Radical Resection in Entero-Pancreatic Neuroendocrine Tumors: Recurrence-Free Survival Rate and Definition of a Risk Score for Recurrence.

BACKGROUND: Surgery with radical intent is the only potentially curative option for entero-pancreatic neuroendocrine tumors (EP-NETs) but many patients develop recurrence even after many years. The subset of patients at high risk of disease recurrence has not been clearly defined to date. OBJECTIVE: The aim of this retrospective study was to define, in a series of completely resected EP-NETs, the recurrence-free survival (RFS) rate and a risk score for disease recurrence. PATIENTS AND METHODS: This was a multicenter retrospective analysis of sporadic pancreatic NETs (PanNETs) or small intestine NETs (SiNETs) [G1/G2] that underwent R0/R1 surgery (years 2000-2016) with at least a 24-month follow-up. Survival analysis was performed using the Kaplan-Meier method and risk factor analysis was performed using the Cox regression model. RESULTS: Overall, 441 patients (224 PanNETs and 217 SiNETs) were included, with a median Ki67 of 2% in tumor tissue and 8.2% stage IV disease. Median RFS was 101 months (5-year rate 67.9%). The derived prognostic score defined by multivariable analysis included prognostic parameters, such as TNM stage, lymph node ratio, margin status, and grading. The score distinguished three risk categories with a significantly different RFS (p < 0.01). CONCLUSIONS: Approximately 30% of patients with EP-NETs recurred within 5 years after radical surgery. Risk factors for recurrence were disease stage, lymph node ratio, margin status, and grading. The definition of risk categories may help in selecting patients who might benefit from adjuvant treatments and more intensive follow-up programs.

Gastroenteropancreatic grade 3 neuroendocrine tumors: a single entity or a heterogeneous group? A retrospective analysis.

PURPOSE: Grade 3 neuroendocrine tumor (NET G3) is a novel pathologic category within gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NENs) but its clinical behavior and therapeutic management still remain challenging. Prognostic and predictive factors aiding NET G3 management are needed. PATIENTS AND METHODS: We performed a retrospective analysis from 2015 to 2020 of all patients with > 20% Ki-67, well-differentiated NETs evaluated within our NEN-dedicated multidisciplinary team. We divided the sample according the timing of NET G3 diagnosis, the radiotracers distribution and Ki-67. We analyzed the correlation between these NET G3 features and clinical outcomes. RESULTS: Among 3238 multidisciplinary discussion reports, we selected 55 patients, 48 from GEP and 7 from an occult GEP origin. In 45 patients, NET G3 diagnosis occurred at the beginning of clinical history (upfront-NET G3), whereas in 10, during the NET G1-G2 clinical history (late-NET G3). Patients with ≤ 30% (34/55) vs. > 30% Ki-67 (21/55) had a better overall survival (OS) (p = 0.042); patients with a homogeneous vs. inhomogeneous/negative 68Gallium(68Ga)-DOTA-Peptide Positron Emission Tomography (PET)/computed tomography (CT) showed a trend to a better OS, and a significant better progression-free survival (PFS) (p = 0.033). A better OS was observed for negative/inhomogeneous vs. homogeneous 18-fluorodeoxyglucose (18FDG)-PET/CT (p = 0.027). A trend to a better OS was reported in late- vs. upfront-NET G3, while the latter showed a significantly better response rate (RR) (p = 0.048). CONCLUSION: Our findings suggested that Ki-67 cutoff, functional imaging and the timing to NET G3 diagnosis may help clinicians in more accurate selection of NET G3 management. Prospective studies are needed.

A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial.

