Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Versus Cetuximab as Maintenance Therapy in First-Line Therapy for RAS and BRAF Wild-Type Metastatic Colorectal Cancer: Phase III ERMES Study.

PURPOSE: The intensity of anti-EGFR-based first-line therapy for RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC), once disease control is achieved, is controversial. A de-escalation strategy with anti-EGFR monotherapy represents a potential option to maintain efficacy while reducing cytotoxicity. METHODS: In this multicenter, open-label, phase III trial, patients with untreated RAS/BRAF wt mCRC were randomly assigned to receive either fluorouracil, leucovorin, and irinotecan/cetuximab (FOLFIRI/Cet) until disease progression (arm A) or FOLFIRI/Cet for eight cycles followed by Cet alone (arm B). The coprimary end points were a noninferior progression-free survival (PFS) in the modified per-protocol (mPP) population (>eight cycles) and a lower incidence of grade (G) 3-4 adverse events (AEs) for arm B compared with arm A. RESULTS: Overall, 606 patients were randomly assigned, with 300 assigned to arm A and 306 to arm B. The median follow-up was 22.3 months. In the mPP population, 291 events occurred with a PFS of 10 versus 12.2 months for arms B and A, respectively (P of noninferiority = .43). In the intention-to-treatment (ITT, ≥one cycle) population, 503 events occurred with a PFS of 9 versus 10.7 months (P = .39). The overall survival was 35.7 versus 30.7 months (P = .119) and 31.0 versus 25.2 months (P = .32) in the mPP and ITT population, respectively. Arm B had lower G3-4 AEs during the maintenance period than arm A (20.2% v 35.1%). CONCLUSION: The ERMES study did not demonstrate noninferiority of maintenance with Cet alone. Despite a more favorable safety profile, maintenance with single-agent Cet after induction with FOLFIRI/Cet cannot be recommended for all patients but could represent an option in selected cases.

De novo variants and recombination at 4q35: Hints for preimplantation genetic testing in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the deletion of an integral number of 3.3 kb units of the polymorphic D4Z4 repeat array at 4q35. The prenatal identification of this defect can be carried out on chorionic villi or amniocytes, whereas preimplantation genetic testing for monogenic disorders (PGT-M) requires molecular markers linked to the D4Z4 allele of reduced size. In this context the reliability of this association is crucial. To test the informativeness of the nearby polymorphic markers we investigated recombination at 4q35 using the polymorphic markers D4S1523, D4S163 and D4S139 positioned at 0.55, 0.5 and 0.21 Mb proximal to the D4Z4 array respectively. We determined the probability of recombination events to occur in the D4Z4-D4S1523 interval considering 86 subjects belonging to 12 FSHD families and found a recombination frequency of 14% between D4Z4 and D4S1523. Our study also revealed the occurrence of de novo variants and germline mosaicism. These findings highlight the recombinogenic nature of the 4q subtelomere and indicate that caution should be taken when interpreting PGT-M results. It is advisable that a woman who underwent a PGT-M cycle undertakes a prenatal DNA analysis to confirm the size of the D4Z4 alleles carried by the fetus.

Association between ambulance prehospital time and maternal and perinatal outcomes in Sierra Leone: a countrywide study.

INTRODUCTION: Sierra Leone, one of the countries with the highest maternal and perinatal mortality in the world, launched its first National Emergency Medical Service (NEMS) in 2018. We carried out a countrywide assessment to analyse NEMS operational times for obstetric emergencies in respect the access to timely essential surgery within 2 hours. Moreover, we evaluated the relationship between operational times and maternal and perinatal mortality. METHODS: We collected prehospital data of 6387 obstetric emergencies referrals from primary health units to hospital facilities between June 2019 and May 2020 and we estimated the proportion of referrals with a prehospital time (PT) within 2 hours. The association between PT and mortality was investigated using Poisson regression models for binary data. RESULTS: At the national level, the proportion of emergency obstetric referrals with a PT within 2 hours was 58.5% (95% CI 56.9% to 60.1%) during the rainy season and 61.4% (95% CI 59.5% to 63.2%) during the dry season. Results were substantially different between districts, with the capital city of Freetown reporting more than 90% of referrals within the benchmark and some rural districts less than 40%. Risk of maternal death at 60, 120 and 180 min of PT was 1.8%, 3.8% and 4.3%, respectively. Corresponding figures for perinatal mortality were 16%, 18% and 25%. CONCLUSION: NEMS operational times for obstetric emergencies in Sierra Leone vary greatly and referral transports in rural areas struggle to reach essential surgery within 2 hours. Maternal and perinatal risk of death increased concurrently with operational times, even beyond the 2-hour target, therefore, any reduction of the time to reach the hospital, may translate into improved patient outcomes.

