THUNDER 2: THeragnostic Utilities for Neoplastic DisEases of the Rectum by MRI guided radiotherapy.

BACKGROUND: Neoadjuvant chemoradiation therapy (nCRT) is the standard treatment modality in locally advanced rectal cancer (LARC). Since response to radiotherapy (RT) is dose dependent in rectal cancer, dose escalation may lead to higher complete response rates. The possibility to predict patients who will achieve complete response (CR) is fundamental. Recently, an early tumour regression index (ERI) was introduced to predict pathological CR (pCR) after nCRT in LARC patients. The primary endpoints will be the increase of CR rate and the evaluation of feasibility of delta radiomics-based predictive MRI guided Radiotherapy (MRgRT) model. METHODS: Patients affected by LARC cT2-3, N0-2 or cT4 for anal sphincter involvement N0-2a, M0 without high risk features will be enrolled in the trial. Neoadjuvant CRT will be administered using MRgRT. The initial RT treatment will consist in delivering 55 Gy in 25 fractions on Gross Tumor Volume (GTV) plus the corresponding mesorectum and 45 Gy in 25 fractions on the drainage nodes. Chemotherapy with 5-fluoracil (5-FU) or oral capecitabine will be administered continuously. A 0.35 Tesla MRI will be acquired at simulation and every day during MRgRT. At fraction 10, ERI will be calculated: if ERI will be inferior than 13.1, the patient will continue the original treatment; if ERI will be higher than 13.1 the treatment plan will be reoptimized, intensifying the dose to the residual tumor at the 11th fraction to reach 60.1 Gy. At the end of nCRT instrumental examinations are to be performed in order to restage patients. In case of stable disease or progression, the patient will undergo surgery. In case of major or complete clinical response, conservative approaches may be chosen. Patients will be followed up to evaluate toxicity and quality of life. The number of cases to be enrolled will be 63: all the patients will be treated at Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome. DISCUSSION: This clinical trial investigates the impact of RT dose escalation in poor responder LARC patients identified using ERI, with the aim of increasing the probability of CR and consequently an organ preservation benefit in this group of patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04815694 (25/03/2021).

Impact of the COVID-19 Pandemic on Enhanced Recovery After Surgery (ERAS) Application and Outcomes: Analysis in the "Lazio Network" Database.

BACKGROUND: The aim of this study was to investigate how the COVID-19 pandemic influenced ERAS program application in colorectal surgery across hospitals in the Lazio region (central district in Italy) participating in the "Lazio Network" project. METHODS: A multi-institutional database was constructed. All patients included in this study underwent elective colorectal surgery for both malignant and benign disease between January 2019 and December 2020. Emergency procedures were excluded. The population was divided into 2 groups: a pre-COVID-19 group (PG) of patients operated on between February and December 2019 and a COVID-19 group (CG) of patients operated on between February and December 2020, during the first 2 waves of the pandemic in Italy. RESULTS: The groups included 622 patients in the PG and 615 in the CG treated in 8 hospitals of the network. The mean number of items applied was higher in the PG (65.6% vs. 56.6%, p < 0.001) in terms of preoperative items (64.2% vs. 50.7%, p < 0.001), intraoperative items (65.0% vs. 53.3%, p < 0.001), and postoperative items (68.8% vs. 63.2%, p < 0.001). Postoperative recovery was faster in the PG, with a shorter time to first flatus, first stool, autonomous mobilization and discharge (6.82 days vs. 7.43 days, p = 0.021). Postoperative complications, mortality and reoperations were similar among the groups. CONCLUSIONS: The COVID-19 pandemic had a negative impact on the application of ERAS in the centers of the "Lazio Network" study group, with a reduction in adherence to the ERAS protocol in terms of preoperative, intraoperative and postoperative items. In addition, in the CG, the patients had worse postoperative outcomes with respect to recovery and discharge.

Enhanced recovery after surgery (ERAS) program in octogenarian patients: a propensity score matching analysis on the "Lazio Network" database.