Background: Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarily targeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generation SSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone in patients with advanced, well-differentiated, progressive pancreatic NET. Patients and methods: Patients were randomized 1 : 1 to receive a combination of everolimus (10 mg/day, orally) and pasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSA use, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response rate, disease control rate, and safety. Biomarker response was evaluated in an exploratory analysis. Results: Of 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographics and disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8 months in combination arm versus 16.6 months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64-1.54). Partial responses were observed in 20.3% versus 6.2% of patients in combination arm versus everolimus arm; however, overall disease control rate was similar (77.2% versus 82.7%, respectively). No significant improvement was observed in median overall survival. Adverse events were consistent with the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37% versus 11% of patients, respectively. Conclusions: The addition of pasireotide to everolimus was not associated with the improvement in PFS compared with everolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted.

Preoperative versus postoperative docetaxel-cisplatin-fluorouracil (TCF) chemotherapy in locally advanced resectable gastric carcinoma: 10-year follow-up of the SAKK 43/99 phase III trial.

BACKGROUND: Fluorouracil-based adjuvant chemotherapy in gastric cancer has been reported to be effective by several meta-analyses. Perioperative chemotherapy in locally advanced resectable gastric cancer (RGC) has been reported improving survival by two large randomized trials and recent meta-analyses but the role of neoadjuvant chemotherapy and optimal regimen remains to be determined. We compared a neoadjuvant with adjuvant docetaxel-based regimen in a prospective randomized phase III trial, of which we present the 10-year follow-up data. PATIENTS AND METHODS: Patients with cT3-4 anyN M0 or anyT cN1-3 M0 gastric carcinoma, staged with endoscopic ultrasound, computed tomography, bone scan, and laparoscopy, were assigned to receive four 21-day/cycles of docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, and fluorouracil 300 mg/m(2)/day over days 1-14, either before (arm A) or after (arm B) gastrectomy. Event-free survival was the primary end point, whereas secondary end points included overall survival, toxicity, down-staging, pathological response, quality of life, and feasibility of adjuvant chemotherapy. RESULTS: This trial was activated in November 1999 and closed in November 2005 due to insufficient accrual. Of the 70 enrolled patients, 69 were randomized, 34 to arm A and 35 to arm B. No difference in EFS (2.5 years in both arms) or OS (4.3 versus 3.7 years, in arms A and B, respectively) was found. A higher dose intensity of chemotherapy was observed in arm A and more frequent chemotherapy-related serious adverse events occurred in arm B. Surgery was safe after preoperative chemotherapy. A 12% pathological complete response was observed in arm A. CONCLUSION: Docetaxel/cisplatin/fluorouracil chemotherapy is promising in preoperative setting of locally advanced RGC. The early stopping could mask the real effectiveness of neoadjuvant treatment. However, the complete pathological tumour responses, feasibility, and safe surgery warrant further investigation of a taxane-based regimen in the preoperative setting.

Fluorodeoxyglucose positron emission tomography in pulmonary carcinoid tumors.

AIM: The role of fluorodeoxyglucose positron emission tomography (FDG-PET) as an additional investigation to computer tomography for pulmonary carcinoid tumors remains controversial. The aim of this study was to assess the role of FDG-PET for the diagnosis and staging of pulmonary carcinoid tumors. METHODS: We performed a retrospective mono-institutional analysis of data from 97 patients with pathologically confirmed pulmonary carcinoid tumor who had been operated on between July 1998 and April 2009 and had had a preoperative FDG-PET scan performed. RESULTS: Sixty-five (67%) of the 97 tumors were typical (TC) and 32 (33%) atypical (AC) carcinoid tumors. Overall FDG-PET sensitivity was 67% being lower for TC (60%) than for AC (81%) (P=0.04). FDG-PET negative tumors were smaller than FDG-PET positive tumors, with a respective median size of 15 and 17 mm (P=0.02). Median SUVmax for FDG-PET-positive tumors was 4.0 (2.8-5.1) with no difference between TC and AC tumors. Median Ki-67 expression was respectively 4.7% and 3.1% for FDG-PET positive and FDG-PET negative tumors (P=0.05). During a median follow-up of 49 months (interquartile range 30-63 months), 9 patients (4TC, 5AC) developed recurrent disease. Neither SUVmax nor Ki-67 expression resulted associated with disease-free survival. CONCLUSION: With an overall sensitivity of 67%, FDG-PET has shown to be useful in the preoperative work-up of patients with suspect lung carcinoid tumors. In particular it could have a role in larger tumors. These results warrant a prospective evaluation of FDG-PET in the staging of lung carcinoid tumor.

