The ABC of Immune-Mediated Hepatitis during Immunotherapy in Patients with Cancer: From Pathogenesis to Multidisciplinary Management.

Immune-mediated hepatotoxicity (IMH) is not-so-rare complication during treatment with immune checkpoint inhibitors (ICIs). This narrative review aims to report the current knowledge on hepatic immune-related adverse events (irAEs) during immunotherapy from pathogenesis to multidisciplinary management. The majority of cases of IMH are asymptomatic and only a few patients may have clinical conditions. The severity of IMH is usually stratified according to Common Terminology for Clinical Adverse Events (CTCAE) criteria, but these scores may overestimate the clinical severity of IMH compared to the Drug-Induced Liver Injury Network (DILIN) scale. The differential diagnosis of IMH is challenging because the elevated liver enzymes can be due to a number of etiologies such as viral infection, autoimmune and metabolic diseases, liver metastases, biliary diseases, and other drugs. The cornerstones of IMH management are represented by withholding or delaying ICI administration and starting immunosuppressive therapy. A multidisciplinary team, including oncologists, hepatologists, internists, and emergency medicine physicians, is essential for the management of IMH.

The Prognostic Role of Diagnostic Criteria for COVID-19-Associated Pulmonary Aspergillosis: A Cross-Sectional Retrospective Study.

Several criteria exist to diagnose pulmonary aspergillosis with varying degrees of certainty in specific populations, including oncohaematological patients (EORTC/MSG), ICU patients (mAspICU) and COVID-19 patients (ECMM). At the beginning of the pandemic, however, the diagnosis of COVID-19-Associated Pulmonary Aspergillosis (CAPA) could not be performed easily, and the decision to treat (DTT) was empirical. In this cross-sectional retrospective study including patients with SARS-CoV-2 infection and suspicion of CAPA, we studied the concordance between the DTT and the three diagnostic criteria using Cohen's coefficient, and then we identified the factors associated with the DTT and corrected them by treatment to study the influence of the diagnostic criteria on survival. We showed good concordance of the DTT and mAspICU and ECMM criteria, with "compatible signs", "positive culture" and "positive galactomannan" influencing the DTT. Treatment also showed a positive effect on survival once corrected for a putative, possible or probable diagnosis of CAPA using mAspICU and ECMM criteria. We conclude that EORTC/MSGERC are not considered applicable in clinical practice due to the lack of inclusion of signs and symptoms and do not lead to improved survival. mAspICU and ECMM criteria showed a good degree of agreement with the DTT and a positive correlation with patient recovery.

Impact of proton pump inhibitors on the onset of gastrointestinal immune-related adverse events during immunotherapy.

INTRODUCTION: The gut microbiota (GM) can influence the pathogenesis of immune-mediated adverse events (irAEs). Proton pump inhibitors (PPIs) can affect the integrity of GM, but their role in promoting irAEs is still poorly understood. METHODS: In this retrospective single-center cohort study, the primary endpoint was the evaluation of the incidence of gastrointestinal (GI) irAEs in cancer patients on PPIs (exposed) versus cancer patients who were not on PPIs (unexposed). RESULTS: Three hundred and sixty three patients' records (248 M/115F, median age 69) were reviewed. Twenty-three exposed patients (92%) developed GI irAEs while only two unexposed patients (8%) developed GI irAEs (hazard ratio [HR] 13.22, 95% confidence interval [CI] 3.11-56.10, p < 0.000). This HR was confirmed after weighting for the propensity score (HR15.13 95% CI 3.22-71.03, p < 0.000). CONCLUSION: Chronic PPI use is associated with an increased risk of GI irAES.

A territory-wide opportunistic, hospital-based HCV screening in the general population from northern Italy: The 1969-1989 birth-cohort.