Improving Access to Healthcare in Sierra Leone: The Role of the Newly Developed National Emergency Medical Service.

We aim to evaluate whether the first National Emergency Medical Service (NEMS) improved access to hospital care for the people of Sierra Leone. We performed an interrupted time-series analysis to assess the effects of NEMS implementation on hospital admissions in 25 facilities. The analysis was also replicated separately for the area of Freetown and the rest of the country. The study population was stratified by the main Free Health Care Initiative (FHCI) categories of pregnant women, children under 5 years of age, and populations excluded from the FHCI. Finally, we calculated direct costs of the service. We report a 43% overall increase in hospital admissions immediately after NEMS inception (RR 1.43; 95% CI 1.2-1.61). Analyses stratified by FHCI categories showed a significant increase among pregnant women (RR 1.54; 95% CI 1.33-1.77) and among individuals excluded from the FHCI (RR 2.95; 95% CI 2.47-3.53). The observed effect was mainly due to the impact of NEMS on the rural districts. The estimated recurrent cost per ambulance ride and NEMS yearly cost per inhabitant were 124 and 0.45 USD, respectively. To our knowledge, this is the first nationwide study documenting the increase in access to healthcare services following the implementation of an ambulance-based medical service in a low-income country. Based on our results, NEMS was able to overcome the existing barriers of geographical accessibility and transport availability, especially in the rural areas of Sierra Leone.

Real-Life Clinical Data of Cabozantinib for Unresectable Hepatocellular Carcinoma.

INTRODUCTION: Cabozantinib has been approved by the European Medicine Agency (EMA) for hepatocellular carcinoma (HCC) previously treated with sorafenib. Cabozantinib is also being tested in combination with immune checkpoint inhibitors in the frontline setting. Real-life clinical data of cabozantinib for HCC are still lacking. Moreover, the prognostic factors for HCC treated with cabozantinib have not been investigated. METHODS: We evaluated clinical data and outcome of HCC patients who received cabozantinib in the legal context of named patient use in Italy. RESULTS: Ninety-six patients from 15 centres received cabozantinib. All patients had preserved liver function (Child-Pugh A), mostly with an advanced HCC (77.1%) in a third-line setting (75.0%). The prevalence of performance status (PS) > 0, macrovascular invasion (MVI), extrahepatic spread, and alpha-fetoprotein (AFP) >400 ng/mL was 50.0, 30.2, 67.7, and 44.8%, respectively. Median overall survival (OS) and progression-free survival were 12.1 (95% confidence interval 9.4-14.8) and 5.1 (3.3-6.9) months, respectively. Most common treatment-related adverse events (AEs) were fatigue (67.7%), diarrhoea (54.2%), anorexia (45.8%), HFSR (43.8%), weight loss (24.0%), and hypertension (24.0%). Most common treatment-related Grade 3-4 AEs were fatigue (6.3%), HFSR (6.3%), and increased aminotransferases (6.3%). MVI, ECOG-PS > 0, and AFP >400 ng/mL predicted a worse OS. Discontinuation for intolerance and no new extrahepatic lesions at the progression were associated with better outcomes. CONCLUSIONS: In a real-life Western scenario (mostly in a third-line setting), cabozantinib efficacy and safety data were comparable with those reported in its registration trial. Data regarding the prognostic factors might help in patient selection and design of clinical trials.