Obstetric Violence in Italy: From Theoretical Premises to Court Judgments.

Introduction: Historical mistreatment and violence directed toward women's bodies extend to the field of medicine, and obstetric and gynecological practices are not immune to such misconduct. Obstetric violence (OV) refers to actions involving disrespectful, abusive, or coercive treatment directed at pregnant and birthing women. This includes institutional and personal attitudes that lead to the violation of women's autonomy, human rights, and sexual and reproductive health. Despite various international legislative initiatives and recommendations from the World Health Organization (WHO) addressing disrespectful and abusive treatment, OV is still poorly known to Italian public opinion. This study aims to investigate whether the concept of OV has been conversely assimilated in judicial decisions. Materials and methods: A retrospective analysis was conducted to scrutinize judgments in Italy until June 2023 related to OV. The Italian legal database 'De Jure Giuffrè', which collects sentences by various Courts, and the terms 'obstetric' and 'violence' as keywords were used for the research. Results: The full-text revision of the results (n. 41 sentences) al-lowed the selection of 5 eligible contributions covering the following issues: Informed Consent, Kristeller maneuver, Vaginal Birth After Cesarean (VBAC), Acceleration of childbirth without indication, and Episiotomy. The analysis of individual judgments was complemented by an examination of the key issues involved. Conclusions: The reviewed judgments frequently seemed to be grounded in technical aspects and inclined towards a predominant evaluation of childbirth outcomes. However, some encouraging aspects emerged, particularly in terms of attention to the female body, acknowledgment of consequences within the intimate-relational dimension, and a commitment to the principle of self-determination through the provision of free and informed consent. Ensuring the psychophysical well-being of women and unborn children, fostering positive interactions between pregnant women and medical staff, and actively working to reduce the grounds for litigation are among actual emerging priorities in healthcare. In this sense, fundamental elements include the implementation of continuous staff training and education as well as a focus on promoting the self-determination of women, leveraging new technologies for this purpose, and ensuring legal protection of their rights.

First-line avelumab treatment in patients with metastatic Merkel cell carcinoma: 4-year follow-up from part B of the JAVELIN Merkel 200 study.

BACKGROUND: Results from the JAVELIN Merkel 200 study led to the approval of avelumab [an anti-programmed death-ligand 1 (PD-L1) antibody] for the treatment of metastatic Merkel cell carcinoma (mMCC) in multiple countries and its inclusion in the treatment guidelines as a preferred or recommended therapy in this setting. Here, we report 4-year follow-up results from the cohort of patients with mMCC who received avelumab as first-line treatment. PATIENTS AND METHODS: In part B of JAVELIN Merkel 200, a single-arm, open-label, phase II study, patients with mMCC who had not received prior systemic therapy for metastatic disease received avelumab 10 mg/kg via intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. In this analysis, long-term overall survival (OS), patient disposition, and subsequent treatment were analyzed. RESULTS: In total, 116 patients received first-line avelumab. At the data cutoff (2 February 2022), the median follow-up was 54.3 months (range 48.0-69.7 months). Seven patients (6.0%) remained on treatment and an additional 21 patients remained in follow-up (18.1%); 72 patients (62.1%) had died. The median OS was 20.3 months [95% confidence interval (CI) 12.4-42.0 months], with a 4-year OS rate of 38% (95% CI 29% to 47%). In patients with PD-L1+ or PD-L1- tumors, the 4-year OS rate was 48% (95% CI 26% to 67%) and 35% (95% CI 25% to 45%), respectively. In total, 48 patients (41.4%) received poststudy anticancer drug therapy, most commonly etoposide (20.7%), carboplatin (19.0%), and avelumab (12.1%). CONCLUSIONS: Avelumab first-line monotherapy in patients with mMCC resulted in meaningful long-term OS, which compared favorably with historical studies of first-line chemotherapy. These results further support the role of avelumab as a standard of care for patients with mMCC.

