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IMbrave150 has established the superiority of atezolizumab plus bevacizumab over sorafenib in patients with unresectable hepatocellular carcinoma (HCC).We generated a prospectively maintained database including patients treated with atezolizumab plus bevacizumab for unresectable HCC across Europe, Asia and USA. Clinico-pathologic characteristics were assessed for their prognostic influence on overall survival (OS) and progression-free survival (PFS) in univariable and multivariate analyses. Overall response rate by RECIST v1.1 and treatment-related adverse events (TRAEs) per CTCAE v.5.0 were reported.Out of 433 patients, 296 Child-Pugh A and ECOG performance status01 patients received atezolizumab plus bevacizumab in first line and were included. Patients were mostly male (82.7%), cirrhotic (75%) with history of viral hepatitis (65.9%). Overall, 68.9% had Barcelona Clinic Liver Cancer C-stage HCC with portal vein tumour thrombosis (PVTT, 35%) and extrahepatic spread (EHS, 51.7%). After a median follow-up of 10.0 months (95% confidence interval (CI): 9.4-10.4), median OS and PFS were 15.7 (95% CI: 14.5-NE) and 6.9 months (95% CI: 6.1-8.3), respectively. In the response-evaluable patients (n = 273), overall response rate was 30.8%. Overall, 221 patients (74.6%) developed TRAEs, with 70 (23.6%) reporting grade 3 or higher TRAEs; 25 (8.4%) patients had bleeding events. OS was independently associated with baseline Albumin-bilirubin (ALBI) grade and PVTT. Shorter PFS was associated with AFP≥ 400 ng/ml, worse ALBI and presence of EHS.This global observational study confirms the reproducible safety and efficacy of atezolizumab plus bevacizumab in routine clinical practice. Within Child-Pugh-A criteria, the presence of PVTT and higher ALBI grade identify patients with poorer survival.

To describe the biological rationale of peripheral blood cells (PBC)-derived inflammatory indexes and assess the related prognostic scores for patients with advanced non-small cell lung cancer (aNSCLC) treated with immune-checkpoint inhibitors (ICI).Inflammatory indexes based on PBC may indicate a pro-inflammatory condition affecting the immune response to cancer. The lung immune prognostic index (LIPI), consisting of derived neutrophils-to-lymphocyte ratio (NLR) and lactate dehydrogenase, is a validated prognostic tool, especially for pretreated aNSCLC patients, where the combination of NLR and PD-L1 tumour expression might also be predictive of immunotherapy benefit. In untreated high-PD-L1 aNSCLC patients, the Lung-Immune-Prognostic score (LIPS), including NLR, ECOG PS and concomitant steroids, is prognostic, and its modified version might indicate patients with favourable outcomes despite an ECOG PS of 2. NLR times platelets (i.e., SII), included in the NHS-Lung score, might improve the prognostication for combined chemoimmunotherapy. PBC-derived inflammatory indexes and related scores represent accurate, reproducible and non-expensive prognostic tools with clinical and research utility.

Immune checkpoint inhibitors are a well-established treatment option for advanced urothelial carcinoma, and biomarkers of response are needed for better patient selection. We show that metastatic disease confined to lymph nodes is associated with better outcomes, while metastases to liver, bone or both are associated with poor outcomes with immune checkpoint inhibitor therapy. Results are hypothesis-generating but relevant to practice. BACKGROUND: Sites of metastasis have prognostic significance in advanced urothelial carcinoma (aUC), but more information is needed regarding outcomes based on metastatic sites in patients treated with immune checkpoint inhibitors (ICI). We hypothesized that presence of liver/bone metastases would be associated with worse outcomes with ICI. METHODS: We identified a retrospective cohort of patients with aUC across 26 institutions, collecting demographics, clinicopathological, treatment, and outcomes information. Outcomes were compared with logistic (observed response rate; ORR) and Cox (progression-free survival; PFS, overall survival; OS) regression between patients with/without metastasis beyond lymph nodes (LN) and those with/without bone/liver/lung metastasis. Analysis was stratified by 1st or 2nd(+) line. RESULTS: We identified 917 ICI-treated patients: in the 1st line, bone/liver metastases were associated with shorter PFS (Hazard ratio; HR: 1.65 and 2.54), OS (HR: 1.60 and 2.35, respectively) and lower ORR (OR: 0.48 and 0.31). In the 2nd(+) line, bone/liver metastases were associated with shorter PFS (HR: 1.71 and 1.62), OS (HR: 1.76 and 1.56) and, for bone-only metastases, lower ORR (OR: 0.29). In the 1st line, LN-confined metastasis was associated with longer PFS (HR: 0.53), OS (HR:0.49) and higher ORR (OR: 2.97). In the 2nd(+) line, LN-confined metastasis was associated with longer PFS (HR: 0.47), OS (HR: 0.54), and higher ORR (OR: 2.79); all associations were significant. CONCLUSION: Bone and/or liver metastases were associated with worse, while LN-confined metastases were associated with better outcomes in patients with aUC receiving ICI. These findings in a large population treated outside clinical trials corroborate data from trial subset analyses.

Background and Aims Combination atezolizumab/bevacizumab is the gold standard for first-line treatment of unresectable hepatocellular carcinoma (HCC). Our study investigated the efficacy and safety of combination therapy in older patients with HCC. Methods 191 consecutive patients from eight centres receiving atezolizumab and bevacizumab were included. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in older (age ≥ 65 years) and younger (age

Hypertensive emergency is well recognised in human medicine, yet there is limited veterinary evidence. This study aimed to determine the presentation, treatment and outcome in dogs and cats with hypertensive emergency.A retrospective case series of dogs and cats with hypertensive emergency identified as follows: acute history with non-invasive Doppler systolic blood pressure greater than 180 mmHg and target organ damage including acute onset seizures, altered mentation with or without lateral recumbency or blindness. Data collected included signalment, history, physical examination and clinicopathological findings, systolic blood pressure, antihypertensive treatment and outcome.Seven dogs and eight cats were included presenting with seizures (n=9), blindness (n=4), altered mentation with (n=2) or without (n=2) lateral recumbency. Median age was 9 years (range 1 to 15) and duration of clinical signs before presentation was 1.5 days (range 1 to 15). Median systolic blood pressure on presentation was 230 mmHg (range 190 to 300). Amlodipine was the most common first-line agent (n=10), followed by hydralazine (n=4) and hypertonic saline (n=1). Aetiology of hypertensive emergency was acute kidney injury (n=9), idiopathic hypertension (n=3), hyperthyroidism (n=1), lymphoma (n=1) and suspected cutaneous and renal glomerular vasculopathy (n=1). Five cats and three dogs survived to discharge with an overall survival of 53.3%.Hypertensive emergencies had various presenting signs in this series. AKI was considered to be the cause of hypertension in the majority of patients. Further evaluation of treatment for hypertensive emergencies is warranted, considering almost half of the cases did not survive to discharge.

Introduction: A significant proportion of patients with cancer who recover from Coronavirus Disease 2019 (COVID-19) may experience COVID-19 sequelae in the early post-infection phase, which negatively affect their continuity of care and oncological outcome. The long-term prevalence and clinical impact of the post-COVID-19 syndrome in patients with cancer are largely unknown. Methods: In this study, we describe the time course of COVID-19 sequelae in patients with non-advanced cancers enrolled in the OnCovid registry. Results: Overall, 186 patients were included, with a median observation period of 9.9 months (95%CI:8,8–11.3) post-COVID-19 resolution. After a median interval of 2.3 months post-COVID-19 (interquartile range: 1.4–3.7), 31 patients (16.6%) reported ≥1 sequelae, including respiratory complications (14, 7.6%), fatigue (13, 7.1%), neuro-cognitive sequelae (7, 3.8%). The vast majority of the patients were not vaccinated prior to COVID-19. COVID-19-related sequelae persisted in 9.8% and 8% of patients 6 and 12 months after COVID-19 resolution. Persistence of sequelae at first oncological follow-up was associated with history of complicated COVID-19 (45.2% vs 24.8%, p = 0.0223), irrespective of oncological features at COVID-19 diagnosis. Conclusion: This study confirms for the first time that, in a largely unvaccinated population, post-COVID-19 syndrome can affect a significant proportion of patients with non-advanced cancer who recovered from the acute illness. COVID-19 sequelae may persist up to 12 months in some patients, highlighting the need for dedicated prevention and supportive strategies.

