-sized vestibular schwannomas with a predominantly intracanalar development. METHODS: This is a series of 54 patients who underwent microsurgical resection of sporadic, unilateral vestibular schwannoma, mainly Koos I-II with non-serviceable hearing, between January 2016 and January 2023 using the expanded transcanal transpromontorial approach. We describe the surgical technique, focusing on anatomical landmarks, and analyzing its advantages and shortcomings. Retrospective analysis of clinical outcomes is presented, including early and late complications. The mean follow-up was 46.7 months. RESULTS: We achieved gross total resection of the lesion in all cases, confirmed on the first follow-up MRI at least 6 months after each procedure. We did not record any intraoperative complication nor disease recurrence. We recorded two postoperative severe facial nerve palsies, one of which was permanent. No cases of disabling vertigo or imbalance were reported, and all patients reported full recovery of autonomy in daily activities. Three cases of otoliquorrhea were managed conservatively successfully. CONCLUSIONS: The transcanal transpromontorial approach combines the advantages of endoscopy with the possibilities provided by microsurgery. Our experience confirms its safety in terms of surgical complications and facial nerve outcome. This approach is amongst the treatment options for small-medium schwannomas in patients with impaired hearing, especially in young patients, ensuring radical resection, disease control, and minimal morbidity.

Predictors of 24-month onset of macular fibrosis in type 3 macular neovascularisation.

AIMS: To explore prognostic multimarker models for progression to macular fibrosis (MF) over 24 months specific to type 3 macular neovascularisation (T3 MNV). METHODS: This retrospective, exploratory, single-centre, cohort study comprised 65 eyes of 43 Caucasian patients with treatment naive T3 MNV, all with a 24-month follow-up post anti-VEGF therapy using a strict pro-re-nata (PRN) regimen. Data on demographic features, clinical findings, frequency of intravitreal treatments and optical coherence tomography biomarkers were collected at baseline and after 12 and 24 months of follow-up. Logistic regression models (LRM) and receiver-operating curve (C-index) analyses were performed to evaluate the prognostic ability of the studied biomarkers in discriminating between MF affected and unaffected patients. RESULTS: At final follow-up, MF was present in 46.2% of eyes. Subretinal hyper-reflective material (SHRM) and subretinal pigment epithelium multilaminar hyper-reflectivity (multilaminae) emerged as significant predictors for MF, with adjusted odds ratios (OR) of 18.0 (95% CL 13.4 to 24.1) and 11.8 (95% CL 8.66 to 16.0), respectively. Additionally, the presence of multifocal lesions (OR 0.04, 95% CL 0.01 to 0.30) appeared to decrease the likelihood of MF. C-indexes for the selected LRMs ranged between 0.92 and 0.88, indicating a comparably high discriminant ability. Despite consistent treatment schedules between the two groups (MF: median intravitreal treatment (IVT) number=10.5, IQR=7; non-MF: median IVT=10, IQR=6), a decline in best-corrected visual acuity was noted in the group with MF onset over the 24-month follow-up (-13.0 ETDRS letters; 95% CL -22.1 to -3.9; p=0.006). CONCLUSION: Our study identifies SHRM and multilaminae as relevant predictors of 24-month onset of MF in patients with T3 MNV. These findings enrich our understanding of the development of MF in T3 MNV and can guide improved risk prognostication. Future research should consider larger samples and prospective designs to validate these predictors.

Stem cells treatment in chronic ischemic heart disease: a narrative review.

Chronic ischemic heart disease remains a major cause of morbidity and mortality worldwide. Several trials have been performed to evaluate benefit of stem cells transplantation to restore cardiac function in short- and long-term period after myocardial infarction. This narrative review analyzes 24 clinical trials between 2005 and 2023 comprising 1824 patients with chronic heart disease without heart failure. Percent increase in left ventricular ejection fraction (LVEF) and decrease in New York Heart Association (NYHA) class at 6/12 months after stem cells transplantation are reported. Thirteen trials showed a statistically significant percent LVEF increase between 4% to 19% at 6/12 months after stem cells transplantation (p values from 0.05 to 0.0001). No significant differences in LVEF were observed between patients who underwent intracoronary or intramyocardial transplantation. NYHA class decrease from severe to mild/moderate was demonstrated in 10 trials reporting a significant LVEF increase. Patients transplanted with bone marrow and peripheral blood CD133+ stem cells showed a doubling of percentage LVEF increase in comparison to patients transplanted with CD133- cells. This narrative review reports the conflicting results on this topic. Multicenter randomized clinical trials should be performed to define the efficacy of stem cells transplantation in chronic ischemic heart disease.

