Prolonged 14-day continuous infusion of high-dose ifosfamide for patients with relapsed and refractory high-grade osteosarcoma: a retrospective multicentre cohort study.

BACKGROUND: The prognosis of patients with Relapsed/Refractory Osteosarcoma (R/R OS) remains dismal without an agreement on systemic therapy. The use of High-Dose Ifosfamide (14 g/sqm) with an external pump in outpatient setting (14-IFO) in R/R OS patients is limited. This study represents the first retrospective cohort analysis focused on evaluating the activity and toxicity of 14-IFO in this setting. PATIENTS AND METHODS: The study investigated 14-IFO activity, in terms of tumour response according to RECIST 1.1 criteria, as well as survival rates and toxicity, according to CTCAE v.5. RESULTS: The trial enrolled 26 patients with R/R OS. The Overall Response Rate (ORR) and Disease Control Rate (DCR) obtained was 23% and 57.5%, respectively. Patients with relapsed OS showed a higher ORR (45%) and DCR (82%) compared to refractory patients, irrespective of the number of prior treatment lines received. The achievement of disease control with 14-IFO administration enabled 27% of patients to undergo new local treatment. Four-month Progression-Free Survival (PFS) was 54% for all patients and 82% for the relapsed OS sub-group. Median Overall Survival (OSurv) was 13.7 months, with 1-year OSurv of 51% for all patients and 71% for relapsed patients. Age over 18 years and the presence of refractory disease were identified as negative prognostic factors for this patient cohort. A total of 101 cycles were evaluated for toxic assessment, demonstrating a tolerable profile without grade 3-4 non-haematological toxicities. CONCLUSIONS: 14-IFO should be considered a viable treatment option for R/R OS, particularly due to its well tolerated toxicity profile and the potential for home-administration, which can improve patient quality of life without compromising efficacy.

Off-label and compassionate use of targeted anticancer therapies: The experience of an Italian pediatric cancer center.

INTRODUCTION: In Europe, despite recent advances in clinical development, most of the drugs currently used to treat childhood cancers are adult medicines, prescribed outside of the authorized indication. In this context, a monocentric retrospective cohort analysis was conducted, evaluating pediatric, adolescent, and young adult patients affected by onco-hematologic disease, treated with targeted therapies used off-label or as compassionate use. METHODS: The analysis was conducted on 45 patients aged less than or equal to 30 years with cancer, having received at least one targeted therapy prescribed as off-label or compassionate use at a large Italian pediatric center between January 1, 2016 and June 30, 2021. Data collected included information on the patient and tumor, data on off-label/compassionate treatment, and data on safety and efficacy. RESULTS: Total 25 out of 45 patients treated with off-label or compassionate targeted therapies were affected by onco-hematological diseases. Overall, 22 out of the 52 agents (42%) were prescribed in patients with relapsed neoplasm and 39% (20/52) in patients with refractory diseases. Complete response was observed in more than half (27/52) of treatments. At least one adverse reaction occurred in 76% (n = 22) of agents administered to patients with onco-hematological tumor and in 43% (n = 10) of agents prescribed to patients with solid tumor. CONCLUSION: This work aims to provide a snapshot of off-label and compassionate use prescriptions in a large Italian pediatric cancer center. This study confirms that targeted agents for unauthorized indications are often prescribed in pediatric patients with cancer, especially after disease relapse and that these treatments are mostly tolerable and effective.

Pediatric gray zone lymphoma according to the 2022 WHO classification: An Italian cohort study.

BACKGROUND: The 2022 World Health Organization (WHO) classification redefines the concept of gray zone lymphoma (GZL), restricting it in practice to cases of mediastinal/thymic origin (mediastinal gray zone lymphoma, MGZL) with overlapping features between primary mediastinal B-cell lymphoma (PMBCL) and classical Hodgkin lymphoma (CHL). Cases with histological characteristics of GZL but occurring without mediastinal involvement are better classified as diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS), with few exceptions. PROCEDURE: We collected clinical and pathological data about all Italian pediatric patients diagnosed with GZL over a 20-year period. RESULTS: We identified only four cases of bona fide MGZL. All patients were adolescent and presented with a mediastinal disease, always associated with other nodal involvement. B symptoms and increased levels of both erythrocyte sedimentation rate (ESR) and lactate dehydrogenase (LDH) were observed. Only two patients achieved a first complete remission, suggesting a more aggressive clinical behavior than either PMBCL or CHL. CONCLUSION: Prospective studies evaluating prognostic factors and establishing the most effective first-line therapy for MGZL are highly needed.