A proinflammatory diathesis, as measured by the neutrophil to lymphocyte ratio (NLR), heralds an adverse disease course for non-small cell lung cancer (NSCLC).This post hoc analysis used data from the phase 3 OAK trial (NCT02008227), which randomized previously treated patients with NSCLC to atezolizumab or docetaxel. The main objective was assessing the differential impact of the pretreatment NLR on overall survival according to the treatment modality. In addition, patients' genomic characteristics were assessed according to their inflammatory status with a circulating free DNA (cfDNA) next-generation sequencing (NGS) analysis.In all, 600 and 575 patients with NLR data were included in the atezolizumab and docetaxel cohorts, respectively, with a median NLR of 4 (interquartile range, 2.6-6.7) for the pooled population. An NLR ≥4 was associated with a positive smoking status (88.6% vs. 78.1%; p .01), male sex (66.4% vs. 57.6%; p = .01), a worse performance status (71.3% vs. 55.2%; p .01), a higher number of metastatic sites (63.2% vs. 51.6%; p = .01), squamous histology (32.1% vs. 21.4%; p .01), and tissue KRAS mutations (30% vs. 18.7%; p = .02) but not with programmed death ligand 1 (PD-L1) expression or the tissue epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) status. A pretreatment NLR ≥4 was more strongly associated with mortality after atezolizumab (adjusted hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.35-2.01) versus docetaxel (HR, 1.32; 95% CI, 1.08-1.60; multivariable [MVA] interaction p = .08). The HR for an increased risk of death for PD-L1-negative/NLR ≥4 patients (compared with PD-L1-positive/NLR 4 patients) was significantly higher in the atezolizumab cohort (MVA interaction p = .01). The exclusion of EGFR/ALK-positive patients further increased the prognostic ability of the baseline NLR in favor of atezolizumab (MVA interaction p = .02). Pretreatment cfDNA data from NGS showed that patients with a high blood tumor mutation burden (cutoff, 16 mut/Mb) had a higher median NLR (4.6 vs. 3.7; p = .01). After adjustments for multiple comparisons, none of the selected variants of interest (EGFR, KRAS, TP53, KEAP1, STK11, SMARCA4, ARID1A, and targeted DNA damage response and repair genes) were significantly associated with the NLR.A low baseline NLR identified patients with NSCLC who derived a greater survival benefit from atezolizumab in comparison with those identified in the docetaxel cohort. The NLR could complement PD-L1 expression in tailoring treatment in this setting.

This study involves a group of 168 teeth in 126 patients treated with crown lengthening and tooth reconstruction (experimental group), and a group of 75 teeth from 62 patients that were judged irrational to treat, extracted, and replaced (control group). In the control group, 13 teeth in 12 patients were not replaced; 37 were replaced with an implant-supported crown, 14 with a tooth-supported partial denture, 2 with a Maryland partial denture; and 9 patients requested a removable prosthesis. In the experimental group, 44 teeth in 37 patients received a conservative restoration (24 direct and 20 indirect), while 124 teeth in 94 patients received a full crown. All 168 teeth were surgically treated with minimally invasive crown lengthening. Endodontic treatment and orthodontic extrusion were applied when necessary. Treatment resulted in healthy periodontal and dental/implant conditions at the 1-year follow-up in both groups. Function and esthetics were described from satisfactory to extremely satisfactory by patients of both groups, with the exception of three patients in the control group who received a mobile prosthesis restoration and reported some difficulties in chewing. When comparing treatment cost and duration of the reconstructed teeth (experimental group) to the treatment cost and duration of extracted and replaced teeth (control group), the difference is significantly in favor of the preservation of natural teeth, both monetarily and in terms treatment time. Saving a tooth with a compromised crown is more favorable for the patient than extraction and replacement. This conservative approach is advisable to clinicians whenever the clinical conditions enable treatment.

BackgroundAs management and prevention strategies against COVID-19 evolve, it is still uncertain whether prior exposure to immune checkpoint inhibitors (ICIs) affects COVID-19 severity in patients with cancer.MethodsIn a joint analysis of ICI recipients from OnCovid (NCT04393974) and European Society for Medical Oncology (ESMO) CoCARE registries, we assessed severity and mortality from SARS-CoV-2 in vaccinated and unvaccinated patients with cancer and explored whether prior immune-related adverse events (irAEs) influenced outcome from COVID-19.FindingsThe study population consisted of 240 patients diagnosed with COVID-19 between January 2020 and February 2022 exposed to ICI within 3 months prior to COVID-19 diagnosis, with a 30-day case fatality rate (CFR30) of 23.6% (95% CI 17.8 to 30.7%). Overall, 42 (17.5%) were fully vaccinated prior to COVID-19 and experienced decreased CFR30(4.8% vs 28.1%, p=0.0009), hospitalization rate (27.5% vs 63.2%, pOverall, 38 patients (15.8%) experienced at least one irAE of any grade at any time prior to COVID-19, at a median time of 3.2 months (range 0.13–48.7) from COVID-19 diagnosis. IrAEs occurred independently of baseline characteristics except for primary tumor (p=0.0373) and were associated with a significantly decreased CFR30(10.8% vs 26.0%, p=0.0462) additionally confirmed by the IPTW-fitted multivariable analysis (aOR 0.47, 95% CI 0.33 to 0.67). Patients who experienced irAEs also presented a higher median absolute lymphocyte count at COVID-19 (1.4 vs 0.8 109 cells/L, p=0.0098).ConclusionAnti-SARS-CoV-2 vaccination reduces morbidity and mortality from COVID-19 in ICI recipients. History of irAEs might identify patients with pre-existing protection from COVID-19, warranting further investigation of adaptive immune determinants of protection from SARS-CoV-2.

Randomised controlled trials (RCTs) with systemic therapies for patients with pre-treated mesothelioma have reported equivocal efficacy results and generated a degree of clinical uncertainty about the choice of active treatment in this poor prognosis malignancy.To compare the effectiveness and safety and weigh the benefit of different systemic treatments in patients with pre-treated mesothelioma by systematic review, meta-analysis and network meta-analysis of RCTs. Full-text articles and abstracts were searched on PubMed, EMBASE, Cochrane Library and oncology conferences proceedings from 2005 through November 2021 for phase 2 and 3 RCTs. The protocol was submitted to the PROSPERO registry. Reporting followed the PRISMA guideline. Outcomes of interest were overall survival (OS) and progression-free (PFS), grade ≥3 treatment-related (Tr) adverse events (AEs), Tr-deaths and Tr-AEs leading to treatment discontinuation.Nine trials at low risk of bias by Cochrane Collaboration's methodology were included, encompassing 2789 patients. Five studies showed PFS benefit in the experimental treatment. In two studies, OS was prolonged by immunotherapy (versus placebo) or by adding an antiangiogenic agent to chemotherapy. Reported Tr-AE were lower with single-agent anti-PD1 compared with chemotherapy or placebo. The meta-analysis revealed a beneficial global effect on OS and PFS from experimental treatments (HR 0.86, 95% CI 0.77-0.96, p = 0.0083 and HR 0.79, 95% CI 0.72-0.86, p 0.001), that for the PFS significantly favoured the comparison with non-active treatments (HR 0.73, 95% CI 0.66-0.81, p 0.001). Younger patients (i.e. 65-70 years) appeared to benefit the most in OS (HR 0.71, 95% CI 0.55-0.92, p = 0.04). The risk of serious Tr-AEs and Tr-deaths was not significantly increased by experimental treatments (RR 1.38, 95% CI 0.81-2.35, p = 0.24 and RR 2.07, 95% CI 0.69-6.24, p = 0.19, respectively) that instead increased TrAEs leading to treatment discontinuation (RR 2.9, 95% CI 1.44-6.08, p = 0.003). The network meta-analysis did not identify any superior treatment in PFS.For patients with pre-treated MPM, single-agent anti-PD1 or chemotherapy ± the antiangiogenic agent can be considered active and safe systemic therapeutic options, particularly for younger patients.

Atezolizumab plus bevacizumab (AtezoBev) is the standard of care for first-line treatment of unresectable HCC. No evidence exists as to its use in routine clinical practice in patients with impaired liver function.In 216 patients with HCC who were consecutively treated with AtezoBev across 11 tertiary centers, we retrospectively evaluated treatment-related adverse events (trAEs) graded (G) according to Common Terminology Criteria for Adverse Events v5.0, including in the analysis all patients treated according to label (n = 202, 94%). We also assessed overall survival (OS), progression-free survival (PFS), overall response (ORR), and disease control rates (DCR) defined by Response Evaluation Criteria in Solid Tumors v1.1. Disease was mostly secondary to viral hepatitis, namely hepatitis C (n = 72; 36%) and hepatitis B infection (n = 35, 17%). Liver function was graded as Child-Pugh (CP)-A in 154 patients (76%) and CP-B in 48 (24%). Any grade trAEs were reported by 143 patients (71%), of which 53 (26%) were G3 and 3 (2%) G4. Compared with CP-A, patients with CP-B showed comparable rates of trAEs. Presence and grade of varices at pretreatment esophagogastroduodenoscopy did not correlate with bleeding events. After a median follow-up of 9.0 months (95% CI, 7.8-10.1), median OS was 14.9 months (95% CI, 13.6-16.3), whereas median PFS was 6.8 months (95% CI, 5.2-8.5). ORR and DCR were respectively 25% and 73%, with no difference across CP classes.This study confirms reproducible safety and efficacy of AtezoBev in routine practice. Patients with CP-B reported similar tolerability compared with CP-A, warranting prospective evaluation of AtezoBev in this treatment-deprived population.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and fourth-leading cause of cancer death. While drug discovery to improve disease survival was historically poor, there is now evidence of significant potential for immune checkpoint inhibitors (ICPIs) in treatment of the disease, and indeed such drug approvals are beginning to emerge.HCC typically arises in the context of cirrhosis and chronic liver disease (CLD), and HCC exhibits significant biological heterogeneity, in part reflecting the broad range of etiologies of CLD. Different classes and combinations of ICPI-based therapy exist, but not all patients will respond and predictive biomarkers are not yet available to guide clinician decision-making, unlike some other cancer types. In this review, we discuss the emerging biomarkers for ICPI sensitivity in HCC, including tumor genomic features, perturbation of the gut microbiome, and systemic inflammatory markers.Additional profiling studies are required to appreciate existing trends with clinical outcome and to further drive clinical studies in disease stratification by response. This will only be possible within collaborative and international efforts, especially regarding biopsy collection. A close collaboration between basic scientists and clinicians will be the key to shape the next future of HCC biomarker research.