A Descriptive Study of Repeated Hospitalizations and Survival of Patients with Metastatic Melanoma in the Northern Italian Region during 2004-2019.

BACKGROUND: Survival rates for metastatic melanoma (MM) patients have improved in recent years, leading to major expenses and health resource use. We conducted a non-concurrent prospective study to describe the burden of hospitalization in a real-world setting for patients with MM. METHODS: Patients were tracked throughout all hospital stays in 2004-2019 by means of hospital discharges. The number of hospitalizations, the rehospitalization rate, the average time spent in the hospital and the time span between consecutive admissions were evaluated. Relative survival was also calculated. RESULTS: Overall, 1570 patients were identified at the first stay (56.5% in 2004-2011 and 43.7% in 2012-2019). A total of 8583 admissions were retrieved. The overall rehospitalization rate was 1.78 per patient/year (95%CI = 1.68-1.89); it increased significantly with the period of first stay (1.51, 95%CI = 1.40-1.64 in 2004-2011 and 2.11, 95%CI = 1.94-2.29 thereafter). The median time span between hospitalizations was lower for patients hospitalized after 2011 (16 vs. 26 months). An improvement in survival for males was highlighted. CONCLUSIONS: The hospitalization rate of patients with MM was higher in the last years of the study. Compared with a shorter length of stay, patients were admitted to hospitals with a higher frequency. Knowledge of the burden of MM is essential for planning the allocation of healthcare resources.

Pulmonary hypertension in systemic sclerosis with usual interstitial pneumonia.

Retrospective study comparing pulmonary hypertension risk in systemic sclerosis (SSc) and non-SSc interstitial lung disease patients with usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP). Retrospective analysis of 144 interstitial lung disease patients, 53 SSc (32 UIP and 21 NSIP) and 91 non-SSc (47 UIP and 44 NSIP). Pulmonary hypertension was diagnosed as pulmonary systolic artery pressure (PAPs) > 25 mmHg. All SSc and non-SSc patients with pulmonary hypertension were classified WHO Group 3. Pulmonary hypertension was identified in 21/32 (65.6%), 9/21 (42.8%), 14/47 (29.7%), and 28/44 (45.4%) SSc-UIP, SSc-NSIP, control-UIP, and control-NSIP groups, respectively. PAPs mean of SSc-UIP group was higher than control-UIP group (32.6 ± 9.8 vs 28.5 ± 6.6, p-value = 0.02). PAPs mean of SSc-NSIP group was lower than control-NSIP group (27.0 ± 7.1 vs 33.9 ± 8.8, p = 0.002). Frequency of patients with PAP > 25 mmHg in SSc-UIP group was 60% higher in comparison to control-UIP (OR = 1.62, 95% CI 0.51-5.16) and SSc-NSIP (OR = 1.60, 95% CI 0.45-5.70) groups. Logistic regression analysis estimating the linear trend per ten-unit increase in PAPs levels demonstrated an increment for the SSc-UIP group compared to the control-UIP (OR = 2.64, 95% CI 1.25-5.58, p = 0.01) and the control-NSIP (OR = 6.34, 95% CI 2.82-14.3, p < 0.001) groups. The case-control study confirms that pulmonary hypertension is frequently found in SSc patients and demonstrates, for the first time, a significant increased risk of pulmonary hypertension among SSc-UIP patients.

Prognostic Role of Soluble and Extracellular Vesicle-Associated PD-L1, B7-H3 and B7-H4 in Non-Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors.