Targeting neuroendocrine tumors with octreotide and lanreotide: Key points for clinical practice from NET specialists.

Octreotide and lanreotide are the two somatostatin analogs (SSA) currently available in clinical practice. They have been approved first to control the clinical syndrome (mainly carcinoid syndrome) associated with functioning neuroendocrine tumors (NET) and later for tumor growth control in advanced low/intermediate grade NET. Although evidence regarding their role, especially as antiproliferative therapy, has been increasing over the years some clinical indications remain controversial. Solicited by AIOM (Italian Association of Medical Oncology) a group of clinicians from various specialties, including medical oncology, endocrinology, and gastroenterology, deeply involved in NET for their clinical and research activity, addressed eight open questions, critically reviewing evidence and guidelines and sharing clinical take-home messages. The questions regarded the use of long-acting octreotide and lanreotide in the following settings: functioning and non-functioning NET refractory to label dose, first-line metastatic pulmonary NET, combination with other therapy with an antiproliferative intent, maintenance in NET responding to other therapies, adjuvant treatment, Ki-67-related cut-off, somatostatin receptor imaging, safety, and feasibility. The level of evidence is not absolute for the majority of these clinical contexts, so it is recommended to distinguish routine versus sporadic utilization in very selected cases. Mention of such specific issues by the main European guidelines (ENETS, European Neuroendocrine Tumor Society, and ESMO, European Society for Medical Oncology) was explored and their position reported. However, different clinical decisions on single patients could be made if the case is carefully discussed within a NET-dedicated multidisciplinary team.

Z-Drugs and their use in Drug-Facilitated Crimes: a review of the literature.

Background: Z-Drugs are a category of non-benzodiazepine sedative-hypnotic drugs that include Zolpidem, Zopiclone and Zaleplon. They are all rapidly adsorbed and have a very short half- life, features that make them first-line treatment of insomnia and, in the meantime, first-choice drugs in cases of poisoning for criminal purposes. Z-drugs are frequently use in Drug Facilitated Crime cases (DFC) and Drug Facilitated Sexual Assault (DFSA), namely crimes, robberies, extortion and sexual violence committed after administration of incapacitating substances able to induce sedative-hypnotic effects. In these circumstances, the psychoactive substance is considered as a weapon and constitutes an aggravating circumstance in the criminal act: accordingly, judicial authority legitimates the analytical determination of these substances. Currently, few tests able to detect such drugs are available in daily clinical practice. Aim: The aim of this work is to evaluate the effective utilization of Z-Drugs. Methods: We have analyzed the literature, focusing on cases in which the criminal use of such incapacitating substances has been demonstrated. Relevant scientific articles were identified from PubMed, Cochrane Central, Scopus, Web of Science, Science Direct, EMBASE up to December 2022 using the following keywords: "z-drugs", "drug facilitated crime", "forensic toxicology". The resulting references were screened to exclude duplicates. In addition, non-English papers were excluded. This evaluation left 10 articles (8 case reports and 2 original studies) divided as follows: 1 case report of a DFC (robbery), 6 cases of confirmed DFSA, 3 cases of suspected DFSA, 2 original studies about DFC. Results: The totality of the selected cases showed positive toxicological tests for a single intake of z-drugs. Conclusions: This work has shown the limitations of screening tests currently in use in the emergency rooms. Forensic toxicology tests should be introduced in daily clinical practice.

Promising targetable biomarkers in pancreatic neuroendocrine tumours.