Comprehensive analysis of DNA damage repair genes reveals pathogenic variants beyond BRCA and suggests the need for extensive genetic testing in pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) is a major cause of cancer death. In an effort to improve treatment strategies and outcomes, DNA damage repair (DDR) pathways have been introduced as a new target in PC and in other cancers, through the exploitation of synthetic lethality. Furthermore, genes involved in DDR are among the major determinants of cancer susceptibility. In addition to the well-known BRCA1 and BRCA2 genes, a plethora of other targets in the same pathways are now emerging. METHODS: We analyzed samples from 60 patients, affected by PC and already tested for BRCA, using a panel with 24 other cancer susceptibility genes. RESULTS: We detected 8 pathogenic or likely pathogenic mutations (13.3% of samples analyzed), 4 of which were found in non-BRCA genes (2 in ATM, 1 each in PALB2 and RAD50). Furthermore, 4 pathogenic or likely pathogenic mutations were found in patients without a personal or familial history of cancer. CONCLUSIONS: Our results suggest that genetic testing with a comprehensive gene panel should be perfomed in all patients with PC, in order to allow screening for PC and other gene-related cancers in all at risk family members and to assess patients' eligibility for emerging therapeutic options.

Designing, Implementing, and Managing a National Emergency Medical Service in Sierra Leone.

Sierra Leone is one of the least developed low-income countries (LICs), slowly recovering from the effects of a devastating civil war and an Ebola outbreak. The health care system is characterized by chronic shortage of skilled human resources, equipment, and essential medicines. The referral system is weak and vulnerable, with 75% of the country having insufficient access to essential health care. Consequently, Sierra Leone has the highest maternal and child mortality rates in the world. This manuscript describes the implementation of a National Emergency Medical Service (NEMS), a project aiming to create the first prehospital emergency medical system in the country. In 2017, a joint venture of Doctors with Africa (CUAMM), Veneto Region, and Research Center in Emergency and Disaster Medicine (CRIMEDIM) was developed to support the Ministry of Health and Sanitation (MOHS) in designing and managing the NEMS system, one of the very few structured, fully equipped, and free-of-charge prehospital service in the African continent. The NEMS design was the result of an in-depth research phase that included a preliminary assessment, literature review, and consultations with key stakeholders and managers of similar systems in other African countries. From May 27, 2019, after a timeframe of six months in which all the districts have been progressively trained and made operational, the NEMS became operative at national level. By the end of March 2020, the NEMS operation center (OC) and the 81 ambulances dispatched on the ground handled a total number of 36,814 emergency calls, 35,493 missions, and 31,036 referrals.

The National Emergency Medical Service Role During the COVID-19 Pandemic in Sierra Leone.

This report describes the main adaptive and transformative changes adopted by the brand-new National Emergency Medical Service (NEMS) to face the novel coronavirus disease 2019 (COVID-19) in Sierra Leone, including ambulance re-distribution, improvements in communication flow, implementation of ad-hoc procedures and trainings, and budget re-allocation. In a time-span of four months, 1,170 COVID-19 cases have been handled by the NEMS through a parallel referral system, while efforts have been made to manage the routine emergencies of the country, causing a substantial intensification of daily activities.

Systematic versus on-demand early palliative care: results from a multicentre, randomised clinical trial.

BACKGROUND: Early palliative care (EPC) in oncology has been shown to have a positive impact on clinical outcome, quality-of-care outcomes, and costs. However, the optimal way for activating EPC has yet to be defined. METHODS: This prospective, multicentre, randomised study was conducted on 207 outpatients with metastatic or locally advanced inoperable pancreatic cancer. Patients were randomised to receive 'standard cancer care plus on-demand EPC' (n = 100) or 'standard cancer care plus systematic EPC' (n = 107). Primary outcome was change in quality of life (QoL) evaluated through the Functional Assessment of Cancer Therapy - Hepatobiliary questionnaire between baseline (T0) and after 12 weeks (T1), in particular the integration of physical, functional, and Hepatic Cancer Subscale (HCS) combined in the Trial Outcome Index (TOI). Patient mood, survival, relatives' satisfaction with care, and indicators of aggressiveness of care were also evaluated. FINDINGS: The mean changes in TOI score and HCS score between T0 and T1 were -4.47 and -0.63, with a difference between groups of 3.83 (95% confidence interval [CI] 0.10-7.57) (p = 0.041), and -2.23 and 0.28 (difference between groups of 2.51, 95% CI 0.40-4.61, p = 0.013), in favour of interventional group. QoL scores at T1 of TOI scale and HCS were 84.4 versus 78.1 (p = 0.022) and 52.0 versus 48.2 (p = 0.008), respectively, for interventional and standard arm. Until February 2016, 143 (76.9%) of the 186 evaluable patients had died. There was no difference in overall survival between treatment arms. INTERPRETATIONS: Systematic EPC in advanced pancreatic cancer patients significantly improved QoL with respect to on-demand EPC.

