What COVID-19 taught us: New opportunities and pathways from telemedicine and novel antiseptics in wound healing.

The COVID-19 pandemic deeply impacted the capacity of the health systems to maintain preventive and curative services, especially for the most vulnerable populations. During the pandemic, the wound healing centres in Italy assisted a significant reduction of the frequency of their hospital admission, since only urgencies, such as severe infections or wound haemorrhagic complications, were allowed to the hospital. The aim of this multidisciplinary work is to highlight the importance of a new pathway of wound care with patient-based therapeutic approach, tailored treatments based on the characteristics of the wound and fast tracks focused on the outpatient management, reserving hospital assessment only for patients with complicated or complex wounds. This analysis highlights the point that patients with chronic wounds need to be critically evaluated in order to find the best and most appropriate care pathway, which should vary according to the patient and, especially, to the characteristics of the wound. Moreover, the most adequate topic antiseptic should be started as soon as possible. An appropriate and correct management of the wound care will allow to link the knowledge based on years of clinical practice with the new challenges and the need to visit patients remotely, when possible.

Intensive multidisciplinary treatment strategies and patient resilience to challenge long-term survival in metastatic colorectal cancer: a case report in real life and clinical practice.

In fit metastatic colorectal cancer (MCRC), multidisciplinary treatment strategy integrating intensive FIr-B/FOx triplet chemotherapy associated to bevacizumab and secondary metastasectomies significantly improved clinical outcomes up to progression-free survival (PFS) 17 months and overall survival (OS) 44 months. A non-elderly woman affected by rectal cancer, lymph nodes involvement, synchronous unresectable liver metastases, was treated with first-line FIr-B/FOx integrated with two-stage liver resections, short course radiotherapy, anterior rectal resection, with a PFS 9 months and progression-free interval (PFI) 4 months off-treatment. After progression characterized by single liver and lymph node inferior mesenteric axis metastases, FIr-B/FOx was re-introduced, liver and lymph node resections were performed, with a PFS 8 months and PFI 3 months. FIr-B/FOx was further proposed due to bilateral lung, and liver metastases with stable disease, PFS 8 months. Patient experienced a limiting toxicity syndrome multiple sites (LTS-ms) with G3 diarrhea, G2 asthenia, nausea, requiring irinotecan reduction and 5-fluorouracil discontinuation, and subsequent oxaliplatin discontinuation, due to infusional hypersensitivity reaction. Overall, integrated first-line medical and surgical treatment strategies gained PFS 26 months. Further lines II-V of treatment obtained a combined PFS 28 months: modulated aflibercept/irinotecan, PFS 8 months; panitumumab, PFS 8 months, proposed due to KRAS/NRAS/BRAF wild-type and EGFR c.2156 G>C (p.G719A) mutation, achieving biomarkers reduction, lung, liver, lymph nodes partial responses; regorafenib, PFS 8 months; trifluridine-tipiracil, PFS 4 months and induced an LTS-ms, with febrile G4 leucopenia, G3 neutropenia, thrombocytopenia, asthenia, G2 anemia, diarrhea, hypotension. After 2 months of palliative care, patient died, at OS 58 months, gained by intensive medical/surgical treatments coupled with patient's resilience. To date, selection of tailored medical treatments, according to clinical (age, performance and comorbidity status) and molecular (RAS/BRAF and pharmacogenomic analyses) evaluations, careful monitoring of individual toxicity syndromes, potential integration of metastasectomies, and furthermore individual resilience as patient life priority need to challenge MCRC long-term survival.

Evaluating Cefiderocol in the Treatment of Multidrug-Resistant Gram-Negative Bacilli: A Review of the Emerging Data.