PURPOSE: The aim of this study was to evaluate the safety and compliance with the enhanced recovery after surgery (ERAS) protocol in octogenarian patients undergoing colorectal surgery in 12 Italian high-volume centers. METHODS: A retrospective analysis was conducted in a consecutive series of patients who underwent elective colorectal surgery between 2016 and 2018. Patients were grouped by age (≥ 80 years vs < 80 years), propensity score matching (PSM) analysis was performed, and the groups were compared regarding clinical outcomes and the mean number of ERAS items applied. RESULTS: Out of 1646 patients identified, 310 were octogenarians. PSM identified 2 cohorts of 125 patients for the comparison of postoperative outcomes and ERAS compliance. The 2 groups were homogeneous regarding the clinical variables and mean number of ERAS items applied (11.3 vs 11.9, p-ns); however, the application of intraoperative items was greater in nonelderly patients (p 0.004). The functional recovery was similar between the two groups, as were the rates of postoperative severe complications and 30-day mortality rate. Elderly patients had more overall complications. Furthermore, the mean hospital stay was higher in the elderly group (p 0.027). Multivariable analyses documented that postoperative stay was inversely correlated with the number of ERAS items applied (p < 0.0001), whereas age ≥ 80 years significantly correlated with the overall complication rate (p 0.0419). CONCLUSION: The ERAS protocol is safe in octogenarian patients, with similar levels of compliance and surgical outcomes. However, octogenarian patients have a higher rate of overall complications and a longer hospital stay than do younger patients.

The Emergency Surgery Frailty Index (EmSFI): development and internal validation of a novel simple bedside risk score for elderly patients undergoing emergency surgery.

BACKGROUND: Frailty assessment has acquired an increasing importance in recent years and it has been demonstrated that this vulnerable profile predisposes elderly patients to a worse outcome after surgery. Therefore, it becomes paramount to perform an accurate stratification of surgical risk in elderly undergoing emergency surgery. STUDY DESIGN: 1024 patients older than 65 years who required urgent surgical procedures were prospectively recruited from 38 Italian centers participating to the multicentric FRAILESEL (Frailty and Emergency Surgery in the Elderly) study, between December 2016 and May 2017. A univariate analysis was carried out, with the purpose of developing a frailty index in emergency surgery called "EmSFI". Receiver operating characteristic curve analysis was then performed to test the accuracy of our predictive score. RESULTS: 784 elderly patients were consecutively enrolled, constituting the development set and results were validated considering further 240 consecutive patients undergoing colorectal surgical procedures. A logistic regression analysis was performed identifying different EmSFI risk classes. The model exhibited good accuracy as regard to mortality for both the development set (AUC = 0.731 [95% CI 0.654-0.772]; HL test χ2 = 6.780; p = 0.238) and the validation set (AUC = 0.762 [95% CI 0.682-0.842]; HL test χ2 = 7.238; p = 0.299). As concern morbidity, our model showed a moderate accuracy in the development group, whereas a poor discrimination ability was observed in the validation cohort. CONCLUSIONS: The validated EmSFI represents a reliable and time-sparing tool, despite its discriminative value decreased regarding complications. Thus, further studies are needed to investigate specifically surgical settings, validating the EmSFI prognostic role in assessing the procedure-related morbidity risk.

Impact of implementation of the ERAS program in colorectal surgery: a multi-center study based on the "Lazio Network" collective database.