Background Improved outcome in tobacco smoking patients with non‐small cell lung cancer (NSCLC) following immunotherapy has previously been reported. However, little is known regarding this association during first‐line immunotherapy in patients with high PD‐L1 expression. In this study we compared clinical outcomes according to the smoking status of two large multicenter cohorts. Methods We compared clinical outcomes according to the smoking status (never smokers vs. current/former smokers) of two retrospective multicenter cohorts of metastatic NSCLC patients, treated with first‐line pembrolizumab and platinum‐based chemotherapy. Results A total of 962 NSCLC patients with PD‐L1 expression ≥50% who received first‐line pembrolizumab and 462 NSCLC patients who received first‐line platinum‐based chemotherapy were included in the study. Never smokers were confirmed to have a significantly higher risk of disease progression (hazard ratio [HR] = 1.49 [95% CI: 1.15–1.92], p = 0.0022) and death (HR = 1.38 [95% CI: 1.02–1.87], p = 0.0348) within the pembrolizumab cohort. On the contrary, a nonsignificant trend towards a reduced risk of disease progression (HR = 0.74 [95% CI: 0.52–1.05], p = 0.1003) and death (HR = 0.67 [95% CI: 0.45–1.01], p = 0.0593) were reported for never smokers within the chemotherapy cohort. After a random case–control matching, 424 patients from both cohorts were paired. Within the matched pembrolizumab cohort, never smokers had a significantly shorter progression‐free survival (PFS) (HR = 1.68 [95% CI: 1.17–2.40], p = 0.0045) and a nonsignificant trend towards a shortened overall survival (OS) (HR = 1.32 [95% CI: 0.84–2.07], p = 0.2205). On the contrary, never smokers had a significantly longer PFS (HR = 0.68 [95% CI: 0.49–0.95], p = 0.0255) and OS (HR = 0.66 [95% CI: 0.45–0.97], p = 0,0356) compared to current/former smoker patients within the matched chemotherapy cohort. On pooled multivariable analysis, the interaction term between smoking status and treatment modality was concordantly statistically significant with respect to ORR (p = 0.0074), PFS (p = 0.0001) and OS (p = 0.0020), confirming the significantly different impact of smoking status across the two cohorts. Conclusions Among metastatic NSCLC patients with PD‐L1 expression ≥50% receiving first‐line pembrolizumab, current/former smokers experienced improved PFS and OS. On the contrary, worse outcomes were reported among current/former smokers receiving first‐line chemotherapy., Improved outcome in tobacco smoking NSCLC patients following treatment with immune checkpoint inhibitors (ICIs) has previously been reported. Little is known regarding this association during first‐line immunotherapy in patients with high PD‐L1 expression. Clinical outcomes according to the smoking status of two large multicenter cohorts were compared in this study. Smokers with high PD‐L1 expression ≥ 50% experienced improved progression‐free survival (PFS) and overall survival (OS) with first‐line pembrolizumab. The opposite trend was found in NSCLC patients treated with first‐line platinum‐based chemotherapy.

Background: Hepatocellular carcinoma (HCC) is the most common primary liver tumor, and it rates fourth as a cause of cancer-related death. The presence of underlying liver disease and poor chemosensitivity pose major treatment challenges in the management of HCC. However, in the last few years, the therapeutic scenario has substantially changed, and immunotherapy in the form of immune checkpoint inhibitors (ICPIs) has become an essential therapeutic strategy in this field. Summary: After controversial results of monotherapy, ICPIs have been mainly investigated in association with antiangiogenic agents or as dual checkpoint inhibition. The combination of atezolizumab plus bevacizumab has become the new therapeutic standard for unresectable HCC. Currently, a number of ICPI-based combinations are being studied in phase III clinical trials as front-line therapy for advanced HCC, with growing interest in integration of early-stage disease management in the form of adjuvant or neoadjuvant therapies. With most of the trials investigating ICPIs as first-line treatment, the second-line scenario relies mainly on tyrosine kinase inhibitors, which however have not been formally trialed after ICPIs. Key Messages: In this review, we summarize the main therapeutic advances in the systemic management of HCC focusing on the most relevant ongoing trials. We also discuss the main issues arising from a such rapidly evolving field including therapeutic sequencing and patient stratification.

Oncology; Public health; COVID-19 Oncología; Salud pública; COVID-19 Oncologia; Salut pública; COVID-19 Background Consolidated evidence suggests spontaneous immunity from SARS-CoV-2 is not durable, leading to the risk of reinfection, especially in the context of newly emerging viral strains. In patients with cancer who survive COVID-19 prevalence and severity of SARS-CoV-2 reinfections are unknown. Methods We aimed to document natural history and outcome from SARS-CoV-2 reinfection in patients recruited to OnCovid (NCT04393974), an active European registry enrolling consecutive patients with a history of solid or haematologic malignancy diagnosed with COVID-19. Results As of December 2021, out of 3108 eligible participants, 1806 COVID-19 survivors were subsequently followed at participating institutions. Among them, 34 reinfections (1.9%) were reported after a median time of 152 days (range: 40–620) from the first COVID-19 diagnosis, and with a median observation period from the second infection of 115 days (95% CI: 27–196). Most of the first infections were diagnosed in 2020 (27, 79.4%), while most of reinfections in 2021 (25, 73.5%). Haematological malignancies were the most frequent primary tumour (12, 35%). Compared to first infections, second infections had lower prevalence of COVID-19 symptoms (52.9% vs 91.2%, P = 0.0008) and required less COVID-19-specific therapy (11.8% vs 50%, P = 0.0013). Overall, 11 patients (32.4%) and 3 (8.8%) were fully and partially vaccinated against SARS-CoV-2 before the second infection, respectively. The 14-day case fatality rate was 11.8%, with four death events, none of which among fully vaccinated patients. Conclusion This study shows that reinfections in COVID-19 survivors with cancer are possible and more common in patients with haematological malignancies. Reinfections carry a 11% risk of mortality, which rises to 15% among unvaccinated patients, highlighting the importance of universal vaccination of patients with cancer. OnCovid is sponsored by Imperial College London and received direct project funding and infrastructural support by the NIHR Imperial Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Neither sponsor nor the funders of the study had any role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had access to all the data reported in the study.

Evidence has been accumulating in the sense that femur may not always be the best option for DNA typing of skeletal remains. Recent studies have shown that bones of the hands and feet appear to be a superior source of preserved DNA. The current study reanalyzed DNA quantitation, degradation, and short tandem repeat typing in femurs, lateral cuneiforms, and distal foot phalanges. Data from 3 human identification cases involving corpses in an advanced decomposition state were collected. We found that in the studied cases, the femur provided equal or inferior results, recovering 84.9% of true alleles. Lateral cuneiforms (99.2%) and distal foot phalanges (96.8%) yielded higher percentages. In addition, more drop-ins and drop-outs were detected in femurs than cuneiforms and phalanges. This study adds to current findings that advocate for further investigation into bone selection for use in forensic practice. The impacts of our findings are limited by the small number of individuals studied and may not apply to old and degraded bones.