The treatment of non-small cell lung cancer (NSCLC) has changed dramatically with the advent of immune checkpoint inhibitors (ICIs). Despite encouraging results, their efficacy remains limited to a subgroup of patients. Circulating immune checkpoints in soluble (s) form and associated with extracellular vesicles (EVs) represent promising markers, especially in ICI-based therapeutic settings. We evaluated the prognostic role of PD-L1 and of two B7 family members (B7-H3, B7-H4), both soluble and EV-associated, in a cohort of advanced NSCLC patients treated with first- (n = 56) or second-line (n = 126) ICIs. In treatment-naïve patients, high baseline concentrations of sPD-L1 (>24.2 pg/mL) were linked to worse survival, whereas high levels of sB7-H3 (>0.5 ng/mL) and sB7-H4 (>63.9 pg/mL) were associated with better outcomes. EV characterization confirmed the presence of EVs positive for PD-L1 and B7-H3, while only a small portion of EVs expressed B7-H4. The comparison between biomarker levels at the baseline and in the first radiological assessment under ICI-based treatment showed a significant decrease in EV-PD-L1 and an increase in EV-B7H3 in patients in the disease response to ICIs. Our study shows that sPD-L1, sB7-H3 and sB7-H4 levels are emerging prognostic markers in patients with advanced NSCLC treated with ICIs and suggests potential EV involvement in the disease response to ICIs.

Descriptive Epidemiology of Hospitalization of Patients with a Rare Tumor in an Italian Region.

OBJECTIVES: Rare tumors (RT) collectively account for one quarter of all malignancies in Italy. The low frequency and the large heterogeneity in natural history and outcome of individual diseases, together with a scarcity of epidemiological information make them a challenge for clinical practice, as well as for public healthcare organizations. We conducted a retrospective study to quantify the burden of hospitalization in a real-word setting in patients diagnosed with these diseases in an Italian region. METHODS: RT patients were tracked along all hospital stays from 2000 to 2019 using hospital discharge records. Frequency of hospitalizations, average time spent in hospital and median timespan between consecutive admissions were considered. Re-hospitalization rates were analyzed through a multivariable negative binomial regression analysis to adjust for confounding and allowing for over-dispersion in count data. RESULTS: As a whole, 57,329 patients were identified at first stay for all studied tumors. A total of 183,959 admissions were retrieved, along a median of 3 hospitalizations per patient. Median timespan between hospitalizations shortened in the course of the study years (12.5 months in 2000-2004 to 5.4 months in 2015-2019). The overall re-hospitalization rate increased from 0.92 per patient/year (95% CI = 0.81-1.04) in 2000-2004 to 2.17 (95% CI = 1.90-2.47) in 2015-2019. CONCLUSIONS: Overall, the hospitalization rate of patients with a RT increased in the twenty years since the 2000 and particularly doubled starting from 2015. A higher burden of hospitalizations was found for tumors of the central nervous system, thoracic cavity, digestive tract and sarcomas. To the best of our knowledge this is the first paper related to access to Italian healthcare facilities of patients with these tumors.

Antibody Response to COVID-19 mRNA Vaccines in Oncologic and Hematologic Patients Undergoing Chemotherapy.

BACKGROUND: Information on immune responses in cancer patients following mRNA COVID-19 vaccines is still insufficient, but generally, patients had impaired serological responses, especially those with hematological malignancies. We evaluated serological response to COVID-19 mRNA vaccine in cancer patients receiving chemotherapy compared with healthy controls. METHODS: In total, 195 cancer patients and 400 randomly selected controls who had been administered a Pfizer-BioNTech or Moderna COVID-19 vaccines in two doses were compared. The threshold of positivity was 4.33 BAU/mL. Patients were receiving anticancer treatment after the first and second dose of the vaccines. RESULTS: a TOTAL OF 169 patients (87%) had solid tumors and 26 hemolymphopoietic diseases. Seropositivity rate was lower in patients than controls (91% vs. 96%), with an age/gender-adjusted rate ratio (RR) of 0.95 (95% CL = 0.89-1.02). Positivity was found in 97% of solid cancers and in 50% of hemolymphopoietic tumors. Both advanced and adjuvant therapy seemed to slightly reduce seropositivity rates in patients when compared to controls (RR = 0.97, 95% CL = 0.89-1.06; RR = 0.94, 95% CL = 0.87-1.01). CONCLUSIONS: the response to vaccination is similar in patients affected by solid tumors to controls. On the contrary, hemolymphopietic patients show a much lower response than controls.