Infections due to multidrug-resistant Gram-negative bacteria (MDR-GNB), especially when carbapenem resistant, have been very difficult to manage in the last fifteen years, owing to the paucity of dependable therapeutic options. Cefiderocol is a siderophore cephalosporin recently approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) that may have the potential to fill some of the remaining gaps in the treatment of MDR-GNB infections. Among others, cefiderocol demonstrated in vitro activity against carbapenem-resistant Acinetobacter baumannii and metallo-ß-lactamases producers. Clinical data from both registrative studies and post-marketing experiences are essential to confirm whether these promises from in vitro studies could readily translate into clinical practice, as well as to delineate the precise place in therapy for cefiderocol for the treatment of MDR-GNB in the near future. Because of its unique potential, it is essential to provide both randomized controlled trials (RCT) and real-life data to improve the ability of clinicians to exploit its benefit in both empirical and targeted treatment of MDR-GNB infections. In this narrative review, we discuss the emerging data from pivotal RCT and initial real-life experiences on the use of cefiderocol for the treatment of MDR-GNB infections.

Intensive first-line FIr-C/FOx-C association of triplet chemotherapy plus cetuximab in RAS wild-type metastatic colorectal cancer patients: preliminary phase II data and prediction of individual limiting toxicity syndromes by pharmacogenomic biomarkers.

BACKGROUND: Intensive triplet chemotherapy/bevacizumab significantly increased metastatic colorectal cancer (MCRC) outcome. This phase II study investigated the safety/activity of FIr-C/FOx-C triplet/cetuximab (CET) in first-line RAS wild-type and the prediction of individual limiting toxicity syndromes (LTS) by pharmacogenomic biomarkers. METHODS: A Simon two-step design was used: p0 70%, p1 85%, power 80%, α5%, ß20%; projected objective response rate (ORR) I step 14/19. FIr-C/FOx-C: 5-fluorouracil (5-FU) 12h-timed flat infusion 900 mg/m2 d1-2, 8-9, 15-16, 22-23; irinotecan (CPT-11) 160 mg/m2 d1 and 15, oxaliplatin 80 mg/m2 d8 and 22; CET 400mg/m2 then 250 mg/m2 d1, 8, 15, 22; every 28 days. Toxicity, and individual LTS were evaluated, compared by a Chi-square test; and activity/efficacy by log-rank. 5-FU/CPT-11 pharmacogenomic biomarkers, 5-FU degradation rate (5-FUDR), single nucleotide polymorphisms (SNPs) ABCB1, CYP3A4, DYPD, UGT1A1 were evaluated in patients with LTS and at a recommended dose. RESULTS: A total of 29 patients <75 years, with a primary/intermediate Cumulative Index Rating Scale were enrolled; the median age was 59 years; there were 7 young-elderly (yE; 24%). Recommended CPT-11/5-FU doses were 120/750 mg/m2. In the intent-to-treat analysis, the ORR was 58.6%. The primary endpoint was met in patients who received the planned three treatment cycles: the objective response (OR) was 14/18 (78%). At a median follow up of 18 months, progression-free survival (PFS) was 12, and overall survival (OS) was 23 months. At the recommended doses (received dose intensity >80%), grade 3-4 toxicities were: diarrhea 23%, asthenia 15%, vomiting 8%, hypertransaminasemy 8%; LTS 19 (65.5%), with 83% in yE patients. LTS prevalently multiple (ms) versus single site were 59% versus 7% (p = 0.006). The prevalence of reduced FUDR was 56%, SNPs CYP3A4 22%, UGT1A1 71%, and of >2 positive pharmacogenomics biomarkers was 78%, prevalently reported in patients who developed gastrointestinal LTS. CONCLUSIONS: FIr-C/FOx-C is highly active and tolerable at recommended doses in non-elderly RAS wild-type MCRC patients. LTS provided an evaluation of the toxicity burden in individual patients. Reduced FUDR, CYP3A4, and UGT1A1 SNPs may predict individual LTS-ms in patients at risk of limiting gastrointestinal toxicity. TRIAL REGISTRATION: The trial was registered at Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2009-016793-32.

Dose-finding study of intensive weekly alternating schedule of docetaxel, 5-fluorouracil, and oxaliplatin, FD/FOx regimen, in metastatic gastric cancer.