BACKGROUND: Mindfulness-based interventions (MBIs) are known for their beneficial effects on positive and negative psychological factors. When applied in an occupational context, MBIs might help workers to cope with stress, increase their professional outcomes and wellbeing. OBJECTIVE: In this two-groups pre-post experimental design we tested the effect of our MBI, called Integral Meditation (IM), among the employers of an Italian service company by measuring positive and negative aspects of psychological wellbeing related to mindfulness and workplace functioning through eight self-report questionnaires (CORE-OM, FFMQ, WEMWBS, MAIA, PSS, PANAS, STAI-X1, SCS). METHOD: Forty-two voluntary non-clinical employers of the company, randomly assigned to the experimental or the control group, were analyzed. The experimental group underwent our IM program, which consists of 12 weekly meditation classes given after the afternoon shift, while the control group did not receive any intervention. Data was analyzed via linear mixed models. RESULTS: Statistically significant results were obtained for FFMQ observing subscale (β= 0.49, p = 0.014), WEMWBS (β= 5.31, p = 0.02), PSS (β= –3.31, p = 0.03), the whole scale of SCS (β= 0.47, p = 0.01) and self-judgment (β= 0.68, p = 0.003) and isolation (β= –0.66, p = 0.01) SCS subscales. Statistically significant results were also found in four out of eight subscales of MAIA: emotional awareness (β= 1.26, p

BACKGROUND: Doublets plus antiepidermal growth factor receptors monoclonal antibodies (EGFRi) are widely considered the preferable first-line regimen in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC), resulting superior in terms of activity and efficacy compared to doublets plus bevacizumab. However, data comparing doublet plus EGFRi and triplet plus bevacizumab are lacking, and the relative benefit of an intensive regimen plus an antiangiogenic backbone in this population is debated. METHODS: This multicenter, retrospective study aimed at evaluating clinicians' attitude to triplet-bevacizumab and doublet-EGFRi as first-line regimen in patients with left-sided RAS/BRAF wild-type mCRC treated in clinical practice at 22 Oncology Units from March 2012 to October 2020. A random case-control matching was performed to compare activity (ORR), and effectiveness (PFS, OS, secondary resection rate of metastases with curative intent) between triplet-bevacizumab and doublet-EGFRi, on the basis of ECOG-PS, age, gender, and burden of disease. RESULTS: A total of 718 patients were consecutively treated with doublet-EGFRi (686, 95.5%) or triplet-bevacizumab (32, 4.5%). After case-control matching, median PFS was 13.6 (95% CI, 8.9-31.7) and 16.1 (95% CI, 12.1-36.8) months (P= .621), while median OS was 30.2 (95% CI, 14.4-69.5) and 38.1 (95% CI, 33.1-101.1) months (P= .0283) in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. The ORR was 65.6% and 90.6% (P= .016), while the secondary resection rate was 18.8% and 46.9% (P= .016), in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. Triplet-bevacizumab was associated with a higher incidence of G3/G4 neutropenia (25.0% vs. 12.5%, P= .041). CONCLUSION: Although a doublet-EGFRi remains the recommended upfront regimen in patients with left-sided RAS and BRAF wild-type mCRC, our real life data suggest a triplet-bevacizumab might be at least equally active and effective in properly selected cases.

Background Inpatients are at risk for inadequate colon cleansing. Experts recommend 4L-polyethylene-glycol (PEG) solution. A higher colon cleansing adequacy rate for a hyperosmolar 1L-PEG plus ascorbate prep has been recently reported. Aims We aimed to determine whether 1L-PEG outperforms 4L-PEG among inpatients. Methods post-hoc analysis of a large Italian multicenter prospective observational study among inpatients (QIPS study). We performed a propensity score matching between 1L-PEG and 4L-PEG group. The primary outcome was the rate of adequate colon cleansing as assessed by unblinded endoscopists through Boston scale. Secondary outcome was the safety profile. Results Among 1,004 patients undergoing colonoscopy, 724 (72%) were prescribed 4L-PEG and 280 (28%) 1L-PEG. The overall adequate colon cleansing rate was 69.2% (n = 695). We matched 274 pairs of patients with similar distribution of confounders. The rate of patients with adequate colon cleansing was higher in 1L-PEG than in 4L-PEG group (84.3% vs. 77.4%, p = 0.039). No different shift in serum concentration of electrolytes (namely Na+, K+, Ca2+), creatinine and hematocrit were observed for both preparations. Conclusion We found a higher rate of adequate colon cleansing for colonoscopy with the 1L-PEG bowel prep vs. 4L-PEG, with apparent similar safety profile, among inpatients. A confirmatory randomized trial is needed. (ClinicalTrials.gov no: NCT04310332)

The modified minimally invasive surgical technique (M-MIST) optimizes wound stability in the treatment of intrabony defects. Short-term observations show similar results as with flap alone or adjunctive regenerative materials. This study aims to compare the stability of the long-term outcomes, complication-free survival, and costs of the three treatment options.Forty-five intrabony defects in 45 patients were randomized to M-MIST alone (N = 15), combined with enamel matrix derivative (M-MIST + EMD, N = 15), or EMD plus bone-mineral-derived xenograph (M-MIST + EMD + BMDX, N = 15). Supportive periodontal care (SPC) and necessary re-treatment were provided for 10 years.Three subjects were lost to follow-up. Clinical attachment level differences between 1 and 10 years were -0.1 ± 0.7 mm for M-MIST, -0.1 ± 0.8 mm for M-MIST + EMD, and -0.3 ± 0.6 mm for M-MIST + EMD + BMDX (p .05 for within- and between-group differences). Four episodes of recurrence occurred in the M-MIST group, four in the M-MIST + EMD group, and five in the M-MIST + EMD + BMDX group. No significant differences in complication-free survival were observed between the three groups (p = .47). Complication-free survival was 7.46 years (95% confidence interval: 7.05-7.87) for the whole population. The M-MIST + EMD + BMDX group lost one treated tooth. Data indicated no significant inter-group difference of the total cost of recurrence over 10 years. When the baseline cost of treatment was considered, the total cost was lower for M-MIST alone.Teeth with deep pockets associated with intrabony defects can be successfully maintained over the long term with either M-MIST alone or by adding a regenerative material in the context of a careful SPC programme. M-MIST alone provided similar short- and long-term benefits as regeneration, at a lower cost. These findings need to be confirmed in larger, independent studies.

Background The clinical observation showed a potential additive effect of anti-PD-1 agents and cetirizine in patients with advanced melanoma. Methods Clinical outcomes of concomitant cetirizine/anti-PD-1 treatment of patients with stage IIIb–IV melanoma were retrospectively collected, and a transcriptomic analysis was performed on blood samples obtained at baseline and after 3 months of treatment. Results Patients treated with cetirizine concomitantly with an anti-PD-1 agent had significantly longer progression-free survival (PFS; mean PFS: 28 vs 15 months, HR 0.46, 95% CI: 0.28–0.76; p = 0.0023) and OS (mean OS was 36 vs 23 months, HR 0.48, 95% CI: 0.29–0.78; p = 0.0032) in comparison with those not receiving cetirizine. The concomitant treatment was significantly associated with ORR and DCR (p FCGR1A/CD64, a specific marker of macrophages, was increased after the treatment in comparison with baseline in blood samples from patients receiving cetirizine, but not in those receiving only the anti-PD1, and positively correlated with the expression of genes linked to the interferon pathway such as CCL8 (rho = 0.32; p = 0.0111), IFIT1 (rho = 0.29; p = 0.0229), IFIT3 (rho = 0.57; p , IFI27 (rho = 0.42; p = 0.008), MX1 (rho = 0.26; p = 0.0383) and RSAD2 (rho = 0.43; p = 0.0005). Conclusions This retrospective study suggests that M1 macrophage polarization may be induced by cetirizine through the interferon-gamma pathway. This effect may synergize with the immunotherapy of advanced melanoma with anti-PD-1 agents.

Background Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era. Methods We investigated the Meet-URO-15 study dataset of 571 pretreated mRCC patients receiving nivolumab as second or further lines about the prognostic role of the previous nephrectomy (received in either the localized or metastatic setting) in the overall population and according to the Meet-URO score groups. Results Patients who underwent nephrectomy showed a significantly reduced risk of death (HR 0.44, 95% CI 0.32–0.60, p p = 0.17). It was statistically significant when merging group 1 with 2 and 3 and group 4 with 5 (p = 0.038) and associated with a longer OS for the first three prognostic groups (p p = 0.54). Conclusions Our study suggests an overall positive impact of the previous nephrectomy on the outcome of pretreated mRCC patients receiving immunotherapy. The clinical relevance of cytoreductive nephrectomy, optimal timing and patient selection deserves further investigation, especially for patients with Meet-URO scores of 1 to 3, who are the once deriving benefit in our analyses. However, that benefit is not evident for IMDC poor-risk patients (including the Meet-URO score groups 4 and 5) and a subgroup of IMDC intermediate-risk patients defined as group 4 by the Meet-URO score.