Pilot Study to Evaluate Serum Soluble Mesothelin-Related Peptide (SMRP) as Marker for Clinical Monitoring of Pleural Mesothelioma (PM): Correlation with Modified RECIST Score.

A soluble mesothelin-related peptide (SMRP) is the only FDA-approved biomarker for diagnosis of pleural mesothelioma (PM) and the most used for monitoring treatment. Radiological assessment of PM, based on modified RECIST (mRECIST) criteria, is challenging. This pilot study was designed to evaluate whether SMRP levels correlated over time with mRECIST score. Serial serum samples from PM patients were collected and SMRP levels were measured and compared with the mRECIST score obtained through centralized CT scans by blinded review. The within-patient SMRP-mRECIST relationship over time was estimated through a normal random-effects regression approach applied to the log-transformed mRECIST score. Overall, 58 PM patients were included (46 males and 12 females) with a median age at diagnosis of 67 years (min-max = 48-79), 44 (76%) with epithelioid and 14 (24%) with non-epithelioid histology. The total number of SMRP measurements and CT scans considered for analysis was 183. There was a statistically significant correlation between SMRP and mRECIST score in the 2 cohorts considered both separately and jointly. These results, although exploratory, suggest that SMRP measurement might be considered as an adjunct to monitor PM patients in order to delay CT scans time interval, thus warranting further investigation.

Ultra-hyper-fractionated radiotherapy for high-grade gliomas.

High-grade gliomas (HGGs; WHO grades III and IV) are invariably lethal brain tumors. Low-dose hyper-radiosensitivity (HRS) of HGG is a well-established phenomenon in vitro. However, possibly linked to the unavailability of accurate animal models of the diseases, this therapeutic effect could not be consistently translated to the animal setting, thus impairing its subsequent clinical development. The purpose of this study was to develop radiotherapeutic (RT) schedules permitting to significantly improve the overall survival of faithful animal models of HGG that have been recently made available. We used primary glioma initiating cell (GIC)-driven orthotopic animal models that accurately recapitulate the heterogeneity and growth patterns of the patients' tumors, to investigate the therapeutic effects of low radiation doses toward HGG. With the same total dose, RT fractions ≤0.5 Gy twice per week [ultra-hyper-fractionation (ultra-hyper-FRT)] started at early stages of tumor progression (a condition that in the clinical setting often occurs at the end of the guidelines treatment) improved the effectiveness of RT and the animal survival in comparison to standard fractions. For the same cumulative dose, the use of fractions ≤0.5 Gy may permit to escape one or more tumor resistance mechanisms thus increasing the effectiveness of RT and the overall animal survival. These findings suggest investigating in the clinical setting the therapeutic effect of an ultra-hyper-FRT schedule promptly extending the conventional RT component of the current guideline ("Stupp") therapeutic protocol.

Age above 70 years and Charlson Comorbidity Index higher than 3 are associated with reduced survival probabilities after radical cystectomy for bladder cancer. Data from a contemporary series of 334 consecutive patients.

OBJECTIVE: To assess the joint effect of age and comorbidities on clinical outcomes of radical cystectomy (RC). METHODS: 334 consecutive patients undergoing open RC for bladder cancer (BC) during the years 2005-2015 were analyzed. Pre-, peri- and post-operative parameters, including age at RC (ARC) and Charlson Comorbidity Index (CCI), were evaluated. Overall and cancer-specific survivals (OS, CSS) were assessed by univariate and multivariate modelling. Furthermore, a three-knot restricted cubic spline (RCS) was fitted to survival data to detect dependency between death-rate ratio (HR) and ARC. RESULTS: Median follow-up time was 3.8 years (IQR = 1.3-7.5) while median OS was 5.9 years (95%CL = 3.8-9.1). Globally, 180 patients died in our cohort (53.8%), 112 of which (62.2%) from BC and 68 patients (37.8%) for unrelated causes. After adjusting for preoperative, pathological and perioperative parameters, patients with CCI > 3 showed significantly higher death rates (HR = 1.61; p = 0.022). The highest death rate was recorded in ARC = 71-76 years (HR = 2.25; p = 0.034). After fitting an RCS to both OS and CSS rates, two overlapping nonlinear trends, with common highest risk values included in ARC = 70-75 years, were observed. CONCLUSIONS: Age over 70 years and CCI > 3 were significant factors limiting the survival of RC and should both be considered when comparing current RC outcomes.