Paraneoplastic lipase and amylase production in a patient with small-cell lung cancer: case report.

BACKGROUND: Small-cell lung cancer (SCLC) is known to express antigens of both the neural crest and epithelium, and to secrete polypeptide hormones and enzymes. Anecdotal reports correlate lung cancer with marked hyperamylasemia, and a review of the literature reveals only one case of metastatic SCLC linked to high paraneoplastic lipase production. CASE PRESENTATION: We present the case of a patient with metastatic SCLC who showed both lipase and pancreatic isoamylase elevation in the absence of acute pancreatitis. Chemotherapy resulted in a rapid reduction in serum lipase and in pancreatic isoamylase which was correlated with the radiological response of the tumor to therapy. Lipase and pancreatic isoamylase expression in tumor cells from the lung biopsy was confirmed by immunohistochemical staining. CONCLUSIONS: This is a very rare case of paraneoplastic syndrome linked to metastatic SCLC. The enzymes secreted could be used as markers of response to treatment until clonal selection mechanisms and intratumor heterogeneity induce changes in biochemical characteristics and consequently in tumor behavior.

Impact of Pre-Treatment Lactate Dehydrogenase Levels on Prognosis and Bevacizumab Efficacy in Patients with Metastatic Colorectal Cancer.

BACKGROUND: To investigate the impact of pre-treatment lactate dehydrogenase (LDH) levels on the outcome of patients with metastatic colorectal cancer treated with first-line chemotherapy with or without the anti-VEGF monoclonal antibody, bevacizumab, in a phase III prospective multicentre randomized ITACa (Italian Trial in Advanced Colorectal Cancer) trial. METHODS: Three hundred and seventy patients enrolled onto the ITACa first-line trial were considered for this study, 176 receiving chemotherapy (either FOLFIRI or FOLFOX) plus bevacizumab and 194 receiving chemotherapy only. Pre-treatment LDH levels were evaluated to identify a potential correlation with progression-free survival (PFS), overall survival (OS) and objective response rate. RESULTS: Information on pre-treatment LDH levels was available for 344 patients. High LDH levels were predictive of a lower median PFS (8.1 months vs. 9.2 months, p< 0.0001) and median OS (16.1 months vs. 25.2 months, p< 0.0001) in the overall population. In the chemotherapy plus bevacizumab group, median PFS was 9.1 and 9.8 months in patients with high LDH and low LDH, respectively (p= 0.073), whereas in the chemotherapy-only arm it was 6.9 and 9.1 months, respectively (p < 0.0001). In patients with high LDH, the addition of bevacizumab to chemotherapy led to a reduction in the rate of progressive disease (16.4 vs. 30.5%, p= 0.081) and to a prolonged PFS (p= 0.028). CONCLUSION: A high LDH value was confirmed as a marker of poor prognosis. Bevacizumab reduced the progressive disease rate and improved PFS in the high-LDH subgroup, making serum LDH a potentially effective an easily available and marker to select patients who benefit from bevacizumab. TRIAL REGISTRATION: NCT01878422 ClinicalTrials.gov.

Long-term survival in an advanced gastric cancer patient treated with cetuximab in association with FOLFIRI: a case report.

In December 2004, a 52-year-old woman with metastatic gastric cancer was enrolled in the phase II clinical trial FOLCETUX, receiving cetuximab at an initial dose of 400 mg/m(2) i.v. followed by weekly doses of 250 mg/m(2), irinotecan 180 mg/m(2) i.v. on day 1, LFA 100 mg/m(2) i.v. followed by 5-FU 400 mg/m(2) i.v. bolus and 600 mg/m(2) i.v. 22-h continuous infusion on days 1 and 2 every two weeks, to a total of 17 cycles. CT and PET-CT performed after six weeks treatment failed to show any residual disease, with complete radiological response in accord to RECIST criteria and complete metabolic response. A total of 24 maintenance administrations with cetuximab alone (250 mg/m(2) weekly) were performed, as foreseen by the protocol in responders. In November 2012 a clinical, radiological (CT) and metabolic (PET-CT) patient examination proved negative for recurrent disease, signifying 95 months' progression free survival.