Introduction: COVID-19 has disrupted the global health care system since March 2020. Lung cancer (LC) patients (pts) represent a vulnerable population highly affected by the pandemic. This multicenter Italian study aimed to evaluate whether the COVID-19 outbreak had an impact on access to cancer diagnosis and treatment of LC pts compared with pre-pandemic time. Methods: Consecutive newly diagnosed LC pts referred to 25 Italian Oncology Departments between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset and diagnostic and therapeutic services were compared with the same period in 2019. Differences between the 2 years were analyzed using the chi-square test for categorical variables and the Mann–Whitney U test for continuous variables. Results: A slight reduction (−6.9%) in newly diagnosed LC cases was observed in 2020 compared with 2019 (1523 versus 1637, P = 0.09). Newly diagnosed LC pts in 2020 were more likely to be diagnosed with stage IV disease (P < 0.01) and to be current smokers (someone who has smoked more than 100 cigarettes, including hand-rolled cigarettes, cigars, cigarillos, in their lifetime and has smoked in the last 28 days) (P < 0.01). The drop in terms of new diagnoses was greater in the lockdown period (percentage drop −12% versus −3.2%) compared with the other months included. More LC pts were referred to a low/medium volume hospital in 2020 compared with 2019 (P = 0.01). No differences emerged in terms of interval between symptoms onset and radiological diagnosis (P = 0.94), symptoms onset and cytohistological diagnosis (P = 0.92), symptoms onset and treatment start (P = 0.40), and treatment start and first radiological revaluation (P = 0.36). Conclusions: Our study pointed out a reduction of new diagnoses with a shift towards higher stage at diagnosis for LC pts in 2020. Despite this, the measures adopted by Italian Oncology Departments ensured the maintenance of the diagnostic-therapeutic pathways of LC pts.

Introduction Underlying liver disease and the intrinsic chemoresistance have historically hampered the development of efficacious treatments in HCC. However, in the last few years, immunotherapy-based combinations have emerged as efficacious therapeutic strategy in this setting. This paper critically summarizes the recent therapeutic progress in the systemic treatment of HCC. Area covered This paper examines the preclinical rationale of the following combinations in HCC: dual checkpoint inhibitors, immune checkpoint inhibitors plus anti-angiogenic agents, and immune checkpoint inhibitors plus tyrosine kinase inhibitors. Results of recent clinical studies are presented, along with a brief overview of ongoing and future trials. Expert opinion The approval of atezolizumab plus bevacizumab and the positive results of the HIMALAYA trial have broadened the therapeutic scenario for advanced HCC, opening, at the same time, new challenges. First of all, predictive biomarkers to allocate patients to the best treatment are eagerly required; second, specific studies are urgently needed to define the use of new combinations in patients usually excluded from clinical trials, e.g. those with deranged liver function and HIV or transplant recipients. Finally, with new combinations being translated into earlier stages, profound changes are soon expected in the adjuvant and neoadjuvant setting.

Despite advances in supportive care, cancer-related symptoms tend to be persistent regardless of cancer type, stage of disease, or treatment received. There is an increasing prescription for complementary and alternative medicines, such as medical cannabis (MC). Knowledge and attitudes of Italian medical oncologists and palliative care physicians toward medical cannabis in cancer care remain unknown. We conducted a cross-sectional study to investigate the knowledge and attitude toward MC prescription among cancer care professionals in Italy. All invited participants received an email with the electronic questionnaire accessible through a direct link. Among the 2616 members who received the invitation, 475 replied to the questionnaire and were considered for the survey analysis. The most prescribed formulations among those available in Italy were cannabis FM2. The most frequent clinical indications for the use of MC were pain, gastrointestinal, and mood disorders. Only 9 responders reported MC-related side effects like anxiety insomnia and muscle spasms. The question regarding the normative references for MC prescription and use in Italy had conflicting results: only 14% indicated the exact legislative reference. Our study highlights a significant discrepancy between personal attitudes, prescription levels, and actual knowledge on MC. This represent a critical issue that should be systemically faced, building educational programs and national guidelines that sublimate personal physicians’ beliefs and predispositions, resulting in a robust science-based MC practice. Only through coordinated interventions on science and health policy of MC, there will be success of safety and efficacy, ensuring the best knowledge for the best outcomes.

Background: We previously demonstrated the cumulative poor prognostic role of concomitant medications on the clinical outcome of patients with advanced cancer treated with immune checkpoint inhibitors, creating and validating a drug-based prognostic score to be calculated before immunotherapy initiation in patients with advanced solid tumours. This ‘drug score’ was calculated assigning score 1 for each between proton-pump inhibitor and antibiotic administration until a month before cancer therapy initiation and score 2 in case of corticosteroid intake. The good risk group included patients with score 0, intermediate risk with score 1–2 and poor risk with score 3–4. Methods: Aiming at validating the prognostic and putative predictive ability depending on the anticancer therapy, we performed the present comparative analysis in two cohorts of advanced non–small-cell lung cancer (NSCLC), respectively, receiving first-line pembrolizumab or chemotherapy through a random case-control matching and through a pooled multivariable analysis including the interaction between the computed score and the therapeutic modality (pembrolizumab vs chemotherapy). Results: Nine hundred fifty and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. After the case-control random matching, 589 patients from the pembrolizumab cohort and 589 from the chemotherapy cohort were paired, with no statistically significant differences between the characteristics of the matched subjects. Among the pembrolizumab-treated group, good, intermediate and poor risk evaluable patients achieved an objective response rate (ORR) of 50.0%, 37.7% and 23.4%, respectively, (p < 0.0001), whereas among the chemotherapy-treated group, patients achieved an ORR of 37.0%, 40.0% and 32.4%, respectively (p = 0.4346). The median progression-free survival (PFS) of good, intermediate and poor risk groups was 13.9 months, 6.3 months and 2.8 months, respectively, within the pembrolizumab cohort (p < 0.0001), and 6.2 months, 6.2 months and 4.3 months, respectively, within the chemotherapy cohort (p = 0.0280). Among the pembrolizumab-treated patients, the median overall survival (OS) for good, intermediate and poor risk patients was 31.4 months, 14.5 months and 5.8 months, respectively, (p < 0.0001), whereas among the chemotherapy-treated patients, it was 18.3 months, 16.8 months and 10.6 months, respectively (p = 0.0003). A similar trend was reported considering the two entire populations. At the pooled analysis, the interaction term between the score and the therapeutic modality was statistically significant with respect to ORR (p = 0.0052), PFS (p = 0.0003) and OS (p < 0.0001), confirming the significantly different effect of the score within the two cohorts. Conclusion: Our ‘drug score’ showed a predictive ability with respect to ORR in the immunotherapy cohort only, suggesting it might be a useful tool for identifying patients unlikely to benefit from first-line single-agent pembrolizumab. In addition, the prognostic stratification in terms of PFS and OS was significantly more pronounced among the pembrolizumab-treated patients.

Aim To report the 36-month follow-up of a trial comparing the adjunct of a xenogenic collagen matrix (CMX) or connective tissue graft (CTG) to coronally advanced flaps (CAF) for coverage of multiple adjacent recessions. Material and methods 125 subjects (61 CMX) with 307 recessions in 8 centres from the parent trial were followed-up for 36-months. Primary outcome was change in position of the gingival margin. Multilevel analysis used centre, subject, and tooth as levels and baseline parameters as covariates. Results No differences were observed between the randomized and the follow-up population. Average baseline recession was 2.6 ± 1.0 mm. 3-year root coverage was 1.5 ± 1.5 mm for CMX and 2.0 ± 1.0 mm for CTG (difference of 0.32 mm, 95%CI from -0.02 to 0.65 mm). The upper limit of the confidence interval was over the non-inferiority margin of 0.25 mm. No treatment differences in position of the gingival margin were observed between 6- and 36-month follow-up (difference 0.06 mm, 95%CI -0.17 to 0.29 mm). Conclusion CMX was not non-inferior with respect to CTG in multiple adjacent recessions. No differences in stability of root coverage were observed between groups and in changes from 6 to 36 months. Previously reported shorter time to recovery, lower morbidity and more natural appearance of tissue texture and contour observed for CMX in this trial are also relevant in clinical decision making.