BACKGROUND AND AIM: The World Health Organization (WHO) goal of Hepatitis C Virus (HCV) elimination by 2030 rose awareness about the need of screening plans, worldwide. In Italy, graduated screening starting from people born in 1969-1989 might be the most-effective strategy. We performed an opportunistic HCV screening study in the general population attending health facilities in Lombardy region, Northern Italy. METHODS: This is a prospective, multicenter, territory-wide, opportunistic study supported by the Regional Government of Lombardy, Italy. Between June 2022 and December 2022, all subjects born in 1969-1989, hospitalized or accessing blood collection centres were offered anti-HCV and HCV-RNA tests. Patients with known anti-HCV positivity and/or previous anti-HCV treatment were excluded. Demographic features were uploaded into a regional web-based platform. RESULTS: In total, 120 193 individuals were screened in 75 centres. Mean age was 44 (±6) years, 65.2% were females, 83.7% were tested at blood collection centres. Anti-HCV tested positive in 604 (0.50%) subjects: mean age 47 (±5), 51.1% females. HCV seroprevalence was higher in males (p < 0.00001), elderly (p < 0.00001) and in- vs. outpatients (p = 0.0009). HCV-RNA was detectable in 125 out of 441 (28.3%) anti-HCV positive subjects. Actively infected patients were 46 (±6) years old, mainly males (56.8%). The overall prevalence of active HCV infection was 0.10%, higher in elderly (p = 0.0003) and in in-patients (p = 0.0007). Among 93 HCV-RNA positive patients, the median age was 48 years, 58% males, 62% Italian born, median HCV-RNA levels were 6,1 log IU/mL, liver stiffness measurement (LSM) values 5.5 (3.1-29.9) kPa and ALT levels 48 U/L. CONCLUSIONS: The prevalence of active HCV infection in the 1969-1989 population attending health facilities in Lombardy was low. Most viremic patients were Italian-born, with mild liver disease but high-HCV-RNA levels. Due to the higher prevalence in the elderly, the extension of such opportunistic screening programs to lower birth cohorts would be warranted.

Gut Microbiota and B Cell Receptor (BCR) Inhibitors for the Treatment of Chronic Lymphocytic Leukemia: Is Biodiversity Correlated with Clinical Response or Immune-Related Adverse Event Occurrence? A Cross-Sectional Study.

Several studies have strengthened the link between the gut microbiota (GM) and the response to immunotherapy in patients with tumors, highlighting the potential role of GM as a biomarker of response. Targeted therapies including B-cell receptor (BCR) inhibitors (BCRi) represent the newest approach to the treatment of chronic lymphocytic leukemia (CLL); however, not all patients achieve a satisfactory response, and immune-related adverse events (irAEs) can also impact the efficacy. The aim of the study was to compare GM biodiversity in patients with CLL, treated with BCRi for at least 12 months. Twelve patients were enrolled: 10 patients in the responder group (R) and 2 patients in the non-responder group (NR). We identified seven patients (58.3%) who experienced adverse reactions (AE). Although we did not observe a significant difference across the study population in terms of relative abundance and alpha and beta diversity, we found a differing distribution of bacterial taxa between the analyzed groups. We noted a higher level of the class Bacteroidia and the order Bacteroidales in the R group, and an inversion in the Firmicutes and Bacteroidetes ratio in the AE group. No prior studies have focused on linking GM and response to BCRi in these patients. Although the analyses are preliminary, they provide suggestions to guide future research.

Dynamic NLR and PLR in Predicting COVID-19 Severity: A Retrospective Cohort Study.