Treatment strategy for rectal cancer with synchronous metastasis: 65 consecutive Italian cases from the Bologna Multidisciplinary Rectal Cancer Group.

BACKGROUND: Twenty percent of rectal cancer patients have synchronous distant metastasis at diagnosis. At present, the treatment strategy in this patient setting is not well defined. This study in one institution evaluates the treatment strategy of three different patient groups. PATIENTS AND METHODS: Between January 2000 and July 2011, 65 patients with M1 rectal cancer were evaluated. Three different groups were defined: rectal cancer with resectable metastatic disease (group A); rectal cancer with potentially resectable metastatic disease (group B), and rectal cancer with unresectable metastatic disease (group C). RESULTS: Group A included 11 patients (16.9%), group B 28 patients (43.1%) and group C 26 patients (40%). Forty-three (66.2%) patients underwent surgery for primary rectal cancer, and 30 (46.2%) patients for metastasis resection (23 liver, 4 lung and 3 ovary). Median overall survival (OS) by group was: 51 (5-86; group A), 32 (24-40; group B) and 16 (7-26; group C) months. Patients undergoing metastasis resection have higher median OS than unresected patients (44 vs. 15 months; p < 0.001). CONCLUSIONS: The treatment strategy in synchronous metastatic rectal cancer must consider the possibility of distant metastasis resection. Long-term survival can be achieved using an integrated approach.

Multimodal sequential approach in colorectal cancer liver metastases: hepatic resection after yttrium-90 selective internal radiation therapy and cetuximab rescue treatment.

Synchronous or metachronous liver metastases occur in up to one-third of patients with colorectal cancer and are associated with a poor prognosis. Many evidences have shown that surgical resection can be curative, with 5-year survival rates ranging from 37% to 50%, but many patients are ineligible for surgery because of multiple liver lesions, bilobar distribution of liver metastases, or the presence of widespread extrahepatic disease. The management of unresectable liver metastases includes many therapeutic options such as systemic chemotherapy, selective internal radiation therapy (SIRT) with yttrium-90 (Y-90), targeted therapy, and surgery. These treatments can be integrated into a sequential multimodal approach to increase the resection rate. We present a case in which such an approach was put into practice. The favorable result suggests that SIRT, along with systemic chemotherapy and surgery, is a valid treatment option for unresectable colorectal liver metastases.

Clinically-staged T3N0 rectal cancer: is preoperative chemoradiotherapy the optimal treatment?

BACKGROUND: Preoperative chemoradiotherapy has been widely adopted as the standard of care for stage II-III rectal cancers. However, patients with T3N0 lesions had been shown to have a better prognosis than other categories of locally advanced tumor. Thus, neoadjuvant chemoradiation is likely to be overtreatment in this subgroup of patients. Nevertheless, the low accuracy rate of preoperative staging techniques for detection of node-negative tumors does not allow to check this hypothesis. We analyzed a group of patients with cT3N0 low rectal cancer who underwent neoadjuvant chemoradiotherapy with the purpose of evaluating the incidence of metastatic nodes in the resected specimens. METHODS: Between January 2002 and February 2008, 100 patients with low rectal cancer underwent clinical staging by means of endorectal ultrasound, computed tomography, positron emission tomography, and magnetic resonance imaging. All patients received preoperative 5-fluorouracil-based chemoradiotherapy and surgical resection with curative aim. RESULTS: Of 100 patients with locally advanced rectal cancer, 32 were clinically staged as T3N0M0. Pathological analysis showed the presence of lymph node metastases in nine patients (28%) (node-positive group). In the remaining 23 cases, clinical N stage was confirmed at pathology (node-negative group). Node-positive and node-negative groups differ only in the number of ypT3 tumors (P < .01). CONCLUSIONS: Our results indicate that immediate surgery for patients with cT3N0 rectal cancer represents an undertreatment risk in at least 28% of cases, making necessary the use of postoperative chemoradiotherapy. Preoperative chemoradiotherapy should be the therapy of choice on the grounds of the principle that overtreatment is less hazardous than undertreatment for cT3N0 rectal cancers.