Prognostic significance of pulmonary multifocal neuroendocrine proliferation with typical carcinoid

Background. Clinical significance of multifocal pulmonary neuroendocrine proliferations (MNEP), including tumorlets and pulmonary neuroendocrine cell hyperplasia, in association with Typical Carcinoid (TC), is still debated. Methods. A large retrospective series of TC with long-term follow-up data prospectively collected from two institutions was evaluated. Recurrence or new TC development was followed-up. Patients with TC alone and MNEP+TC were compared. Results. 234 TC patients undergone surgery were included: 41 MNEP+TC (17.5%) and 193 TC alone (82.5%). In the MNEP+TC group older age (p<0.001), peripheral tumors (p=0.0032), smaller tumor size (p=0.011) and lymph-nodal spread (p=0.02) were observed in comparison with TC group. Relapses occurred in 8 patients (19.5%) in the MNEP+TC group and in 7 (3.6%) of the TC group. The 10-years progression-free survival were 96.1% in TC and 83.8% in MNEP+TC (p<0.001). After matching, in 36 pairs of patients a significantly higher 5-years progression-free survival was calculated for TC group (p<0.01). Furthermore the odds of belonging to MNEP+TC group was higher with work-related exposure to inhalant agents (p=0.008), asthma/bronchitis (p=0.002), emphysema, fibrosis and inflammatory status (p=0.032), micronodules on the chest CT scan and respiratory insufficiency (p=0.036). Conclusions. The identification of MNEP requires careful pathological examination and postoperative follow-up. MNEP seems to be an adverse prognostic factor in patients with synchronous TC. Therefore, suspicion of MNEP during the pre-operative assessment should not be underestimated, enabling changes in the surgical strategy.

Predictive And Prognostic Role Of Biological Markers In Neuroendocrine Neoplasia And Evaluation Of Activity And Safety Of Second Line Treatments In Neuroendocrine Carcinoma Patients

BACKGROUND Neuroendocrine neoplasia (NEN) are divided in well differentiated G1,G2 and G3 neuroendocrine tumors (NETs) and G3 neuroendocrine carcinomas (NECs). For the latter no standard therapy in second-line is available and prognosis is poor. METHODS Primary aim was to evaluate new prognostic and predictive biomarkers (WP1-3). In WP4 we explored the activity of FOLFIRI and CAPTEM as second-line in NEC patients in a multicenter non-comparative phase II trial RESULTS In WP1-2 we found that 4 of 6 GEP-NEC patients with a negative 68Ga-PET/CT had a loss of expression of RB1. In WP3 on 47 GEP-NENs patients the presence of DLL3 in 76.9% of G3 NEC correlate with RB1-loss (p<0.001), negative 68Ga-PET/CT(p=0.001) and a poor prognosis. In the WP4 we conducted a multicenter non-comparative phase II trial to explore the activity of FOLFIRI or CAPTEM in terms of DCR, PFS and OS given as second-line in NEC patients. From 06/03/2017 to 18/01/2021 53 out of 112 patients were enrolled in 17 of 23 participating centers. Median follow-up was 10.8 (range 1.4 – 38.6) months. The 3-month DCR was 39.3% in the FOLFIRI and 32.0 % in the CAPTEM arm. The 6-months PFS rate was 34.6% ( 95%CI 17.5-52.5) in FOLFIRI and 9.6% (95%CI 1.8-25.7) in CAPTEM group. In the FOLFIRI subgroup the 6-months and 12-months OS rate were 55.4% (95%CI 32.6-73.3) and 30.3% (CI 11.1-52.2) respectively. In CAPTEM arm the 6-months and 12-months OS rate were 57.2% (95%34.9-74.3) and 29.0% (95%10.0-43.3). The miRNA analysis of 20 patients compared with 20 healthy subjects shows an overexpression of miRNAs involved in staminality , neo-angiogenesis and mitochontrial anaerobic glycolysis activation. CONCLUSION WP1-3 support the hypothesis that G3NECs carrying RB1 loss is associated with a DLL3 expression highlighting a potential therapeutic opportunity. Our study unfortunately didn’t met the primary end–point but the results are promising