INTRODUCTION: The hyperinflammation phase of severe SARS-CoV-2 is characterised by complete blood count alterations. In this context, the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) can be used as prognostic factors. We studied NLR and PLR trends at different timepoints and computed optimal cutoffs to predict four outcomes: use of continuous positive airways pressure (CPAP), intensive care unit (ICU) admission, invasive ventilation and death. METHODS: We retrospectively included all adult patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia admitted from 23 January 2020 to 18 May 2021. Analyses included non-parametric tests to study the ability of NLR and PLR to distinguish the patients' outcomes at each timepoint. Receiver operating characteristic (ROC) curves were built for NLR and PLR at each timepoint (minus discharge) to identify cutoffs to distinguish severe and non-severe disease. Their statistical significance was assessed with the chi-square test. Collection of data under the SMACORE database was approved with protocol number 20200046877. RESULTS: We included 2169 patients. NLR and PLR were higher in severe coronavirus disease 2019 (COVID-19). Both ratios were able to distinguish the outcomes at each timepoint. For NLR, the areas under the receiver operating characteristic curve (AUROC) ranged between 0.59 and 0.81, and for PLR between 0.53 and 0.67. From each ROC curve we computed an optimal cutoff value. CONCLUSION: NLR and PLR cutoffs are able to distinguish severity grades and mortality at different timepoints during the course of disease, and, as such, they allow a tailored approach. Future prospects include validating our cutoffs in a prospective cohort and comparing their performance against other COVID-19 scores.

Postvaccination immune-mediated hepatitis: what do we really know?

Tweetable abstract The percentage of patients with immune-mediated vaccine-associated hepatitis is minimal compared with the number of patients vaccinated worldwide.

Implementation of an antimicrobial stewardship program in the Vascular Surgery ward of a university tertiary care hospital in Pavia, Northern Italy.

PURPOSE: The commitment of multidisciplinary teams in antimicrobial stewardship programs (ASPs) is often inadequately considered, especially in surgical wards. We wanted to evaluate clinical, microbiological, and pharmacological outcomes before and after the implementation of an ASP in the Vascular Surgery ward of Fondazione IRCCS Policlinico San Matteo, a tertiary care hospital in Pavia, Italy. METHODS: This was a quasi-experimental quality-improvement study. The antimicrobial stewardship activity was conducted twice a week for 12 months and consisted of both prospective audit and feedback of all the ongoing antimicrobial prescriptions by the infectious diseases' consultants and educational meetings for the healthcare workers of the Vascular Surgery ward. For comparison between the study periods, Student t test (Mann-Whitney test for skewed distributions) was used for quantitative variables (ANOVA or Kruskall-Wallis for > 2 groups respectively), and Pearson's chi-squared test (Fisher exact test where appropriate) for categorical variables. 2-tailed tests were used. P-value significance cut-off was 0.05. RESULTS: During the 12-month intervention period, among a total number of 698 patients, 186 prescriptions were revised, mostly leading to de-escalating an ongoing antimicrobial therapy (39, 20.97%). A statistically significant reduction in isolates of carbapenem-resistant Pseudomonas aeruginosa (p-value 0.003) and the absence of Clostridioides difficile infections were reported. No statistically significant changes were observed in terms of length of stay and all-cause in-hospital mortality. A significant decrease in the administration of carbapenems (p-value 0.01), daptomycin (p-value < 0.01) and linezolid (p-value 0.43) was registered. A significant reduction in antimicrobial costs was also observed. CONCLUSIONS: The implementation of a 12-month ASP brought significant clinical and economic results, highlighting the benefits of a multidisciplinary teamwork.

Occult hepatitis B in patients with cancer during immunotherapy with or without chemotherapy: A real-life retrospective single-center cohort study.