Immune checkpoint inhibitors improve overall survival in advanced urothelial carcinoma, but response rates remain modest. We performed a multi-institutional retrospective cohort study comparing outcomes (observed response rate, progression-free, and overall survival) between patients based on time from initiation of first line platinum-based chemotherapy to second line immune checkpoint inhibitor. This study provides preliminary data that earlier resistance to platinum-based chemotherapy may be associated with shorter survival in those who receive subsequent ICI. BACKGROUND: Early progression on first-line (1L) platinum-based therapy or between therapy lines may be a surrogate of more aggressive disease and poor outcomes in advanced urothelial carcinoma (aUC), but its prognostic role regarding immune checkpoint inhibitor (ICI) response and survival is unclear. We hypothesized that shorter time until start of second-line (2L) ICI would be associated with worse outcomes in aUC. PATIENTS AND METHODS: We performed a retrospective multi-institution cohort study in patients with aUC treated with 1L platinum-based chemotherapy, who received 2L ICI. Patients receiving switch maintenance ICI were excluded. We defined time to 2L ICI therapy as the time between the start of 1L platinum-based chemotherapy to the start of 2L ICI and categorized patients a priori into 1 of 3 groups: less than 3 months versus 3–6 months versus more than 6 months. We calculated overall response rate (ORR) with 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI. ORR was compared among the 3 groups using multivariable logistic regression, and PFS, OS using cox regression. Multivariable models were adjusted for known prognostic factors. RESULTS: We included 215, 215, and 219 patients in the ORR, PFS, and OS analyses, respectively, after exclusions. ORR difference did not reach statistical significance between patients with less than 3 months versus 3–6 months versus more than 6 months to 2L ICI. However, PFS (HR 1.64; 95% CI 1.02–2.63) and OS (HR 1.77; 95% CI 1.10–2.84) was shorter among those with time to 2L ICI less than 3 months compared to those who initiated 2L ICI more than 6 months. CONCLUSION: Among patients with aUC treated with 2L ICI, time to 2L ICI less than 3 months was associated with lower, but not significantly different ORR, but shorter PFS and OS compared to 2L ICI more than 6 months. This highlights potential cross resistance mechanisms between ICI and platinum-based chemotherapy.

The present study introduces a novel anatomic recession ratio (ARR) and evaluates the clinical outcomes of using a tunnel technique (TUN) with a connective tissue graft (CTG) for root coverage (RC). Sixteen systemically healthy patients contributing a total of 33 recession types 1 and 2 were treated with TUN + CTG. The predictive value of a panel of baseline clinical parameters (ARR) on RC was evaluated 12 months postoperatively. At 12 months, mean recession depth decreased from 2.74 +/- 0.22 mm to 0.46 +/- 0.13 mm (P < .0001); 19 sites (58%) showed complete RC, and the mean RC rate was 88.85% +/- 2.73%. The mean ARR value was 0.74 +/- 0.3, revealing a positive correlation with RC (r(2): 0.73, P < .0001). The 12-month esthetic evaluation resulted in a score of 8.52 +/- 1.75 using the root coverage esthetic score. TUN + CTG is effective in reducing recession depth and obtaining good esthetic outcomes. Within the limits of the present study, it may be suggested that ARR has potential as an analytical baseline parameter for RC outcomes with TUN + CTG.

IMPORTANCE Whether the severity and mortality of COVID-19 in patients with cancer have improved in terms of disease management and capacity is yet to be defined. OBJECTIVE To test whether severity and mortality from COVID-19 among patients with cancer have improved during the course of the pandemic. DESIGN, SETTING, AND PARTICIPANTS OnCovid is a European registry that collects data on consecutive patients with solid or hematologic cancer and COVID-19. This multicenter case series study included real-world data from 35 institutions across 6 countries (UK, Italy, Spain, France, Belgium, and Germany). This update included patients diagnosed between February 27, 2020, and February, 14, 2021. Inclusion criteria were confirmed diagnosis of SARS-CoV-2 infection and a history of solid or hematologic cancer. EXPOSURES SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES Deaths were differentiated at 14 days and 3 months as the 2 landmark end points. Patient characteristics and outcomes were compared by stratifying patients across 5 phases (February to March 2020, April to June 2020, July to September 2020, October to December 2020, and January to February 2021) and across 2 major outbreaks (February to June 2020 and July 2020 to February 2021). RESULTS At data cutoff, 2795 consecutive patients were included, with 2634 patients eligible for analysis (median [IQR] age, 68 [18-77] years ; 52.8% men). Eligible patients demonstrated significant time-dependent improvement in 14-day case-fatality rate (CFR) with estimates of 29.8% (95% CI, 0.26-0.33) for February to March 2020; 20.3% (95% CI, 0.17-0.23) for April to June 2020;12.5% (95% Cl, 0.06-22.90) for July to September 2020; 17.2% (95% CI, 0.15-0.21) for October to December 2020; and 14.5% (95% CI, 0.09-0.21) for January to February 2021(all P < .001) across the predefined phases. Compared with the second major outbreak, patients diagnosed in the first outbreak were more likely to be 65 years or older (974 of 1626 [60.3%] vs 564 of 1008 [56.1%]; P = .03), have at least 2 comorbidities (793 of 1626 [48.8%) vs 427 of 1008 [42.4%); P = .001), and have advanced tumors (708 of 1626 [46.4%) vs 536 of 1008 [56.1%]: P < .001). Complications of COVID-19 were more likely to be seen (738 of 1626 [45.4%) vs 342 of 1008 [33.9%]; P < .001) and require hospitalization (969 of 1626 [59.8%) vs 418 of 1008 [42.1%); P < .001) and anti-COVID-19 therapy (1004 of 1626 [61.7%) vs 501of 1008 [49.7%); P < .001) during the first major outbreak. The 14-day CFRs for the first and second major outbreaks were 25.6% (95% CI, 0.23-0.28) vs 16.2% (95% CI, 0.13-0.19; P < .001), respectively. After adjusting for country, sex, age, comorbidities, tumor stage and status, anti-COVID-19 and anticancer therapy, and COVID-19 complications, patients diagnosed in the first outbreak had an increased risk of death at 14 days (hazard ratio [HR], 1.85; 95% CI, 1.47-2.32) and 3 months (HR, 1.28; 95% CI, 1.08-1.51) compared with those diagnosed in the second outbreak. CONCLUSIONS AND RELEVANCE The findings of this registry-based study suggest that mortality in patients with cancer diagnosed with COVID-19 has improved in Europe; this improvement may be associated with earlier diagnosis, improved management, and dynamic changes in community transmission over time.

Background: The medium-term and long-term impact of COVID-19 in patients with cancer is not yet known. In this study, we aimed to describe the prevalence of COVID-19 sequelae and their impact on the survival of patients with cancer. We also aimed to describe patterns of resumption and modifications of systemic anti-cancer therapy following recovery from SARS-CoV-2 infection. Methods: OnCovid is an active European registry study enrolling consecutive patients aged 18 years or older with a history of solid or haematological malignancy and who had a diagnosis of RT-PCR confirmed SARS-CoV-2 infection. For this retrospective study, patients were enrolled from 35 institutions across Belgium, France, Germany, Italy, Spain, and the UK. Patients who were diagnosed with SARS-CoV-2 infection between Feb 27, 2020, and Feb 14, 2021, and entered into the registry at the point of data lock (March 1, 2021), were eligible for analysis. The present analysis was focused on COVID-19 survivors who underwent clinical reassessment at each participating institution. We documented prevalence of COVID-19 sequelae and described factors associated with their development and their association with post-COVID-19 survival, which was defined as the interval from post-COVID-19 reassessment to the patients’ death or last follow-up. We also evaluated resumption of systemic anti-cancer therapy in patients treated within 4 weeks of COVID-19 diagnosis. The OnCovid study is registered in ClinicalTrials.gov, NCT04393974. Findings: 2795 patients diagnosed with SARS-CoV-2 infection between Feb 27, 2020, and Feb 14, 2021, were entered into the study by the time of the data lock on March 1, 2021. After the exclusion of ineligible patients, the final study population consisted of 2634 patients. 1557 COVID-19 survivors underwent a formal clinical reassessment after a median of 22·1 months (IQR 8·4–57·8) from cancer diagnosis and 44 days (28–329) from COVID-19 diagnosis. 234 (15·0%) patients reported COVID-19 sequelae, including respiratory symptoms (116 [49·6%]) and residual fatigue (96 [41·0%]). Sequelae were more common in men (vs women; p=0·041), patients aged 65 years or older (vs other age groups; p=0·048), patients with two or more comorbidities (vs one or none; p=0·0006), and patients with a history of smoking (vs no smoking history; p=0·0004). Sequelae were associated with hospitalisation for COVID-19 (p

The present article describes a treatment planning clinical strategy based on a flowchart developed to facilitate the treatment of teeth with severely compromised clinical crowns. The study comprised a group of 978 patients presenting with 2327 teeth needing clinical crown reconstruction. The patients were screened, diagnosed, and treated with a multidisciplinary approach according to a flowchart structure. A subgroup of 75 teeth in 62 patients was considered irrational to treat when a composite risk-evaluation model was applied. Another subgroup of 168 teeth in 126 patients required periodontal surgery and received a minimally invasive crown lengthening (MICL) procedure. Endodontic treatment was necessary for 73 teeth, and retreatment for 51. Most of the teeth (124 in 94 patients) received a full crown, while the remaining 44 teeth received a direct (24 teeth) or an indirect (20 teeth) reconstruction. Six teeth were orthodontically extruded before surgery. The 1-year average probing depth and clinical attachment level at the treated teeth was 2.5 ± 0.5 mm and 2.7 ± 0.6 mm, respectively. Bleeding on probing was detected in 19 sites (11.3%). No side effects or short-term recurrences were detected in 168 treated sites. Patients described function and esthetics as extremely satisfactory, very satisfactory, or satisfactory. In conclusion, an accurate screening based on a flowchart supported the clinical decision to treat 168 teeth with MICL and to replace 75 out of 2327 teeth presented at our clinic for restorations. The use of MICL and the high-quality restorations resulted in a healthy periodontal and dental condition of all the treated teeth as well as patient satisfaction at the 1-year follow-up.