Influenza dell'Omeostasi Idrico-Elettrolitica sul Ciclo Veglia-Sonno

During the wake sleep (W-S) cycle in mammals, the alternation of the different states, wake, NREM sleep (NREMS) and REM sleep (REMS), is associated not only with electroencephalographic or behavioural changes, but also with modifications in the physiological regulations of the organism. The most evident change is the existence of a suspension of the somatic and autonomic thermoregulatory responses during REMS. Since thermoregulation is prevalently controlled by the Preoptic Area-Anterior Hypothalamus (PO-AH), its suspension during REM sleep has been taken as a sign of an impairment of the hypothalamic integrative activity that could explain the modifications in physiological regulation observed in this sleep stage. The recent finding from our laboratory that the secretion of the antidiuretic hormone arginine-vasopressin (AVP) in response to a central osmotic stimulation is quantitatively the same throughout the different stages of the W-S cycle, has shown that hypothalamic osmoregulation is not suspended during REMS. In order to clarify the extent of the hypothalamic involvement in the regulation of the W-S cycle, we have studied the effects of three days of water deprivation and of two days of recovery during which animals were allowed a free access to water, on the architecture of the W-S cycle. The condition of water deprivation represents a severe challenge involving neuroendocrine and autonomic hypothalamic regulations. In contradiction with thermoregulatory studies, in which it has been clearly demonstrated that a thermal challenge selectively reduces REMS occurrence, the results of this study show that REMS occurrence is mildly reduced only in the third day of water deprivation. The most striking effects produced by water deprivation appear to concern NREMS, which shows a selective and significant reduction in its slow EEG activity (delta-power) but not in its duration. The recovery period is mainly characterized by a disruption of the normal circadian rhythm of REMS occurrence and by a rebound of the delta power in NREMS. Thus, an autonomic challenge different from those related to thermoregulation and an endocrine challenge as the continuous secretion of AVP show to exert different effects on the stages of the wake-sleep cycle. Also, this study demonstrates that the impairment of the hypothalamic integrative activity thought to characterize the occurrence of REMS only involves thermoregulatory structures.

Applications of metrological techniques for clinical implementation of dosimetry and radiobiology in molecular radiotherapy

Molecular radiotherapy (MRT) is a fast developing and promising treatment for metastasised neuroendocrine tumours. Efficacy of MRT is based on the capability to selectively "deliver" radiation to tumour cells, minimizing administered dose to normal tissues. Outcome of MRT depends on the individual patient characteristics. For that reason, personalized treatment planning is important to improve outcomes of therapy. Dosimetry plays a key role in this setting, as it is the main physical quantity related to radiation effects on cells. Dosimetry in MRT consists in a complex series of procedures ranging from imaging quantification to dose calculation. This doctoral thesis focused on several aspects concerning the clinical implementation of absorbed dose calculations in MRT. Accuracy of SPECT/CT quantification was assessed in order to determine the optimal reconstruction parameters. A model of PVE correction was developed in order to improve the activity quantification in small volume, such us lesions in clinical patterns. Advanced dosimetric methods were compared with the aim of defining the most accurate modality, applicable in clinical routine. Also, for the first time on a large number of clinical cases, the overall uncertainty of tumour dose calculation was assessed. As part of the MRTDosimetry project, protocols for calibration of SPECT/CT systems and implementation of dosimetry were drawn up in order to provide standard guidelines to the clinics offering MRT. To estimate the risk of experiencing radio-toxicity side effects and the chance of inducing damage on neoplastic cells is crucial for patient selection and treatment planning. In this thesis, the NTCP and TCP models were derived based on clinical data as help to clinicians to decide the pharmaceutical dosage in relation to the therapy control and the limitation of damage to healthy tissues. Moreover, a model for tumour response prediction based on Machine Learning analysis was developed.

A phase II, single arm study of CarbopLatin plus Etoposide with Bevacizumab and Atezolizumab in patients with exTEnded-disease small-cell lung cancer (SCLC) – CeLEBrATE trial

Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor diagnosed at extended disease SCLC (ES-SCLC) stage in about 70% of cases. The new standard of treatment for patients with ES-SCLC is a combination of platinum-etoposide chemotherapy and atezolizumab or durvalumab, two programmed cell death ligand 1 (PD-L1) inhibitory monoclonal antibodies (mAb). However, the benefit derived from the addition of PD-L1 inhibitors to chemotherapy in ES-SCLC was limited and restricted to a subset of patients. The vascular endothelial growth factor (VEGF) is the most important pro-angiogenic factor implicated in cancer angiogenesis, which is abundant in SCLC and associated with poor prognosis. Antiangiogenic agents, such as bevacizumab, a humanized mAb against VEGF, added to platinum-etoposide chemotherapy improved progression-free survival in SCLC in two trials, but it did not translate into a benefit in overall survival. Nevertheless, VEGF has also acts as a mediator of an immunosuppressive microenvironment and its inhibition can revert the immune-suppressive tumor microenvironment and potentially enhance the efficacy of immunotherapies. Based on available preclinical data, we hypothesized that VEGF inhibition by bevacizumab could improve atezolizumab efficacy in a synergistic way and designed a phase II single-arm trial of bevacizumab in combination with carboplatin, etoposide, and atezolizumab as first-line treatment in ES-SCLC. The trial, which is still ongoing, enrolled 53 patients, including those with treated or untreated asymptomatic brain metastases (provided criteria are met), who received atezolizumab, bevacizumab, carboplatin and etoposide for 4-6 cycles (induction phase), followed by maintenance with atezolizumab and bevacizumab for a maximum of 18 total cycles or until disease progression, patient refusal, unacceptable toxicity. The evaluation of efficacy of the experimental combination in terms of 1-year overall survival rate is not yet mature (primary objective of the trial). The combination was feasible and the toxicity profile manageable (secondary objective of the trial).