Potential role of serum mesothelin in predicting survival of patients with malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor survival rates. Therefore, it is essential to have effective biological markers predicting the course of the disease and prognosis. The aim of the present study was to highlight the prognostic significance of serum soluble mesothelin-related protein (Se-SMRP) in patients with MPM at diagnosis. Se-SMRP was determined in 60 patients using an ELISA commercial kit. Se-SMRP levels were subdivided into three tertile-based categories and in each category overall survival (OS) indexes were determined using the Kaplan-Meier and Cox regression analyses. The association between Se-SMRP levels and OS was also assessed by restricted cubic spline (RCS) analysis. No notable differences in the Kaplan-Meier probabilities were identified across the Se-SMRP categories (<0.66 nM, 0.66-1.46 nM, >1.46 nM) although an upward trend in death rate ratios (RR) was pointed out by comparing the higher (RR=1.95) and intermediate (RR=1.86) categories with the lower category (RR=1.00). In addition, such an increasing tendency, particularly when the biomarker exceeded 1.0 nM, was confirmed by an RCS function of Se-SMPR levels fitted to survival data using the Cox regression equation. The present study provided evidence in favor of a prognostic value of Se-SMRP in patients with MPM.

Dietary Habits and Risk of Esophagitis and Barrett's Esophagus: A Multicenter Italian Case-Control Study.

BACKGROUND: Barrett's esophagus (BE) and esophagitis share potentially modifiable risk factors such as obesity, smoking, and alcohol. The role of diet on BE and esophagitis is still debated. AIMS: The objective of this study was to examine the association between some dietary habits and the risk of BE and esophagitis in Italy. METHODS: A multicenter case-control study involving 1285 individuals was carried out in 12 areas. Patients with a new diagnosis of BE (320) or esophagitis (359) and a group of endoscopic controls (606) were included. Information on personal history and dietary habits was collected using a structured questionnaire. RESULTS: No clear monotonic significant dose-response relationship was found for most of the considered food items. Nevertheless, the most extreme consumption category of red meat, cold cuts, dairy products, and fried foods showed esophagitis risk excesses varying from 19 to 49%. A higher fat rich diet seemed to increase risk by 49% for BE and 94% for esophagitis. A downward tendency in esophagitis (- 27%) and BE risk (- 20%) was found associated with higher frequency of fresh fruit intake. In addition, a statistically significant twofold increased risk for both BE and esophagitis was found for subjects eating late evening snacks more than once every three days in comparison with the lowest intake category (no consumption). CONCLUSIONS: BE and esophagitis patients appeared to be more likely than controls to follow a diet rich in fats and poor in fruit and vegetables. Late evening snacks were found to be associated with both disorders.

Radiation-Related Deregulation of TUBB3 and BRCA1/2 and Risk of Secondary Lung Cancer in Women With Breast Cancer.

INTRODUCTION: Breast cancer survivors are at increased risk of developing unrelated primary cancers, particularly lung cancer. Evidence indicates that sex hormones as well as a deregulation of DNA-repair pathways may contribute to lung cancer onset. We investigated whether the hormone status and expression of markers involved in DNA repair (BRCA1/2, ERCC1, and P53R2), synthesis (TS and RRM1), and cell division (TUBB3) might be linked to lung cancer risk. PATIENTS AND METHODS: Thirty-seven breast cancer survivors with unrelated lung cancer and 84 control subjects comprising women with breast cancer (42/84) or lung cancer (42/84) were enrolled. Immunohistochemistry on tumor tissue was performed. Geometric mean ratio was used to assess the association of marker levels with patient groups. RESULTS: Estrogen receptor was expressed in approximately 90% of the breast cancer group but was negative in the majority of the lung cancer group, a result similar to the lung cancer control group. Likewise, ER isoform ß was weakly expressed in the lung cancer group. Protein analysis of breast cancer versus control had a significantly lower expression of BRCA1, P53R2, and TUBB3. Likewise, a BRCA1 reduction was observed in the lung cancer group concomitant with a BRCA2 increase. Furthermore, BRCA2 and TUBB3 increased in ipsilateral lung cancer in women who had previously received radiotherapy for breast cancer. CONCLUSION: The decrease of DNA-repair proteins in breast cancer could make these women more susceptible to therapy-related cancer. The increase of BRCA2 and TUBB3 in lung cancer from patients who previously received radiotherapy for breast cancer might reflect a tissue response to exposure to ionizing radiation.