BACKGROUND: ERAS implementation improved outcomes in patients undergoing colorectal surgery. The process of incorporating this pathway in clinical practice may be challenging. This observational study investigated the impact of systematic ERAS implementation on surgical outcomes in patients undergoing colorectal resections in a regional network of 10 institutions. METHODS: Implementation of ERAS pathway was designed using regular audits and a common protocol. All patients undergoing elective colorectal surgery between 2016 and 2017 were considered eligible. A collective database including 18 ERAS items, clinical and surgical data, and outcomes was designed. Univariate and multivariate analyses were performed for the following outcomes: morbidity, anastomotic leak, reinterventions, hospital stay, and readmissions. RESULTS: A total of 827 patients were included, and a mean of 11.3 ERAS items applied/patient was reported. Logistic regression indicated that an increased number of ERAS items applied reduced overall and severe morbidity (OR 0.86 and 0.87, respectively 95%CI 0.8197-0.9202 and 95%CI 0.7821-0.9603), hospitalization (OR 0.53 95%CI 0.4917-0.5845) and reinterventions (OR 0.84 95%CI 0.7536-0.9518) in the entire series. The same results were obtained for a prolonged hospitalization differentiating right-sided (OR 0.48 95%CI 0.4036-0.5801), left-sided (OR 0.48 95%CI 0.3984-0.5815), and rectal resections (OR 0.46 95%CI 0.3753-0.5851). An inverse correlation was found between the application of ERAS items and morbidity in right-sided and rectal procedures (OR 0.89 and 0.84, respectively 95%CI 0.7976-0.9773 and 95%CI 0.7418-0.9634). CONCLUSIONS: Systematic implementation of the ERAS pathway using multi-institutional audits can increase protocol adherence and improve surgical outcomes in patients undergoing colorectal surgery.

Correction to: Perioperative Management of Elderly patients (PriME): recommendations from an Italian intersociety consensus.

The article Perioperative Management of Elderly patients (PriME).

Perioperative Management of Elderly patients (PriME): recommendations from an Italian intersociety consensus.

BACKGROUND: Surgical outcomes in geriatric patients may be complicated by factors such as multiple comorbidities, low functional performance, frailty, reduced homeostatic capacity, and cognitive impairment. An integrated multidisciplinary approach to management is, therefore, essential in this population, but at present, the use of such an approach is uncommon. The Perioperative Management of Elderly patients (PriME) project has been established to address this issue. AIMS: To develop evidence-based recommendations for the integrated care of geriatric surgical patients. METHODS: A 14-member Expert Task Force of surgeons, anesthetists, and geriatricians was established to develop evidence-based recommendations for the pre-, intra-, and postoperative care of hospitalized older patients (≥ 65 years) undergoing elective surgery. A modified Delphi approach was used to achieve consensus, and the strength of recommendations and quality of evidence was rated using the U.S. Preventative Services Task Force criteria. RESULTS: A total of 81 recommendations were proposed, covering preoperative evaluation and care (30 items), intraoperative management (19 items), and postoperative care and discharge (32 items). CONCLUSIONS: These recommendations should facilitate the multidisciplinary management of older surgical patients, integrating the expertise of the surgeon, the anesthetist, the geriatrician, and other specialists and health care professionals (where available) as needed. These roles may vary according to the phase and setting of care and the patient's conditions.

The predictive value of 18F-FDG PET/CT for assessing pathological response and survival in locally advanced rectal cancer after neoadjuvant radiochemotherapy.

PURPOSE: To evaluate whether metabolic changes in the primary tumour during and after preoperative radiochemotherapy (RCT) can predict the histopathological response in patients with locally advanced rectal cancer as well as disease-free survival (DFS) and overall survival (OS). METHODS: Consecutive patients with cT2-4 N0-2 rectal adenocarcinoma were included. (18)F-FDG PET/CT was performed at baseline, at the end of the second week of RCT (early PET/CT) and before surgery (late PET/CT). The PET/CT results were compared with histopathological data (ypT0 N0 vs. ypT1-4 N0-2 as well as TRG1 vs.TRG2-5) and survival. RESULTS: The study included 126 patients. Among 124 patients in whom TNM classification was available, 28 (22.6 %) were ypT0 N0, and among all 126 patients, 31 (24.6 %) were TRG1. The areas under the curve of the early response index (RI) for identifying non-complete pathological response (non-cPR) were 0.74 (95 % CI 0.61 - 0.87) for ypT1-4 N0-2 patients and 0.75 (95 % CI 0.62 - 0.88) for TRG2-5 patients. The optimal cut-off for differentiating patients with non-cPR and cPR was found to be a reduction of 61.2 % (83.1 % sensitivity and 65 % specificity in ypT1-4 N0-2 patients; 85.4 % sensitivity and 65.2 % specificity in TRG2-5 patients). The optimal cut-off for late RI could not be found. The qualitative analysis of images obtained after RCT demonstrated 81.5 % sensitivity and 61.3 % specificity in predicting TRG2-5. After a median follow-up of 68 months, the low number of patients with local/distant recurrence or who had died did not allow the value of PET/CT for predicting DFS and OS to be calculated. CONCLUSION: The early assessment of response to RCT by (18)F-FDG PET/CT can predict non-cPR allowing practical modification of preoperative treatment. Conversely, late RI is not sufficiently accurate for guiding the decision as to whether local excision or even observation is appropriate in an individual patient. Qualitative analysis of late PET/CT images is also not sensitive enough alone to rule out the presence of residual disease.