Bacterial ligands as flexible and sensitive detectors in rapid tests for antibodies to SARS-CoV-2.

Lateral flow immunoassay (LFIA) is widely employed as point-of-care tests (POCT) for the diagnosis of infectious diseases. The accuracy of LFIA largely depends on the quality of the immunoreagents used. Typical LFIAs to reveal the immune response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) employ anti-human immunoglobulin (hIG) antibodies and recombinant viral antigens, which usually are unstable and poorly soluble. Broad selective bacterial proteins, such as Staphylococcal protein A (SpA) and Streptococcal protein G (SpG) can be considered alternatives to anti-hIG to increase versatility and sensitivity of serological LFIAs because of their high binding capacity, interspecies reactivity, and robustness. We developed two colorimetric LFA devices including SpA and SpG linked to gold nanoparticles (GNP) as detectors and explored the use of a specific, stable, and soluble immunodominant fraction of the nucleocapsid protein from SARS-CoV-2 as the capturing agent. The optimal amount of SpA-GNP and SpG-GNP conjugates and the protein-to-GNP ratios were defined through a full factorial experimental design to maximize the diagnostic sensitivity of the LFIAs. The new LFA devices were applied to analyze 105 human serum samples (69 positive and 36 negatives according to reference molecular diagnostic methods). The results showed higher sensitivity (89.9%, 95% CI 82.7-97.0) and selectivity (91.7%, 82.6-100) for the SpA-based compared to the SpG-based LFA. In addition, 18 serum samples from cats and dogs living with COVID-19 patients were analyzed and 14 showed detectable levels of anti-SARS-CoV-2 antibodies, thus illustrating the flexibility of the SpA- and SpG-based LFAs.

The prognostic nutritional index predicts survival and response to first-line chemotherapy in advanced biliary cancer.

BACKGROUND: An accurate risk-stratification is key to optimize the benefit-to-risk ratio of palliative treatment in advanced biliary cancer. We aimed at assessing the impact of the prognostic nutritional index (PNI) on survival and treatment response in advanced biliary cancer (ABC) receiving first-line chemotherapy. METHODS: Medical records of ABC treated with standard chemotherapy at the Modena Cancer Centre were retrospectively reviewed for variables deemed of potential interest, including the PNI. Univariate and multivariate analyses were performed to investigate the association between the covariates and overall survival (OS). RESULTS: 114 ABC fulfilled the inclusion criteria and made up the training cohort. A PNI cut-off value of 36.7 was established using the receiver operating characteristic (ROC) analysis. At both the univariate and the multivariate analysis, low PNI value (<36.7) was associated with shorter OS (P = .0011), together with increased NLR (P = .0046) and ECOG >1 (P < .0001). The median OS was 5.4 vs 12.1 months in the low- vs high PNI-group. Moreover, a PNI value >36.7 resulted in a higher disease control in patients treated with gemcitabine/platinum combination (61.4% vs 34.3%). These results were validated in an independent cohort of 253 ABC. CONCLUSIONS: We demonstrated and externally validated a prognostic role for the PNI in ABC treated with first-line chemotherapy. Although the PNI turned out to be predictive in the subset of patients receiving platinum/gemcitabine combination, future prospective confirmation is needed.

Solid urban wastes and toxicity among residents of Ghemme and Cavaglio (Piedmont region, Italy). Results from a historical cohort 1980 to 2013.