INTRODUCTION: In the treatment scenario of PanNETs-targeted therapies are desired but limited, as rarity and heterogeneity on PanNETs pose limitations to their development. AREAS COVERED: We performed a literature review searching for promising druggable biomarkers and potential treatments to be implemented in the next future. We focused on treatments which have already reached clinical experimentation, although in early phases. Six targets were identified, namely Hsp90, HIFa, HDACs, CDKs, uPAR, and DDR. Even though biological rational is strong, so far reported efficacy outcomes are quite disappointing. The reason of that should be searched in the patients' heterogeneity, lack of biomarker selection, poor knowledge of interfering mechanisms as well as difficulties in patients accrual. Moreover, different ways to assess treatment efficacy should be considered, other than response rate, in light of the more indolent nature of NETs. EXPERT OPINION: Development of targeted treatments in PanNETs is still an uncovered area, far behind other more frequent cancers. Rarity of NETs led to accrual of unselected populations, possibly jeopardizing the drug efficacy. Better patients' selection, both in terms of topography, grading and biomarkers is crucial and will help understanding which role targeted therapies can really play in these tumors.

Gas gangrene, not a common infection: case report of post-traumatic fulminant death.

ABSTRACT: Post-traumatic gas gangrene is a rare but potentially life-threa-tening condition due to soft tissues infection by Clostridium species. These anaerobic microaerophile bacteria are highly resistant to external insults related to their ability to produce spores, which can survive on any surface for long periods. Under certain conditions suitable for proliferation (such as in ischemic tissues), bacteria produce many to-xins. In particular, Clostridium perfringens type A represents the most frequent cause of traumatic gas gangrene nowadays. It produces toxins responsible for thrombotic and necrotic phenomena in soft tissues and rapid disease diffusion to muscles. Clinical manifestations usually start as local edema and emphysema but rapidly evolve into a septic state. Prognosis is poor in 20-30% of cases, and death occurs due to multiorgan failure. Because of its rapid evolution, clinical diagnosis is not always obtained, thus determining the need for post-mortem investigation. This case report presents a rare case of fulminant gas gangrene due to Clostridium Perfrigens infection developed after trau-matic injury. Despite the prompt antibiotic administration and surgical intervention on the site of trauma, gas gangrene rapidly evolved into septic shock, leading to the patient's death. Post-mortem investigations were conducted and confirmed multiorgan failure as the cause of death. Cultural analysis was also performed but showed no bacterial growth. Negativity on culture tests should be related to antibiotic administration before blood sampling and bacterial characteristics. In such cases, the correct identification of the cause of death was only possible following a careful and detailed forensic methodological approach.

Ten years-experience of sunitinib in the treatment of advanced pan-NETs: an update on safety profile.

INTRODUCTION: Sunitinib still represents a milestone in the treatment for progressive, well-differentiated, advanced panNETs. AREAS COVERED: We performed an evidence reappraisal to critically discuss its safety profile. We included nine studies, five clinical trials and four real-world (RW) studies. Within non-real-world (NRW) studies, diarrhea was the most frequent clinical AE. With regard to G3-4 AEs, fatigue and hypertension were the two most frequent, while neutropenia was the most recurrent hematological one. Considering four real-world trials, hand-foot-syndrome (HFS) was the most frequent clinical any-grade AE of any grade and neutropenia was the most common G3-4. Alongside to the AEs rate, the discontinuation rate of sunitinib due to TRAEs was variable among all the nine selected studies, ranging from 10% to 35% in the NRW setting and from 7% to 31% in the RW setting. Conversely, temporary interruption is an accepted strategy to reduce toxicity, even though not specifically tested in pan-NET. EXPERT OPINION: Till now, sunitinib continues to be one of the main therapeutic options for patients with well differentiated advanced panNETs, potentially covering any line of treatment. Therefore, tolerability plays a crucial role to increase adherence to therapy and maximize QoL.

Voluntary interruption of pregnancy (VIP) in Italy: interpretation of the current situation according to the report 2019-2020 of the Italian Ministry of Health.