Safety of MF59-adjuvanted influenza vaccination in the elderly: results of a comparative study of MF59-adjuvanted vaccine versus nonadjuvanted influenza vaccine in northern Italy.

MF59-adjuvanted trivalent influenza vaccine (Novartis Vaccines and Diagnostics, Siena, Italy) has been shown to be more effective than nonadjuvanted vaccine in the elderly population. Here we present results from a large-scale, observational, noninterventional, prospective postlicensure study that evaluated the safety of MF59-adjuvanted vaccine in elderly subjects aged 65 years or more. The study was performed in 5 northern Italian health districts during the 2006-2007, 2007-2008, and 2008-2009 influenza seasons. The choice of vaccine-either adjuvanted vaccine or a nonadjuvanted influenza vaccine-was determined by individual providers on the basis of local influenza vaccination policy. Hospitalizations for potential adverse events of special interest (AESIs) were identified from hospital databases and then reviewed against recognized case definitions to identify confirmed cases of AESI. Cumulative incidences were calculated for AESIs in predefined biologically plausible time windows, as well as in a 6-month window following vaccination. During the 3-year study period, 170,988 vaccine doses were administered to a total of 107,661 persons. Despite the large study size, cases of AESI resulting in hospitalization were rare, and risks of AESI were similar in both the MF59-adjuvanted and nonadjuvanted vaccination groups. In conclusion, similar safety profiles were observed for both nonadjuvanted and MF59-adjuvanted seasonal influenza vaccines in elderly recipients.

Long-term analysis of gemcitabine-based chemoradiation after surgical resection for pancreatic adenocarcinoma.

PURPOSE: To evaluate the efficacy in terms of local control (LC) of 24 h infusion of gemcitabine plus radiotherapy after surgery for pancreatic cancer. METHODS: Weekly gemcitabine (100 mg/m(2)) was provided as a 24-hour infusion during the course of radiotherapy (50.4 Gy to the tumor, 39.6 Gy to the nodes). Patients subsequently received five cycles of gemcitabine monochemotherapy (1,000 mg/m(2) 1, 8, q21). The primary end point of the study was to achieve a 2-year LC rate of ≥80 % with type I and II errors of 5 and 20 %. The study was designed to accrue a maximum sample size of 35 patients. Secondary end points were toxicity evaluation, metastasis-free survival (MFS), and overall survival (OS). RESULTS: Data of 35 patients were available. Most of the patients (n = 27; 77.1 %) had duodeno-cephalo-pancreatectomy, 5 (14.3 %) distal pancreatectomy, and 3 (8.6 %) total pancreatectomy. The pathological stages were T1-T2 (n = 7; 20.0 %), T3-T4 (n = 28; 80.0 %), N0 (n = 17; 48.6 %), and N1 (n = 18; 51.4 %). Thirty patients (85.7 %) completed chemoradiation. Twenty-three patients (65.7 %) received further sequential chemotherapy. Acute toxicity was acceptable. No late toxicity occurred. The median follow-up period was 64 (range 24-118) months, and 2-year crude rate of LC was 83 (median not reached). Median MFS and OS were 26.5 and 22.5 months, respectively. CONCLUSIONS: The rate of LC met the main goal of the study. The regimen resulted in a high LC rate but failed to show a benefit in terms of OS or MFS, thus suggesting the need for a more intensified multimodal approach.