BACKGROUND: There is plenty of evidence for a relation between certain environmental pollutants and ecological damage. Landfills, especially if uncontrolled and located near human settlements, may cause an increase in cancer incidence and in various diseases. METHODS: The area of study is represented by the cities of Ghemme (population 6,139) and Cavaglio (population 2,216), in the province of Novara, northern Italy. A solid urban waste landfill is located between these two cities. We analysed mortality data from 1980 to 2013 among subjects residing in the two cities since at least 6 months, according to distance from the landfill. Mortality data was obtained from the National Statistics Institute ( ISTAT). RESULTS: A mortality increase was shown, according to Cox model, in residential areas closer to the landfill. In Cavaglio D'Agogna the total number of cancer deaths occurring in the 0-44 age group and the total death causes were relevant. A significant increase in leukemia cases was detected in Ghemme city. CONCLUSIONS: Our analysis shows an increased risk of diseases (cancer and other diseases), with a possible environmental etiological link.

Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti-BIL study).

BACKGROUND: Biliary tract cancer (BTC) is a rare and lethal disease with few therapeutic options. Preclinical data suggest that the epidermal growth factor receptor (EGFR) pathway could be involved in its progression. METHODS: This open-label, randomized phase 2 trial recruited chemotherapy-naive patients with advanced BTC displaying a wild-type (WT) KRAS status. Patients were randomized to gemcitabine (1000 mg/m(2) ) and oxaliplatin (100 mg/m(2) ) with (arm A) or without (arm B) panitumumab (6 mg/kg) for up to 12 cycles. The primary endpoint was progression-free survival (PFS) analyzed in an intention-to-treat fashion. RESULTS: Eighty-nine patients (45 in arm A and 44 in arm B) were enrolled between June 2010 and September 2013. After a median follow-up of 10.1 months, the median PFS was 5.3 months (95% confidence interval, 3.3-7.2 months) in arm A and 4.4 months (95% confidence interval, 2.6-6.2 months) in arm B (P = .27). No survival differences were observed: the median overall survival was 9.9 months in arm A and 10.2 months in arm B (P = .42). In a subgroup analysis, no differences in PFS according to the site of the primary tumor were observed; patients with intrahepatic cholangiocarcinoma treated with panitumumab may have had a survival benefit in comparison with the control group (15.1 vs 11.8 months, P = .13). As for safety, skin toxicity was the main adverse event in arm A (80% of the patients). A higher incidence of diarrhea (55.5% vs 31.8%), mucositis (22.2% vs 13.6%), and constipation (24.4% vs 15.9%) was seen in arm A. CONCLUSIONS: These results confirm the marginal role of anti-EGFR therapy even for WT KRAS-selected BTC.

Mind the gap with Europe. Why public interest cannot be a good reason to perform observational and epidemiological research?

The consequences of the Italian privacy legislation, that represents a very restrictive implementation of the general European regulation on data protection, have mainly been felt at the level of observational research. In this field is not always possible to obtain the consent of subjects, and as for retrospective studies, it is not currently clear which is the correct regulatory procedure to follow. This uncertainty in the law's implementation has given way to multiple interpretations, making it difficult to obtain a homogeneous path in Italy. However, it is possible that the observation point has been totally wrong so far and that it would be more correct to choose a different legal bases than consent, both to preserve scientific progress and collective ethics, without losing the protection of the subject. This approach, which has already been followed by other European countries, could bring us closer to the rest of Europe and allow us to competitively participate in community projects that we are often cut off from.

Registries or non-pharmacological observational studies? An operational attempt to draw the line and to provide some suggestions for the ethical evaluation of rare disease registries.

Originally established to evaluate the ethical aspects of clinical trials, Ethics Committees (ECs) are now requested to review different types of projects, including, among others, observational studies and disease registries. In Italy, clinical trials on medicinal products for human use and on medical devices are regulated by EU Regulation 536/2014, EU Regulation 2017/745, and 2017/746 while pharmacological observational studies are regulated by the Italian Medicines Agency guidelines of 2008 and by Ministerial Decree of November 30th, 2021. The other types of studies are not strictly regulated, causing discrepancies in their definition and assessment by the ECs, and slowdowns in the start of projects. The present contribution aims to propose definitions and distinctions between non-pharmacological observational studies and disease registries, which constitute different entities but are often assimilated by ECs, and to formulate suggestions for the evaluation of rare disease registries, which are an expanding research area of interest.