Characterization of soluble PD-L1 in pleural effusions of mesothelioma patients: potential implications in the immune response and prognosis.

PURPOSE: Programmed death-ligand 1 (PD-L1) protein plays a central role in the antitumor immune response, and appears to be a predictor of prognosis and efficacy for PD-L1 and programmed death 1 (PD-1) blockade therapy. The immunoregulatory role and prognostic impact of PD-L1 soluble form (sPD-L1) have been investigated in biological fluids of patients with different tumors. In malignant pleural mesothelioma (MPM), circulating sPD-L1 has been recently reported in patients' sera, but no data are available in pleural effusions (PE). In our study, we evaluated the baseline expression levels of sPD-L1 in PE from 84 MPM patients and correlated them with PD-L1-status in matched tumors and patients' overall survival (OS). METHODS: sPD-L1 in PE was determined by ELISA and tumor PD-L1 by immunohistochemistry. Association of sPD-L1 with OS was estimated using the Cox regression model. RESULTS: We observed that sPD-L1 was variably expressed in all the PE and tended to be higher (by 30%) in patients with PD-L1-positive tumors (cut-off ≥ 1% stained cells) as compared to patients with PD-L1-negative tumors (geometric mean ratio = 1.28, P value = 0.288). sPD-L1 levels were significantly higher than those of sPD-1 (P value = 0.001) regardless of the MPM histotypes and they were positively correlated (r = 0.50, P value < 0.001). Moreover, high PE sPD-L1 concentrations were associated with a trend towards increased OS (hazard ratio 0.79, 95% CL 0.62-1.01, P value = 0.062). CONCLUSIONS: Our study documents the presence of sPD-L1 in PE of MPM patients, and suggests its possible biological and prognostic role in MPM.

Enhanced therapeutic index of liposomal doxorubicin Myocet locally delivered by fibrin gels in immunodeficient mice bearing human neuroblastoma.

Caelyx and Myocet are clinically used liposomal forms of doxorubicin (Dox). To explore ways to improve their therapeutic index, we have studied their activity in vitro and in vivo when locally delivered by fibrin gels (FBGs). In vivo local toxic and anti-tumour activities of loaded FBGs were assessed in two immunodeficient mouse orthotopic human neuroblastoma (NB) models after application in the visceral space above the adrenal gland, either still tumour-bearing or after tumour removal. In parallel, in vitro assays were used to mimic the in vivo overlaying of FBGs on the tumour surface. FBGs were prepared with different concentrations of fibrinogen (FG) and clotted in the presence of Ca2+ and thrombin. The in vitro assays showed that FBGs loaded with Myocet possess a cytotoxic activity against NB cell lines generally greater than those loaded with free Dox or Caelyx. In vivo FBGs loaded with Myocet showed lower general and local toxicities as compared to gels loaded with Caelyx or free Dox, and also to free Dox administered i.v. (all treatments with Dox at 2.5 mg/Kg). The anti-tumour activity, evaluated in the two mouse orthotopic NB models of adjuvant and neo-adjuvant therapy, resulted in a better performance of FBGs loaded with Myocet compared to the other local (FBGs loaded with Caelyx or free Dox) or systemic (free Dox) treatments (administered at 2.5 and 5 mg/Kg Dox). Specifically, the application of FBGs at 40 mg/mL in the adjuvant model caused 92 % tumour volume reduction, while by the neo-adjuvant application of FBGs at 22 mg/mL a re-growing tumour volume reduction of 89 % was obtained. Taken together, our in vitro and in vivo results indicate a significantly higher activity for the FBGs loaded with Myocet. In particular, the lower toicity coupled with the higher anti-tumour activity on both the local treatment modalities strongly suggest a better therapeutic index when Myocet is administered through FBGs. Therefore, FBGs loaded with Myocet may be considered as a possible new tool for the loco-regional treatment of NB or even other tumour histotypes treatable by loco-regional chemotherapy.