Introduction: Few data about the safety of immune checkpoint inhibitors (ICIs) in the patients with solid tumor with Occult Hepatitis B Virus (OBI) are available. According to the Taormina Workshop on Occult HBV Infection Faculty Members we defined as potential-OBI (pOBI) the HBV DNA negativity with anti-hepatitis B core antibody (anti-HBc) positivity (pOBI seropositive), and the patients with HBsAg-negative and anti-HBc-negative and Hepatitis B surface antibody (anti-HBs)-negative are defined pOBI seronegative. The aim of this study is to investigate the prevalence of OBI in patients with solid tumors undergoing ICIs with or without chemotherapy and the incidence of reactivation (HBVr). Methods: We retrospectively enrolled all HBsAg negative subjects who had received ICIs for at least three months. HBsAg and HBV DNA levels were repeated every 3 months until the end of the study and/or in case of ALT alterations. A univariate analysis was conducted in order to study for each variable available its ability to distinguish a potential OBI seropositive patient from a seronegative one. Results: 150 patients in our Oncology Unit were eligible. One hundred and seventeen patients (78%) received ICI as monotherapy, whereas 33 patients (22%) were treated with chemo-immunotherapy. The mainly used drugs for the ICI monotherapy were Pembrolizumab (47%), Nivolumab (33%) and Atezolizumab (11%). The prevalence of pOBI seropositive patients was 25.3%. We did not observe alterations of liver biochemistry nor HBVr. Discussion: This study highlights that about a quarter of our population had a potential occult hepatitis B. Immunotherapy might be considered as low risk of reactivation, regardless of the potential presence of episomal covalently closed circular DNA (cccDNA) in the liver, but the correct management still represents a challenge for oncologists and hepatologists.

Long-COVID in Patients with Cancer Previously Treated with Early Anti-SARS-CoV-2 Therapies in an Out-of-Hospital Setting: A Single-Center Experience.

The incidence of long COVID in a cohort of patients with cancer with or without previous treatment with early therapies anti-SARS-CoV-2 in an out-of-hospital setting have to be elucidated. We prospectively enrolled all patients treated for a solid tumor at the department of Medical Oncology of the Fondazione IRCCS Policlinico San Matteo with a positive SARS-CoV-2 antigen or polymerase chain reaction test from January to September 2022 (Omicron surge). Ninety-seven patients answered the survey questions by telephone at least 12 weeks after COVID-19 diagnosis in order to evaluate the incidence of long COVID symptoms. Only twelve patients (12.4%) reported long COVID. No significant difference between early therapies anti-SARS-CoV-2 31 and long COVID (p = 0.443) was seen. The female sex (p = 0.024) and diabetes mellitus (p = 0.014) are significantly associated with long COVID. No statistically significant difference between the two groups (Long COVID vs. No Long COVID) according to the time to nasal swab viral clearance (p = 0.078). The overlap between the symptoms related to the oncological disease/oncological treatment and the symptoms of long COVID is one of the main future challenges that oncologists will have to manage.

Early detection of variants of concern via funnel plots of regional reproduction numbers.

Early detection of the emergence of a new variant of concern (VoC) is essential to develop strategies that contain epidemic outbreaks. For example, knowing in which region a VoC starts spreading enables prompt actions to circumscribe the geographical area where the new variant can spread, by containing it locally. This paper presents 'funnel plots' as a statistical process control method that, unlike tools whose purpose is to identify rises of the reproduction number ([Formula: see text]), detects when a regional [Formula: see text] departs from the national average and thus represents an anomaly. The name of the method refers to the funnel-like shape of the scatter plot that the data take on. Control limits with prescribed false alarm rate are derived from the observation that regional [Formula: see text]'s are normally distributed with variance inversely proportional to the number of infectious cases. The method is validated on public COVID-19 data demonstrating its efficacy in the early detection of SARS-CoV-2 variants in India, South Africa, England, and Italy, as well as of a malfunctioning episode of the diagnostic infrastructure in England, during which the Immensa lab in Wolverhampton gave 43,000 incorrect negative tests relative to South West and West Midlands territories.

The Bio-Diversity and the Role of Gut Microbiota in Postmenopausal Women with Luminal Breast Cancer Treated with Aromatase Inhibitors: An Observational Cohort Study.