Panitumumab in combination with infusional oxaliplatin and oral capecitabine for conversion therapy in patients with colon cancer and advanced liver metastases. The MetaPan study.

BACKGROUND: Preoperative chemotherapy improves the outcome in patients with colorectal cancer with liver metastases. In the current study, the authors evaluated the activity of a conversion treatment with the combination of capecitabine plus oxaliplatin (XELOX) used in association with panitumumab in patients with unresectable, liver-only, metastatic colon cancer. METHODS: Chemotherapy-naive patients with unresectable liver metastases from colon cancer with no other metastatic disease sites were enrolled. All patients received upfront therapy with XELOX plus panitumumab (P-XELOX) and were reevaluated for resectability every 4 cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints were overall survival (OS), progression-free survival, the percentage of patients whose disease became radically resectable, and the safety of the P-XELOX combination. RESULTS: A total of 49 patients were recruited, 35 of whom had wild-type KRAS (wtKRAS) and 14 of whom (who were enrolled before study amendment) had unknown (9 patients) or mutated (5 patients) KRAS mutational status. Forty-six patients were evaluable for response. After conversion P-XELOX therapy, the ORR in the general population was 54%, with 2 complete responses, 23 partial responses, and 14 cases of stable disease. In patients with wtKRAS, the ORR of the patients reached 65% (2 CRs and 19 PRs), which allowed 15 patients with initial unresectable liver metastasis to be reclassified as having resectable disease. Survival analysis demonstrated a median progression-free survival of 8.5 months and a median OS of 21.9 months. Patients who underwent surgery were found to have a significantly better OS when compared with those who did not undergo surgery (P < .001). Overall, toxicities were found to be predictable and manageable, with the most common being cutaneous, gastrointestinal, and neurologic toxicities. CONCLUSIONS: Conversion P-XELOX therapy yields high response and resectability rates for patients with metastatic colon cancer with extensive liver involvement.

Observational studies - The Cinderella of the Italian research system.

Observational trials are crucial to assess the generalizability in the real world of evidence deriving from registration studies. Despite the unquestionable importance of this type of studies, Italian researchers have had to face many obstacles over the years, mainly due to ambiguous definitions and to a complex but at the same time incomplete legislation. The regulatory adjustments to the European Regulation 536/2014 have further complicated the operating and operational framework, making observational research a real "Cinderella" of the Italian system.

Neurocognitive and Psychological Outcomes among Children and Adolescents with Brain Tumors: Development of an Observational and Longitudinal Prospective Study Protocol.

Children and adolescents affected by brain tumors are at risk for neuropsychological sequelae that need to be evaluated in order to plan adequate rehabilitation programs, and to support their development and recovery. This work aims to describe an innovative prospective observational study protocol for the early evaluation and monitoring over time of neuropsychological outcomes in this pediatric population. Pediatric patients aged 3-17 with a brain tumor diagnosis will be assessed through the use of a battery of Italian standardized neuropsychological tests, with good psychometric properties and age-appropiate, at three different time points of their clinical course: at diagnosis and before surgery (T0), after surgical removal and before the start of potential adjuvant therapies (T1), and at the one-year follow-up after potential adjuvant therapies (T2). This study will allow clinicians to support the neuropsychological development of these children by promoting appropriate and timely rehabilitation and educational programs from the early phases of their clinical course.

Fluoropyrimidine­induced cardiotoxicity in colorectal cancer patients: a prospective observational trial (CHECKPOINT).