Abstract: Voluntary interruption of pregnancy (VIP) in Italy is regulated by Law no. 194/1978. Its monitoring is carried out by the VIP Epidemio-logical Surveillance System, which periodically analyses the results of questionnaires compiled by the territorial healthcare structures and sent by each Region. The latest report, covering the years 2019 and 2020, highlights the adequacy of preventive and proactive strategies, an improvement in the quality and effectiveness of the service offered. Furthermore, considering the COVID-19 pandemic, the reorganization of the IVG application guidelines showed a considerable adaptation to the emergency context through measures such as the increase in pharmacological procedures compared to surgical procedures. The interpretation of the data shows that in Italy there is one of the lowest VIP rates in Europe, reflecting the effectiveness of campaigns that promote responsible procreation. Further implementations should be extended to the foreign population, which still shows a medium-high VIP rate. The efficiency of the service offered resulted to be high. The latter was assessed considering the waiting period required for the performance of the VIP procedure. Furthermore, the high percentage of conscientious objectors does not harm the healthcare service. The estimates show an adequate territorial coverage by the authorized structures compared to the female population of fertile age. In conclusion, the central action of planning, organization, and monitoring finds a valid ally in the territorial management entrusted to the Regions. The analyzed report reflects even more margins of efficiency and adequacy when considered within the particular historical context of the pandemic by COVID-19.

Italian law no. 1/2021 on the subject of vaccination against Covid-19 in people with mental disabilities within the nursing homes.

ABSTRACT: The Coronavirus Disease-19 (Covid-19) pandemic, in the last year, has resulted in a significant number of infections and deaths among nursing homes' residents. This phenomenon has set up the necessity to subject these patients, often suffering from mental disabilities to a vaccination against Covid-19. However, vaccination has long been the subject of public atten-tion, being regulated differently in many European countries. In Italy, the Ministry of Health has given priority, vaccination-wise, to health facilities' patients. The government has regulated through-law no. 1 of January 5, 2021, art. 5, the manifestation of consent to be Covid-19 vac-cinated in incapacitated subjects admitted to assisted health facilities. This rule arose from the need to protect fragile individuals as well as providing real dispositions for the involved health professionals. Nursing homes' elderly guests could be divided into four catego-ries: a) subjects capable to express their will (affected by physical problems); b) subjects who, due to varying degrees of incapacitation, have their own legal guardian, curator or support administrator, ap-pointed in accordance with the law; c) incapacitated subjects without legal representatives d) subjects who, pursuant to law no. 219/2017, have appointed their own trustee. This paper provides for a clear exemplification of all the possible scenarios identified by the Italian law no.1/2021.

Recent Judgement of the Italian Judiciary about medical assisted procreation (MAP): is informed consent valid after parents separation?

ABSTRACT: Law No 40/2004 regulates in Italy the matter of medically assisted procreation (MAP). Recently, the Tribunal of Capua Vetere expressed its position on the subject of informed consent in a case of MAP. In the specific case, a couple entered the preliminary stages of the PMA procedures, carrying out the fertilization of the ovum and the embryo production. Afterwards, the couple separated and the man denied consent to the continuation of the MAP. The woman, willing to proceed with the implantation, the woman made an urgent judicial appeal, obtaining the judge's permission to transfer the embryo to the uterus. This paper analyses the different bioethical positions on MAP's informed consent. In fact, on the one hand, the paper highlight what is set out in Law 219/2017 which provides for the possibility of the patient to revoke at any time the consent to the treatment given. On the other hand, it should be noted that Law 40/2004, willing to protect the embryo, establishes the irrevocability of the position of parental consent after fertilization. The judgment in question seems to favour this latter position, placing itself in the protection of the cryopreserved embryo and recall-ing the principle of entrustment following the fertilization of the egg. Nevertheless, the matter is controversial a consistent amount of legal developments are expected to arise in the next future.