The interactions between aromatase inhibitors (AI) in breast cancer (BC) and gut microbiota (GM) have not been completely established yet. The aim of the study is to evaluate the bio-diversity of GM and the relationship between GM, inflammation and tumor-infiltrating lymphocytes (TILs) in postmenopausal women with BC during adjuvant AI treatment compared to women with disease relapse during or after one year of AI therapy ("endocrine-resistant"). We conducted a monocenter observational case-control study. Eighty-four women with BC (8 cases, 76 controls) were enrolled from 2019 to 2021. We observed a significant difference in the mean microbial abundance between the two groups for the taxonomic rank of order (p 0.035) and family (p 0.029); specifically, the case group showed higher diversity than the control group. Veillonella reached its maximum abundance in cases (p 0.022). Cytokine levels were compared among the groups created considering the TILs levels. We obtained a statistically significant difference (p 0.045) in IL-17 levels among the groups, with patients with low TILs levels showing a higher median value for IL-17 (0.15 vs. 0.08 pg/mL). Further studies about the bio-diversity in women with BC may lead to the development of new biomarkers and targeted interventions.

Assessing the Efficacy of Early Therapies against SARS-CoV-2 in Hematological Patients: A Real-Life Study from a COVID-19 Referral Centre in Northern Italy.

Early therapies to prevent severe COVID-19 have an unclear impact on patients with hematological malignancies. The aim of this study was to assess their efficacy in this group of high-risk patients with COVID-19 in preventing hospitalizations and reducing the SARS-CoV-2 shedding. This was a single-center, retrospective, observational study conducted in the Fondazione IRCSS Policlinico San Matteo of Pavia, Northern Italy. We extracted the data of patients with hematologic malignancies and COVID-19 who received and did not receive early COVID-19 treatment between 23 December 2021, and May 2022. We used a Cox proportional hazard model to assess whether receiving any early treatment was associated with lower rates of hospitalization and reduced viral shedding. Data from 88 patients with hematologic malignancies were extracted. Among the patients, 55 (62%) received any early treatment, whereas 33 (38%) did not. Receiving any early therapy did not significantly reduce the hospitalization rate in patients with hematologic malignancies (HR 0.51; SE 0.63; p-value = 0.28), except in the vaccinated non-responders subgroup of patients with negative anti SARS-CoV-2 antibodies at the time of infection, who benefited from early therapies against SARS-CoV-2 (HR 0.07; SE 1.04; p-value = 0.001). Moreover, no difference on viral load decay was observed. In our cohort of patients with hematologic malignancies infected with SARS-CoV-2, early treatment were not effective in reducing the hospitalization rate due to COVID-19, neither in reducing its viral shedding.

Effectiveness of the available early therapies in reducing severe COVID-19 in non-hospitalized patients with solid tumors on active treatment.

Emergency use authorization of drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by regulatory authorities has provided new options to treat high-risk outpatients with mild-to-moderate Coronavirus disease 2019 (COVID-19). We conducted an ambispective cohort study of patients with solid tumors on active treatment to examine the effectiveness of these drugs in preventing the progression to severe COVID-19. Sixty-nine patients with solid tumors (43 women, 26 men; median age 61, range 26-80) reported a laboratory-confirmed diagnosis of SARS-CoV-2 infection. Forty-nine patients received early therapy. Only one patient (14.5%) required hospitalization for COVID-19. As for safety, two patients (5.9%) reported nausea during nirmatrelvir/ritonavir. The majority of treated patients showed a reduced time to negative sample (73 vs. 18%, p = 0.0011) and shorter symptoms' duration (94 vs. 27%; p < 0.0001) compared to the patients not treated with the early COVID-19 therapies. Our data suggest that early therapies may reduce the morbidity of COVID-19 in patients with solid tumors.

Despite Vaccination: A Real-Life Experience of Severe and Life-Threatening COVID-19 in Vaccinated and Unvaccinated Patients.