Fluoropyrimidines (FP) are the backbone chemotherapy in colorectal cancer (CRC) treatment; however, their use is associated with cardiotoxicity, which is underreported. In the present study, it was aimed to prospectively determine the incidence rates and related risk factors of FP­induced cardiotoxicity (FIC) in CRC patients and at identifying predictive biomarkers. A total of 129 consecutive previously untreated CRC patients underwent active cardiological monitoring, including 5­items simplified questionnaire on symptoms, electrocardiogram (ECG) and plasma sample collection during FP chemotherapy. FIC was defined as the presence of ECG alterations and/or the arising of at least one symptom of chest pain, dyspnoea, palpitations or syncope. The primary objective was the evaluation of FIC incidence. Secondary objectives were the correlation of FIC with well­known cardiological risk factors and the identification of circulating biomarkers (serum levels of troponin I, pro hormone BNP; miRNA analysis) as predictors of FIC. A total of 20 out of 129 (15.5%) patients experienced FIC. The most common symptoms were dyspnoea (60%) and chest pain (40%), while only 15% of patients presented ECG alterations, including one acute myocardial infarction. Retreatment with FP was attempted in 90% of patients with a favourable outcome. Despite 48% of patients having cardiological comorbidities, an increased FIC was not observed in this subgroup. Only the subgroup of females with the habit of alcohol consumption showed an increased risk of FIC. None of the circulating biomarkers evaluated demonstrated a clinical utility as FIC predictors. FIC can be an unexpected, life­threatening adverse event that can limit the subsequent treatment choices in patients with CRC. In this prospective study, well­known cardiological comorbidities were not related to higher FIC risk and circulating biomarkers predictive of toxicity could not be found. With careful monitoring, mainly based on symptoms, almost all patients completed the FP treatment.

Polarized light microscopy-detectable structures of human oocytes and embryos are related to the likelihood of conception in IVF.

PURPOSE: To clarify if birefringent structures of human oocytes and embryos, measurable by polarized light microscopy, have any value in predicting the chance of pregnancy in human in vitro fertilization and may halp to identify the most competent oocytes and embryos. METHODS: The inner layer of the zona pellucida (IL-ZP) and the meiotic spindle (MS) were analyzed by polarized light microscopy in 258 oocytes and in the 209 embryos deriving from them. Data obtained from 102 ICSI cycles with conception were compared with those obtained in 156 cycles without conception. The retardance and area of the IL-ZP, as well as the retardance, length of the major axis, and area of the MS were measured. Furthermore, polarized light microscopy parameters were related to the embryo morphological score by multiple regression analysis. RESULT(S): The mean area of the IL-ZP of both oocytes and embryos was significantly lower in conception than in non-conception cycles (p = 0.0001 for oocytes and p = 0.002 for embryos). The area of the IL-ZP in embryos was significantly, inversely related to the embryo morphological score (p = 0.011). The area, the major axis length and the retarcance of the MS, as well as the retardance of the IL-ZP in oocytes and embryos were comparable in conception and non-conception cycles. CONCLUSION: The area of the IL-ZP of the human oocytes may represent a marker of oocyte competence, as oocytes with a low IL-ZP area are more frequently obtained in conception cycles. When measured in embryos, a low IL-ZP area identifies embryos with a high chance of implantation.

[Implementation of the European regulation 536/2014 in Italy: the neverending story.] / Implementazione del regolamento europeo 536/2014 in Italia: la storia infinita.