The predictive ability of metabolic conditions, such as hypercholesterolemia, on the outcome of cancer patients to immune-checkpoint inhibitors (ICIs) therapy, has been recently explored. The reasons for their value in this setting are to be searched in the individual himself more than in his tumor, as the target of the immune-checkpoint blockade is the immune system. The efficacy of ICIs on the tumor may be based on two simple premises: 1) the physiological immune function has been blocked, and 2) the tumor progression (mainly) depends on this block. The metabolic syndrome may represent the epiphenomenon of an “inflamed patient,” no longer able of physiological functions required to prevent chronic inflammatory events. The metabolic dysfunction could represent merely “a biomarker” of the patient who satisfies both the two premises reported above. Suggestions from preclinical and translational researches should be transferred in the clinical setting, implementing randomized clinical trials with observational endpoints such as the effect of concomitant drug medications and the impact of blood cholesterol levels and other metabolic conditions on the outcome of ICI treatment.

Background Immunotherapy has brought clinical benefits to patients with metastatic renal cell cancer (mRCC). Most patients tolerate immunotherapy but serious immune-related adverse events (irAEs) have been reported. Some studies indicate a correlation between irAEs and clinical response in other cancer types (eg, lung cancer and melanoma). For patients with mRCC, the impact of irAE on clinical outcome is unknown. Patients and Methods A retrospective review of 167 patients with mRCC treated with nivolumab as standard of care between March 2017 and January 2018 in 16 Italian centers was performed. irAEs were assessed using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. Results Any grade and grade 3/4 irAEs occurred in 46% and 8.9% of patients, respectively. The median time to appearance of irAEs was 10 weeks; 38.8% of patients required steroid treatment. The most common irAEs were cutaneous (33.7%) and gastrointestinal (23.3%). The median overall survival and progression-free survival were 20.13 and 7.86 months, respectively. Patients with irAEs showed a greater overall survival (hazard ratio, 0.38; 95% confidence interval [CI], 0.23-0.63) and progression-free survival (hazard ratio, 0.44; 95% CI, 0.29-0.66) benefit as well as better overall response rate (27.3% vs. 13.7%; odds ratio, 2.36; 95% CI, 1.03-5.44) and disease control rate (68.8% vs. 48%; odds ratio, 2.4; 95% CI, 1.23-4.67) if compared with those without irAEs. No correlation was found between steroid use and clinical outcomes. Conclusions Our analysis revealed that the appearance of irAEs was associated with better outcomes in patients treated with nivolumab. This data may be limited by sample size and the retrospective nature of the study.

Data on spectrum and grade of immune-related adverse events (irAEs) in long-term responders to immune checkpoint inhibitors (ICI) are lacking.We performed a retrospective multicenter study to characterized irAEs occurring after a 12-months minimum treatment period with PD-(L)1 ICIs in advanced cancer patients. IrAEs were categorized into “early” (≤12 months) and “late” (>12 months).From September 2013 to October 2019, 436 consecutive patients were evaluated. 223 experienced any grade early-irAEs (51.1%), while 132 experienced any grade late-irAEs (30.3%) (p < 0.0001). Among the latter, 29 (22%) experienced a recurrence of an early-irAEs, while 103 (78%) experienced de novo late-irAEs involving different system/organ. Among patients with late-irAEs, 21 experienced G3/G4 irAEs (4.8%). Median time to onset of early-irAEs was 3.4 months (95%CI: 2.8-4.2), while the median time to onset of late-irAEs was 16.6 months (95%CI: 15.8-17.6). Cumulative time-adjusted risk of disease progression according to both the early-irAEs (HR = 0.63 [95%CI: 0.30-1.29], p = 0.204) and late-irAEs occurrence revealed no statistically significant differences (HR = 0.75 [95%CI: 0.37-1.56], p = 0.452). Also the time-adjusted cumulative risk of death according to both early-irAEs (HR = 0.79 [95%CI: 0.34-1.86], p = 0.598) and late-irAEs (HR = 0.92 [95%CI: 0.49-1.74], p = 0.811) did not show statistically significant differences.Although less frequent than early-irAEs, late-irAEs are quite common in long responders to PD-(L)1 ICIs, and are different in terms of spectrum and grade. Time-adjusted analysis revealed that the cumulative risk of disease progression and death were not significantly reduced in patients who experienced late-irAEs.

Contains fulltext : 229846.pdf (Publisher’s version ) (Closed access) BACKGROUND: Early reports on patients with cancer and COVID-19 have suggested a high mortality rate compared with the general population. Patients with thoracic malignancies are thought to be particularly susceptible to COVID-19 given their older age, smoking habits, and pre-existing cardiopulmonary comorbidities, in addition to cancer treatments. We aimed to study the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with thoracic malignancies. METHODS: The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry is a multicentre observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria were the presence of any thoracic cancer (non-small-cell lung cancer [NSCLC], small-cell lung cancer, mesothelioma, thymic epithelial tumours, and other pulmonary neuroendocrine neoplasms) and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms. Patients of any age, sex, histology, or stage were considered eligible, including those in active treatment and clinical follow-up. Clinical data were extracted from medical records of consecutive patients from Jan 1, 2020, and will be collected until the end of pandemic declared by WHO. Data on demographics, oncological history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes were collected. Associations between demographic or clinical characteristics and outcomes were measured with odds ratios (ORs) with 95% CIs using univariable and multivariable logistic regression, with sex, age, smoking status, hypertension, and chronic obstructive pulmonary disease included in multivariable analysis. This is a preliminary analysis of the first 200 patients. The registry continues to accept new sites and patient data. FINDINGS: Between March 26 and April 12, 2020, 200 patients with COVID-19 and thoracic cancers from eight countries were identified and included in the TERAVOLT registry; median age was 68.0 years (61.8-75.0) and the majority had an Eastern Cooperative Oncology Group performance status of 0-1 (142 [72%] of 196 patients), were current or former smokers (159 [81%] of 196), had non-small-cell lung cancer (151 [76%] of 200), and were on therapy at the time of COVID-19 diagnosis (147 [74%] of 199), with 112 (57%) of 197 on first-line treatment. 152 (76%) patients were hospitalised and 66 (33%) died. 13 (10%) of 134 patients who met criteria for ICU admission were admitted to ICU; the remaining 121 were hospitalised, but were not admitted to ICU. Univariable analyses revealed that being older than 65 years (OR 1.88, 95% 1.00-3.62), being a current or former smoker (4.24, 1.70-12.95), receiving treatment with chemotherapy alone (2.54, 1.09-6.11), and the presence of any comorbidities (2.65, 1.09-7.46) were associated with increased risk of death. However, in multivariable analysis, only smoking history (OR 3.18, 95% CI 1.11-9.06) was associated with increased risk of death. INTERPRETATION: With an ongoing global pandemic of COVID-19, our data suggest high mortality and low admission to intensive care in patients with thoracic cancer. Whether mortality could be reduced with treatment in intensive care remains to be determined. With improved cancer therapeutic options, access to intensive care should be discussed in a multidisciplinary setting based on cancer specific mortality and patients' preference. FUNDING: None.

Prior publications on small subsets of cancer patients infected with SARS CoV-2 have shown an increased risk of mortality compared to the general population. Furthermore, patients with thoracic malignancies are thought to be at particularly high risk given their older age, smoking habits, and pre-existing cardio-pulmonary comorbidities. For this reason, physicians around the world have formed TERAVOLT, a global consortium dedicated to understanding the impact of COVID-19 on patients with thoracic malignancies.

Advanced age is associated with comorbidities and immune system impairment, which may influence the efficacy and tolerability of immune checkpoint inhibitors. There is evidence that anti-PD1 antibodies in advanced melanoma are equally effective in patients65 years. However, data on patients75 years are lacking as co-morbidities and logistics often exclude them from clinical trials.We retrospectively reviewed the clinical records of older patients with advanced melanoma undergoing any-line treatment with an anti-PD1 (nivolumab/pembrolizumab) to investigate its clinical effectiveness and toxicity in a real-life setting. Clinical response was assessed using RECIST criteria and toxicity was evaluated according to CTCAE 4.0. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and the Cox model was used to assess potential prognostic factors.174 patients were considered; 59.2% males, median age 79 years (range 75-93). The majority had a performance status of 0 and normal lactate dehydrogenase (LDH) levels (55.2% and 52.4%, respectively). 69.1% had multiple co-morbidities. 56.9% received nivolumab. 36.7% of cases showed an objective response and the disease control rate was 56.3%. Median OS was 17.2 months [95% CI: 8.87-not reached] and a better prognosis was observed for patients with normal LDH (p .001) and lower performance status (p .001). Treatment was well tolerated, only 11 patients experiencing severe (grade 3/4) toxicity. There were no treatment-related deaths. Adverse events were managed with corticosteroids and additional immunosuppressive agents were unnecessary.Anti-PD1 antibodies appear effective and well tolerated in older patients with advanced melanoma.

