Gastrointestinal Toxicity of Antibody Drug Conjugates (ADCs) in Metastatic Breast Cancer: A Pooled Analysis.

Trastuzumab emtansine (T-DM1), sacituzumab govitecan (SG), and trastuzumab deruxtecan (T-DXd) are three ADCs approved for the treatment of metastatic breast cancer (MBC). Since gastrointestinal toxicities have been commonly observed with these drugs in clinical trials, a pooled analysis evaluating gastrointestinal adverse events (AEs) in patients with MBC treated with ADCs in clinical trials was performed. PubMed, Embase, and the Cochrane Library were searched from inception until May 2023 for phase II and III clinical trials reporting frequency and severity of gastrointestinal AEs during treatment with ADCs. Data were retrieved for nausea, vomiting, diarrhea, constipation, and abdominal pain: overall and grade 3-4 toxicity rates according to NCI-CTCAE were collected and expressed as proportions. A pre-specified subgroup analysis according to the agent was also carried out. Fourteen studies, comprising 5608 patients, were included in the analysis. Gastrointestinal AEs were frequently registered with SG and T-DXd. A significantly higher frequency of nausea (65.6% with SG, 75% with T-DXd), vomiting (43.7% with SG, 45% with T-DXd), and diarrhea (59.7% with SG, 29% with T-DXd) was noticed with these ADCs compared to TDM-1. Furthermore, diarrhea was more frequently associated with SG (grade 3 in 7.5% of patients), while constipation and abdominal pain were less common. Gastrointestinal AEs, notably nausea and diarrhea, were frequently reported by MBC patients treated with SG and T-DXd in clinical trials. Since these ADCs are administered continuously until disease progression or occurrence of unbearable AEs, gastrointestinal toxicity may have a negative impact on patient quality of life. Therefore, appropriate management of gastrointestinal AEs is mandatory to ensure treatment efficacy and adherence.

Is weight gain preventable in women with early breast cancer undergoing chemotherapy? A real-world study on dietary pattern, physical activity, and body weight before and after chemotherapy.

PURPOSE: We aimed to investigate the role of a lifestyle intervention and clinical and therapeutic factors for preventing weight gain in early breast cancer (BC) patients from one week before to 12 months after chemotherapy. METHODS: Dietary assessments were conducted by a trained dietician using a food-frequency questionnaire at each clinical assessment. Total energy, macronutrients intakes, and physical activity were estimated and the Mediterranean Diet Score (MDS) for adherence to Mediterranean diet was calculated. At each follow-up visit, patients were provided with dietary advices according to Mediterranean and Italian guidelines by a registered dietician, after evaluation of their food records. The associations of clinical characteristics, dietary pattern, and physical activity with weight gain were evaluated by multiple logistic regression, with weight gain ≥5% from baseline value as a dichotomous dependent variable. RESULTS: 169 early BC patients who met all follow-up visits and provided complete data were included in the analysis. From baseline to last assessment, weight loss (≥5% decrease from baseline value), stable weight, and weight gain were observed in 23.1%, 58%, and 18.9% women, respectively. Overall, a 0.68 kg mean decrease in women's weight (-1.1% from baseline) was observed. The risk of gaining weight increased for having normal weight/underweight at baseline, receiving hormone therapy, MDS worsening, and physical activity decreasing from baseline to last assessment. CONCLUSION: Providing simple suggestions on Mediterranean diet principles was effective for preventing weight gain in normal weight women and favoring weight loss in overweight and obese women.

Does hypointense HCC in the Hepatobiliary Phase at Gadoxetate-Enhanced MRI Predict Recurrence After Surgery? A Systematic Review and Meta-analysis.