The European regulation 536/2014, unapplied for several years due to the inoperability of the European Portal, represented an epochal turning point in the legislation concerning pharmacological clinical trials. Although, unlike the directive, it could be directly applied without national transpositions, in Italy this has not been possible and for three months now we have been witnessing a haemorrhage of guidelines/operational proposals/decrees that to date do not make us ready to fully operate according to the new rules. Il regolamento europeo 536/20141, in vigore dal 16 giugno 2014 e rimasto per diversi anni non applicato per un ritardo nella messa in funzione del portale unico europeo, ha rappresentato una svolta epocale nella normativa inerente le sperimentazioni cliniche con farmaco. La normativa precedentemente in vigore2, infatti, pur rappresentando la prima trasformazione in legge delle Good Clinical Practices e un primo tentativo di armonizzazione tra le procedure regolatorie dei diversi stati membri, aveva portato a una serie di risvolti negativi, come un aumento vertiginoso dei costi e dei tempi necessari ad avviare uno studio. Tutto ciò, negli anni, si è tradotto in una deflessione delle richieste di autorizzazione delle sperimentazioni e in una grande difformità tra gli stati membri3,4. Il regolamento introduce delle novità mirate a ottimizzare profondamente l'iter regolatorio di approvazione delle sperimentazioni, primo fra tutti il nuovo processo di autorizzazione, che prevede l'espressione di un unico parere a livello europeo e la singola decisione, a livello di singolo stato membro, di accettare o non accettare tale decisione. Il nuovo processo, molto ambizioso da un punto di vista della riduzione dei tempi, doveva rappresentare una occasione storica per l'incremento delle performance di Paesi come l'Italia, da sempre penalizzata da una burocrazia molto complessa e dalla necessità di procedere con molteplici valutazioni da parte dell'autorità competente e di numerosi comitati etici5,6. I ritardi nella messa in funzione del portale, inizialmente prevista per maggio 2016, hanno portato a un lungo e continuo slittamento dei tempi di applicazione del regolamento, alla fine calendarizzata per il 31 gennaio 2022. Sei anni di attesa che, almeno sulla carta, hanno fornito l'occasione a tutti gli stati membri di prepararsi al meglio a tutti i cambiamenti che il regolamento avrebbe comportato.La scelta, da un punto di vista prettamente legale, di un regolamento piuttosto che di una nuova direttiva aveva lo scopo di evitare una ulteriore difformità di azione tra le diverse nazioni; il regolamento, infatti, a differenza della direttiva non necessita di successivi passaggi legislativi a livello nazionale e poteva essere direttamente implementato nei singoli stati membri. Alcune nazioni si sono preparate all'applicazione del regolamento procedendo con una profonda revisione e semplificazione del proprio apparato regolatorio; è il caso, per esempio, della Spagna, che ha optato per un unico decreto in grado di regolare tutti gli aspetti inerenti le sperimentazioni interventistiche con farmaco7.Situazione completamente opposta in Italia, dove l'implementazione della vecchia direttiva aveva causato una emorragia di decreti ministeriali e di altri atti legislativi che difficilmente potevano venire riorganizzati, come accaduto in Spagna, in un unico atto. Uno stato che ha portato, ancora una volta e forse in maniera ancora più complessa di quanto accaduto a inizio millennio, a un lungo processo di riorganizzazione legislativa, avviato con il decreto Lorenzin e ancora molto lontano dall'essere completato con tutti i decreti attuativi necessari.

Adherence of systematic reviews to Cochrane RoB2 guidance was frequently poor: a meta epidemiological study.

OBJECTIVES: To assess whether the use of the revised Cochrane risk of bias tool for randomized trials (RoB2) in systematic reviews (SRs) adheres to RoB2 guidance. METHODS: We searched MEDLINE, Embase, Cochrane Library from 2019 to May 2021 to identify SRs using RoB2. We analyzed methods and results sections to see whether risk of bias was assessed at outcome measure level and applied to primary outcomes of the SR as per RoB2 guidance. The relation between SR characteristics and adequacy of RoB2 use was examined by logistic regression analysis. RESULTS: Two hundred-eight SRs were included. We could assess adherence in 137 SRs as 12 declared using RoB2 but actually used RoB1 and 59 did not report the number of primary outcomes. The tool usage was adherent in 69.3% SRs. Considering SRs with multiple primary outcomes, adherence dropped to 28.8%. We found a positive association between RoB2 guidance adherence and the methodological quality of the reviews assessed by AMSTAR2 (p-for-trend 0.007). Multivariable regression analysis suggested journal impact factor [first quartile vs. other quartiles] was associated with RoB2 adherence (OR 0.34; 95% CI: 0.16-0.72). CONCLUSIONS: Many SRs did not adhere to RoB2 guidance as they applied the tool at the study level rather than at the outcome measure level. Lack of adherence was more likely among low and very low quality reviews.

Temozolomide Followed by Combination With Low-Dose Ipilimumab and Nivolumab in Patients With Microsatellite-Stable, O6-Methylguanine-DNA Methyltransferase-Silenced Metastatic Colorectal Cancer: The MAYA Trial.