Some vaccinated individuals still develop severe COVID-19, and the underlying causes are not entirely understood. We aimed at identifying demographic, clinical, and coinfection characteristics of vaccinated patients who were hospitalized. We also hypothesized that coinfections might play a role in disease severity and mortality. We retrospectively collected data from our COVID-19 registry for whom vaccination data were available. Patients were split into groups based on the number of administered doses (zero, one, two, or three). Data were assessed with Chi-square and Kruskal−Wallis tests and multiple logistic regression analysis. We collected data from 1686 patients and found that intra-hospital mortality was not associated to the vaccination status (e.g., p = 0.2 with three doses), while older age, sepsis, and non-viral pneumonia were (p < 0.001). Unvaccinated patients needed mechanical ventilation more often (8.5%) than vaccinated patients, in whom the probability of mechanical ventilation decreased with increasing doses (8.7%, 2.8%, 0%). We did not find more coinfections in vaccinated people. We concluded that there is a lack of real-life data to adequately characterize the pathophysiology and risk factors of patients who develop severe COVID-19, but coinfections do not appear to play a role in disease severity.

Case report: Successful outcome of COVID-19 in the context of autologous hematopoietic stem cell transplantation: The impact of the anti-SARS-CoV-2 vaccine and early remdesivir.

Coronavirus disease (COVID-19) in patients undergoing hematopoietic stem cell transplantation (HSCT) is a major issue. None of the published papers have reported data on the outcome of HSCT patients with COVID-19 according to the vaccination status and the short course of remdesivir (RDV). Therefore, we present the case of a 22-year-old man with relapsed testicular non-seminomatous germ-cell tumor who was diagnosed with COVID-19 during his first auto-HSCT. Our case report is the first one describing the efficacy of early RDV (and its anti-inflammatory effects that might counterbalance the negative effect of the recombinant human granulocyte-colony stimulating factors -rhG-CSF-) in the context of severe neutropenia following HSCT with the concomitant onset of COVID-19.

Ventilator-Associated Pneumonia Due to MRSA vs. MSSA: What Should Guide Empiric Therapy?

The guidelines on ventilator-associated pneumonia (VAP) recommend an empiric therapy against methicillin-resistant Staphylococcus aureus (MRSA) according to its prevalence rate. Considering the MRSA and MSSA VAP prevalence over the last 9 years in our tertiary care hospital, we assessed the clinical value of the MRSA nasal-swab screening in either predicting or ruling out MRSA VAP. We extracted the data of 1461 patients with positive bronchoalveolar lavage (BAL). Regarding the MRSA nasal-swab screening, 170 patients were positive for MRSA or MSSA. Overall, MRSA had a high prevalence in our ICU. Despite the COVID-19 pandemic, there was a significant downward trend in MRSA prevalence, while MSSA remained steady over time. Having VAP due to MRSA did not have any impact on LOS and mortality. Finally, the MRSA nasal-swab testing demonstrated a very high negative predictive value for MRSA VAP. Our results suggested the potential value of a patient-centered approach to improve antibiotic stewardship.

The infection risk after transjugular intrahepatic portosystemic shunt: A multiple competing risk analysis from a tertiary care center.

BACKGROUND: Infections following transjugular intrahepatic portosystemic shunt (TIPS) placement have been poorly described. We aim to investigate the rate and the potential predictors of infections occurring after TIPS placement. METHODS: Single center, retrospective, observational study. All patients who had undergone TIPS placement in the last 10 years with a minimum 1-year FU, were considered. Multiple competing risk analyses were performed to identify infection risk factors and a multivariable Cox proportional-hazard regression model to evaluate the predictors of death. RESULTS: Forty-nine patients were considered. Among these, 23 (46%) developed at least 1 infection during the FU, at a median time of 237.7 days (IQR 151.5) from the TIPS placement. We did not find any predictor of infection, while MELD score and cancer were associated with death (p = .04; HR 1.14; CI 1.00- 1.30). CONCLUSION: We found a high rate of all-type infections during the FU times. However, most of these infections occurred as late-onset infections and were caused by Gram-positive microorganisms. Thus, TIPS procedure itself does not seem to be burdened with high infectious perioperative risk.