RATIONALE AND OBJECTIVES: The aim of the current study was to investigate whether hypointense hepatocellular carcinoma (HCC) in the hepatobiliary phase (HBP) on gadoxetic acid-enhanced MRI at pretreatment is a potential prognostic marker for tumor recurrence within 3 years after surgery conducted for a curative purpose (resection or liver transplantation). MATERIALS AND METHODS: Systematic review was performed in the PubMed, Embase, Cochrane Library, and LILACS databases. Original articles focused on evaluating HCC signal intensity (SI) in HBP, as well as recurrence at least 3 years after surgery were included in the study. Odds ratio (OR) was measured based on the inverse variance method and the random-effects model. The Quality in Prognosis Studies (QUIPS) tool was used to assess the quality of the included articles. RESULTS: Five studies with 718 patients, in total, were analyzed. The odds ratio of disease recurrence in patients with hypointense HCC in the HBP, within 3 years after surgery, was 3.12 times higher than that observed in patients with hyperintense HCC in the HBP (OR 3.12; 95% CI 1.27-7.68; p = 0.01). Heterogeneity was classified as intermediate (I2 = 52%). Articles included in the review overall presented a low risk of bias. CONCLUSION: Hypointense HCC in the HBP on gadoxetic acid-enhanced MRI at pretreatment has increased the likelihood of tumor recurrence in patients subjected to resection or liver transplantation. HCC SI in the HBP is a potential non-invasive imaging biomarker associated with patient prognosis.

The Cecum Revisited: A Multimodality Imaging Case-based Review of Common and Uncommon Cecal Diseases.

A wide range of conditions involving the cecum may be found in patients undergoing imaging work-up for conditions as various as right lower pain, diarrhea, fever, and weight loss. The cecum may be the only area of involvement by a particular disease. However, it may also be affected by a more diffuse process of the gastrointestinal tract or even as part of systemic diseases. Imaging provides an excellent evaluation of the cecal region and its surrounding planes, with an impactful clinical application in multiple scenarios. While typical features in many situations allow establishing a confident diagnosis, there are also challenging entities with overlapping features, making it critical for the radiologist awareness of the whole gamut of these conditions, as well as the ability to correlate imaging findings with other clinical data. Additional challenges to the imaging evaluation include anatomical variations of the cecal position and the absence of proper colonic distention in some cases. This article aims to revisit the spectrum of cross-sectional imaging features of common and uncommon pathologies involving the cecum, ranging from inflammatory and infectious to vascular and neoplastic ones.

The Ductal Plate From the Inside Out: An Illustrated Review of Fibropolycystic Liver Disease.

Fibropolycystic liver disease is a continuum of disorders that result from insults to the ductal plate at different stages of development and are often associated with each other. Caroli's syndrome, polycystic liver disease, biliary hamartomas, and congenital hepatic fibrosis are included in this complex spectrum that also shows frequent association with renal anomalies, such as polycystic kidney disease and medullary sponge kidney. Choledochal cysts are a controversial point in this topic since they have long been considered part of this spectrum due to morphological similarities, but studies have shown different pathogenesis. This article's purpose is to review these abnormalities through a multimodality radiological perspective offering correlation with its key embryological aspects. Knowing these numerous anomalies and their possible associations may ease an accurate diagnosis and prompt management.

SARS-CoV-2 Infection of Airway Epithelium Triggers Pulmonary Endothelial Cell Activation and Senescence Associated with Type I IFN Production.

Airway epithelial cells represent the main target of SARS-CoV-2 replication but several pieces of evidence suggest that endothelial cells (ECs), lining pulmonary blood vessels, are key players in lung injury in COVID-19 patients. Although in vivo evidence of SARS-CoV-2 affecting the vascular endothelium exists, in vitro data are limited. In the present study, we set up an organotypic model to dissect the crosstalk between airway epithelium and pulmonary endothelial cells during SARS-CoV-2 infection. We showed that SARS-CoV-2 infected airway epithelium triggers the induction of endothelial adhesion molecules in ECs, suggesting a bystander effect of dangerous soluble signals from the infected epithelium. The endothelial activation was correlated with inflammatory cytokines (IL-1ß, IL-6, IL-8) and with the viral replication in the airway epithelium. Interestingly, SARS-CoV-2 infection determined a modulation of endothelial p21, which could be partially reversed by inhibiting IFN-ß production from ECs when co-cultured with HAE. Altogether, we demonstrated that SARS-CoV-2 infected epithelium triggers activation/senescence processes in ECs involving type I IFN-ß production, suggesting possible antiviral/damage mechanisms occurring in the endothelium.