PURPOSE: This is a multicenter, single-arm phase II trial evaluating the efficacy and safety of an immune-sensitizing strategy with temozolomide priming followed by a combination of low-dose ipilimumab and nivolumab in patients with microsatellite-stable (MSS) and O6-methylguanine-DNA methyltransferase (MGMT)-silenced metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with pretreated mCRC were centrally prescreened for MSS status and MGMT silencing (ie, lack of MGMT expression by immunohistochemistry plus MGMT methylation by pyrosequencing). Eligible patients received two priming cycles of oral temozolomide 150 mg/sqm once daily, days 1-5, once every 4 weeks (first treatment part) followed, in absence of progression, by its combination with ipilimumab 1 mg/kg once every 8 weeks and nivolumab 480 mg once every 4 weeks (second treatment part). The primary end point was the 8-month progression-free survival (PFS) rate calculated from enrollment in patients who started the second treatment part, with ≥ 4 out of 27 subjects progression-free by the 8-month time point as decision rule. RESULTS: Among 716 prescreened patients, 204 (29%) were molecularly eligible and 135 started the first treatment part. Among these, 102 (76%) were discontinued because of death or disease progression on temozolomide priming, whereas 33 patients (24%) who achieved disease control started the second treatment part and represented the final study population. After a median follow-up of 23.1 months (interquartile range, 14.9-24.6 months), 8-month PFS rate was 36%. Median PFS and overall survival were 7.0 and 18.4 months, respectively, and overall response rate was 45%. Grade 3-4 immune-related adverse events were skin rash (6%), colitis (3%), and hypophysitis (3%). No unexpected adverse events or treatment-related deaths were reported. CONCLUSION: The MAYA study provided proof-of-concept that a sequence of temozolomide priming followed by a combination of low-dose ipilimumab and nivolumab may induce durable clinical benefit in MSS and MGMT-silenced mCRC.

A multi-target lateral flow immunoassay enabling the specific and sensitive detection of total antibodies to SARS COV-2.

A rapid test for detecting total immunoglobulins directed towards the nucleocapsid protein (N) of severe acute syndrome coronavirus 2 (SARS CoV-2) was developed, based on a multi-target lateral flow immunoassay comprising two test lines. Both test lines bound to several classes of immunoglobulins (G, M, and A). Specific anti-SARS immunoglobulins were revealed by a colorimetric probe formed by N and gold nanoparticles. Targeting the total antibodies response to infection enabled achieving 100% diagnostic specificity (95.75-100, C.I. 95%, n = 85 healthy and with other infections individuals) and 94.6% sensitivity (84.9-98.9, C.I. 95%, n = 62 SARS CoV-2 infected subjects) as early as 7 days post confirmation of positivity. Agreeing results with a reference serological ELISA were achieved, except for the earlier detection capability of the rapid test. Follow up of the three seroconverting patients endorsed the hypothesis of the random rise of the different immunoglobulins and strengthened the 'total antibodies' approach for the trustworthy detection of serological response to SARS CoV-2 infection.

Clinical research and burnout syndrome in Italy - only a physicians' affair?

BACKGROUND: The burnout phenomenon has been extensively investigated among health care professionals, particularly focusing on physicians and nurses. However, literature concerning burnout in clinical research is poor and often neglects the other professional categories involved. METHODS: In March 2019, all members of Italian Group of Clinical Research Coordinator were invited to participate to a web survey, consisting of three sections: general information and workload; Maslach Burnout Inventory (MBI) test; subjective perception of oneself's work stress and possible causes. RESULTS: The majority of respondents felt a form of distress. The main source was contract type (31.2%), followed by workload (20.5%) and lack of skills recognition (17.8%). Results from MBI test confirmed the interviewees' subjective perception: an intermediate level of emotional exhaustion (19.1 points) and a very high sense of reduced professional achievement (26.8 points) were observed. Both depersonalization and sense of reduced professional achievement showed weak to moderate correlations with emotional exhaustion. Emotional exhaustion was associated with contract type with high significance. CONCLUSION: It is necessary to act on those qualitative factors that are greatly increasing the level of perceived stress, jeopardizing the quality of clinical research coordinators work and significantly amplifying the phenomenon of migration towards the private sector.