INTRODUCTION: Proper administration timing, dose-intensity, efficacy/toxicity ratio of triplet docetaxel (DTX), 5-fluorouracil (5-FU), and oxaliplatin (OXP) should be improved to safely perform three-drugs intensive first line in advanced gastric cancer (GC). This dose-finding study investigated recommended 5-FU and OXP doses, safety of triplet regimen and preliminary activity. METHODS: Schedule: 12h-timed-flat-infusion 5-FU 700-1000 mg/m2/d 1-2, 8-9, 15-16, 22-23, with 100 mg/m2/d increase for dose level; DTX 50 mg/m2 d 1, 15 fixed dose, OXP at three increasing dose-levels 60-70-80 mg/m2 d 8, 22, every 4 weeks. Intra- and inter-patients dose-escalation was planned. RESULTS: Ten fit <75 years patients were enrolled: median age 59; young-elderly 4 (40%). From first to fifth dose level, 5 patients (1 per cohort) were enrolled according to intra-patient dose escalation, no dose-limiting toxicity (DLT) were reported. At sixth level, 1 DLT, G2 diarrhea, was reported, thus other 2 patients were enrolled, DLT 1/3 patients (33%). Maximum tolerated dose (MTD) was not reached. 5-FU and OXP recommended doses (RD) were 1000 mg/m2/d and 80 mg/m2, respectively. To confirm RD, other 3 patients were enrolled, without DLT. Cumulative G3-4 toxicities were: neutropenia 50%, leucopenia 20%, hypoalbuminemia 10%, mucositis 10%, asthenia 20%. Limiting toxicity syndromes were 30%, 25% in young-elderly, all multiple site. Objective response rate intent-to-treat 60%, disease control rate 90%. After 15 months follow-up, progression-free and overall survival, 6 and 17 months, respectively. CONCLUSIONS: First line intensive FD/FOx regimen adding DXT/5-FU/OXP can be safely administered at recommended doses in advanced GC, with promising high activity and efficacy.

Real life triplet FIr/FOx chemotherapy in first-line metastatic pancreatic ductal adenocarcinoma patients: recommended schedule for expected activity and safety and phase II study.

BACKGROUND: Gemcitabine/nab-paclitaxel and FOLFIRINOX demonstrated significantly increased survival compared with gemcitabine in metastatic pancreatic ductal adenocarcinoma (PDAC): objective response rate (ORR) 23 and 31.6%, progression-free survival (PFS) 5.5 and 6.4 months, overall survival (OS) 8.7 and 11.1 months. Present phase II study evaluated recommended first-line triplet FIr/FOx schedule. METHODS: Simon two-step design: p010%, p130%, power 80%, α5%, ß20%. Projected ORR: I step, 1/10; II 5/29. Schedule: 12h-timed-flat-infusion/5-fluorouracil 750-800-900 mg/m2 d1-2,8-9,15-16,22-23; irinotecan 120-140-160 mg/m2 d1,15; oxaliplatin 70-80 mg/m2 d8,22; every 4 weeks, according to clinical parameters (age, comorbidities, performance status (PS), liver function). Activity and efficacy were evaluated, and compared using log-rank; limiting toxicity syndromes (LTS), using chi-square. RESULTS: Twenty-nine consecutive patients were enrolled, according to primary/intermediate/secondary Cumulative Illness Rating Scale (CIRS). Median age 62; elderly 13 (44.7%); PS2 3 (10.4%), secondary CIRS 5 (17.2%). Primary endpoint was met: ORR 53% (7/13 patients) as-treated, 50% intent-to-treat. Cumulative G3-4 toxicities: diarrhea 17%, asthenia 14%, hypertransaminasemy 7%, mucositis 7%, vomiting 3%, anemia 3%, thrombocytopenia 3%. LTS were 27.5% overall, 38.4% in elderly. At 3 months median follow-up, PFS 4 months, OS 11 months. PS2 patients showed significantly worse OS (P 0.022). CONCLUSION: Intensive first-line triplet FIr/FOx is tolerable at modulated doses, and confirms high activity/efficacy in metastatic PDAC. Patients' careful selection, and exclusion of PS2, can maintain safety profile and efficient dose intensity.