Phenotypic characterization of tumor CTLA-4 expression in melanoma tissues and its possible role in clinical response to Ipilimumab.

The expression of the immune checkpoint molecule CTLA-4 has been almost exclusively studied in the T cell lineage, but increasing evidence has shown its expression on tumors with implications for immunotherapy. To date, the degree of expression of CTLA-4 on tumor cells as a predictive biomarker of response to immune checkpoint inhibitors has not been studied. In this report, we analyzed this issue in melanoma patients treated with CTLA-4 inhibitor Ipilimumab (IPI). We show that the level of CTLA-4 expression on melanoma cells is higher than that on tumor infiltrating lymphocytes (TIL) and it is associated with clinical response to IPI therapy supporting the idea of its possible role as a predictive biomarker.

Association Between Response to Nivolumab Treatment and Peripheral Blood Lymphocyte Subsets in Patients With Non-small Cell Lung Cancer.

Immune checkpoint blockade represents a major breakthrough in advanced non-small cell lung cancer (NSCLC) therapy. However, success is limited to a subset of patients and there is a critical need to identify robust biomarkers associated with clinical response. In this study, we assessed whether pre-existing immunological characteristics, as well as immune parameters measured during treatment, might provide such clinical guidance. We studied blood samples collected at baseline and during treatment in a cohort of advanced NSCLC patients (n = 74) treated with nivolumab. Several lymphocyte subsets and biomarkers were then correlated with overall survival (OS) as well as clinical response, assessed using RECIST criteria. We found that patients characterized by longer OS had higher levels of CD3+, CD4+, and CD8+ T cells but lower levels of NK cells at baseline. Moreover, that they displayed a statistically significant lower expression of PD-1 on both CD3+ and CD8+ T cells (p = 0.013 and p = 0.033, respectively). The pre-treatment level of exhausted T cells (CD8+PD1+Eomes+) was significantly lower in patients with controlled disease (CD), defined as partial response (PR), and stable disease (SD), compared to those with progressive disease (PD) (p = 0.046). In CD patients, the frequency of exhausted CD8+ T cells further decreased during treatment cycles (p = <0.0001, p = 0.0032, and p = 0.0239, respectively). In conclusion, our results suggest that the distribution of lymphocyte subsets and expression of PD-1 on T cells before treatment may help predict the outcome of anti-PD-1 treatment in NSCLC patients. In addition, assessing the initial levels of exhausted T cells as well as their decrease upon treatment may also predict response and clinical outcome.

Response to ipilimumab therapy in metastatic melanoma patients: potential relevance of CTLA-4+ tumor infiltrating lymphocytes and their in situ localization.

Immune checkpoint inhibitors, including ipilimumab (IPI), achieve a clinical benefit in a small proportion of melanoma patients highlighting the need to investigate predictive biomarkers. In this study, we characterized tumor infiltrating lymphocytes (TILs), focusing on the CTLA-4+ subset, and evaluated their possible predictive significance. We characterized TIL density, cell type, and localization in 40 melanoma lesions from 17 patients treated with IPI. Associations of TILs with IPI timing, tissue localization, and response to IPI were estimated using a linear mixed-effects modelling approach. We found that most of TIL subsets increased in situ upon IPI therapy, with particular reference to FoxP3+ cells. TILs and TIL subsets, such as CD3+, CD45RO+, CTLA-4+, CD4+, CD8+ T cells, CD20+ B cells, and NKp46+ NK cells, showed significantly different spatial distributions in the tumor microenvironment being higher at the invasive margin (IM) as compared to the tumor center (TC) (P value < 0.001 for TIL score and P value < 0.05 for all subsets). Remarkably, high TIL score and density of CD3+, CD8+ T cells, and CTLA-4+ immune cells were significantly associated with a better response to IPI (P values = 0.002, 0.023, 0.007, and 0.001, respectively, for responders vs non-responders). In conclusion, we provide a detailed analysis of CTLA-4+ TIL distribution in melanoma tissues taking into account localization, relationship with CD3+/CD8+ TILs, and changes in response to IPI treatment. We identified that CTLA-4+ TILs may represent a marker of IPI response, alone or with CD3+/CD8+ subsets, although this requires confirmation in larger studies.