Several studies have found an association between higher body mass index (BMI) and improved clinical outcomes in cancer patients receiving programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors. In a previous study, we found that overweight/obese patients were significantly more likely to experience any grade immune-related adverse events (irAEs) compared to non-overweight patients.We conducted a 'real-life', multi centre, retrospective observational study aimed at comparing the incidence of irAEs among cancer patients treated with PD-1/PD-L1 inhibitors according to baseline BMI.One thousand and seventy advanced cancer patients were evaluated. The median age was 68 years (range: 21-92), male/female ratio was 724/346. Primary tumours were: non-small-cell lung carcinoma (NSCLC) (653 patients), melanoma (233 patients), renal cell carcinoma (RCC) (152 patients) and others (29 patients). Median BMI was 25 (13.6-46.6); according to World Health Organisation (WHO) classification, 44 patients (4.1%) were defined as underweight, 480 patients (44.9%) as having a normal weight, 416 patients (38.9%) as overweight and 130 patients (12.1%) as obese. Higher BMI was significantly related to higher occurrence of any grade immune-related adverse events [irAEs] (p 0.0001), G3/G4 irAEs (p 0.0001) and irAEs leading to discontinuation (LTD) (p 0.0001). Overweight and obesity were confirmed predictors for irAEs of any grade at both univariate and multivariate analysis. The adjusted odds ratios (ORs) (compared to normal-weight) were 10.6; 95% confidence interval (95%CI): 7.5-14.9 for overweight, and 16.6 (95%CI: 10.3-26.7) for obese patients. Obesity was the only factor significantly related to a higher incidence of G3/G4 irAEs (OR = 11.9 [95%CI: 6.4-22.3], p 0.0001) and LTD irAEs (OR = 8.8 [95%CI: 4.3-18.2], p 0.0001). Overweight and obese patients experienced a significantly higher occurrence of cutaneous, endocrine, gastro-intestinal (GI), hepatic and 'others' irAEs, compared to normal-weight patients. Only obese patients experienced a significantly higher occurrence of pulmonary and rheumatic irAEs, compared to normal-weight patients.Considering the previously evidenced association between higher BMI and better outcome, the current finding about the relationship between BMI and irAEs occurrence can contribute to consideration of these findings as the upside of the downside, which underlies an 'immunogenic phenotype'.

Background: efficacy outcomes and prognostic factors of real-world patients with advanced non-small cell lung cancer (aNSCLC) treated with first-line chemoimmunotherapy are still limited.Patients and methods: in the retrospective Spinnaker study, data was collected from patients in six United Kingdom and one Swiss oncology centres with first-line pembrolizumab plus platinum-based chemotherapy. Efficacy outcomes and potential prognostic factors were estimated aiming at developing a prognostic model.Results: three-hundred-eight patients were included, 32% ≥ 70 years, with ≥ 3 metastatic sites in 33%, brain or liver metastases in 10% and 12%, respectively. With a median follow-up of 18.0 months (mo.) (range, 15.9-20.1), median overall survival (OS) and progression-free survival (PFS) were 12.7 mo. (range, 10.2-15.2), and 8.0 mo. (range, 7.1-8.8), respectively. The neutrophils-to-lymphocytes ratio (NLR) and systemic immune-inflammatory index (SII) (i.e., NLR × platelet count) were both significantly higher in ECOG PS 1 (p = 0.0147 and p = 0.0018, respectively), underweight or normal body mass index (p = 0.0456 and p = 0.0062, respectively), ≥3 metastatic sites (p = 0.0069 and p = 0.112), pretreatment steroids (p = 0.0019 and p = 0.0017). By MVA, the number of metastatic sites ≥ 3 (p < 0.001 and p = 0.002), squamous histology (p = 0.033 and p = 0.013) and SII ≥ 1444 (p = 0.031 and p = 0.009, respectively) were associated with both worse OS and PFS and led to a highly discriminating three-class risk prognostic model.Conclusions: real-world PFS with chemoimmunotherapy in aNSCLC patients is similar to that reported in clinical trials. A high number of metastatic sites, squamous histology and high SII are adverse prognostic factors that might contribute to a clinically useful prognostic model.

We previously validated in European patients with NSCLC treated with programmed death-1 (PD-1) checkpoint inhibitors the cumulative detrimental effect of concomitant medications.We evaluated the prognostic ability of a "drug score" computed on the basis of baseline corticosteroids, proton pump inhibitors, and antibiotics, in an independent cohort of Japanese patients with advanced NSCLC treated with PD-1 monotherapy. Subsequently, we assessed the impact of baseline probiotics on the score's diagnostic ability and their interaction with antibiotics in influencing survival.Among the 293 eligible patients, good (19.5 months), intermediate (13.4 months), and poor (3.7 months) risk groups displayed a significantly different overall survival (OS) (log-rank test for trend: p = 0.016), but with a limited diagnostic ability (C-index: 0.57, 95%CI: 0.53-0.61), while no significant impact on progression-free survival (PFS) was reported (log-rank test for trend: p = 0.080; C-index: 0.55, 95%CI: 0.52-0.58). Considering the impact of the probiotics∗antibiotics interaction (p-value 0.0510) on OS, we implemented the drug score by assigning 0 points to concomitant antibiotics and probiotics. With the adapted drug score good, intermediate, and poor risk patients achieved a median OS of 19.6 months, 13.1 months, and 3.7 months, respectively, with a similar diagnostic ability (log-rank test for trend: p = 0.006; C-index: 0.58, 95%CI: 0.54-0.61). However, the diagnostic ability for PFS of the adapted score was improved (log-rank test for trend: p = 0.034; C-index: 0.62, 95%CI: 0.54-0.69).Although we failed to validate the drug score in this independent Japanese cohort, we showed that probiotics may have an antibiotic-dependent impact on its prognostic value. Further investigation looking at the effect of concomitant medications and probiotics across cohorts of different ethnicities is warranted.

Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS-mutant (KRASClinicopathologic and genomic information were collected from patients with NSCLCs harboring a KRAS mutation at the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and Imperial College of London. Multiplexed immunofluorescence for CK7, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Foxp3, and CD8 was carried out on a subset of samples with available tissue at the DFCI. Clinical outcomes to PD-(L)1 inhibition ± chemotherapy were analyzed according to KRAS mutation subtype.Of 2327 patients with KRAS-mutated (KRASKRAS

Although SARS-CoV-2 vaccines immunogenicity in patients with cancer has been investigated, whether they can significantly improve the severity of COVID-19 in this specific population is undefined.Capitalizing on OnCovid (NCT04393974) registry data we reported COVID-19 mortality and proxies of COVID-19 morbidity, including post-COVID-19 outcomes, according to the vaccination status of the included patients.2090 eligible patients diagnosed with COVID-19 between 02/2020 and 11/2021 were included, of whom 1930 (92.3%) unvaccinated, 91 (4.4%) fully vaccinated and 69 (3.3%) partially vaccinated. With the exception of a higher prevalence of patients from the UK (p = 0.0003) and receiving systemic anticancer therapy at COVID-19 diagnosis (p = 0.0082) among fully vaccinated patients, no demographics/oncological features were associated with vaccination status. The 14-days case fatality rate (CFR) (5.5% vs 20.7%, p = 0.0004) and the 28-days CFR (13.2% vs 27.4%, p = 0.0028) demonstrated a significant improvement for fully vaccinated patients in comparison with unvaccinated patients. The receipt of prior full vaccination was also associated with reduced symptomatic COVID-19 (79.1% vs 88.5%, p = 0.0070), need of COVID-19 oriented therapy (34.9% vs 63.2%, p 0.0001), complications from COVID-19 (28.6% vs 39.4%, p = 0.0379), hospitalizations due to COVID-19 (42.2% vs 52.5%, p = 0.0007) and oxygen therapy requirement (35.7% vs 52%, p = 0.0036). Following Inverse Probability Treatment Weighting (IPTW) procedure no statistically significant difference according to the vaccination status was confirmed; however, all COVID-19 related outcomes were concordantly in favour of full vaccination. Among the 1228 (58.8%) patients who underwent a formal reassessment at participating centres after COVID-19 resolution, fully vaccinated patients experienced less sequelae than unvaccinated patients (6.7% vs 17.2%, p = 0.0320).This analysis provides initial evidence in support of the beneficial effect of SARS-CoV-2 vaccines against morbidity and mortality from COVID-19 in patients with cancer.