Safety and immune response kinetics of GRAd-COV2 vaccine: phase 1 clinical trial results.

Despite the successful deployment of efficacious vaccines and therapeutics, the development of novel vaccines for SARS-CoV-2 remains a major goal to increase vaccine doses availability and accessibility for lower income setting. We report here on the kinetics of Spike-specific humoral and T-cell response in young and old volunteers over 6 months follow-up after a single intramuscular administration of GRAd-COV2, a gorilla adenoviral vector-based vaccine candidate currently in phase-2 of clinical development. At all three tested vaccine dosages, Spike binding and neutralizing antibodies were induced and substantially maintained up to 3 months, to then contract at 6 months. Potent T-cell responses were readily induced and sustained throughout the study period, with only minor decline. No major differences in immune response to GRAd-COV2 vaccination were observed in the two age cohorts. In light of its favorable safety and immunogenicity, GRAd-COV2 is a valuable candidate for further clinical development and potential addition to the COVID-19 vaccine toolbox to help fighting SARS-CoV-2 pandemic.

Detection of recombinant breakpoint in the genome of human enterovirus E11 strain associated with a fatal nosocomial outbreak.

BACKGROUND: The aim of this study was to characterize the genome of a recombinant Enterovirus associated with severe and fatal nosocomial infection; it was typed as Echovirus 11 (E-11) according to the VP1 gene. Enterovirus infection is generally asymptomatic and self-limited, but occasionally it may progress to a more severe clinical manifestation, as in the case described here. Recombination plays a crucial role in the evolution of Enteroviruses (EVs) and has been recognized as the main driving force behind the emergence of epidemic strains associated with severe infection. Therefore, it is of utmost importance to monitor the circulation of recombinant strains for surveillance purposes. METHODS: Enterovirus-RNA was detected in the serum and liver biopsy of patients involved in the nosocomial cluster by commercial One-Step qRT-PCR method and the Enterovirus strains were isolated in vitro. The EVs typing was determined by analyzing the partial-length of the 5'UTR and VP1 sequences with the web-based open-access Enterovirus Genotyping Tool Version 0.1. The amplicons targeting 5'UTR, VP1 and overlapping fragments of the entire genome were sequenced with the Sanger method. Phylogenetic analysis was performed comparing the VP1 and the full-genome sequences of our strains against an appropriate reference set of Enterovirus prototypes of the Picornaviridae genera and species retrieved from the Enterovirus Genotyping Tool. Recombination analysis was performed using RDP4 software. RESULTS: The Neighbor-Joining tree of the VP1 gene revealed that the 4 patients were infected with an identical molecular variant of Echovirus 11 (E-11). While the phylogenetic and the RDP4 analysis of the full-genome sequences provided evidence that it was a chimeric strain between an E-11 and a Coxsackievirus B (CV-B). CONCLUSIONS: The chimeric structure of the E-11 genome might have contributed to the severe infection and epidemic feature of the strain, but further biological characterizations are needed. The evidence reported in this study, highlights the limit of typing techniques based on the VP1 gene, as they fail to identify the emergence of recombinant strains with potentially more pathogenic or epidemic properties, thus providing only partial information on the epidemiology and pathogenesis of Enteroviruses.

Vaginal cancer: Why should we care? Anatomy, staging and in-depth imaging-based review of vaginal malignancies focusing on MRI and PET/CT.

Vaginal cancer often poses a challenge for clinical and radiological diagnosis, and its risk factors, progression, and treatment are still poorly established. Although vaginal malignancies are rare, even globally, their rates have increased due to the increased access to healthcare and the evolution of screening measures and diagnostic methods. Because the vaginal cavity is a virtual space, it can harbor lesions that often go unnoticed and, not infrequently, diagnosed belatedly. MRI and, more recently, PET/CT are part of the imaging armamentarium that have already been incorporated into the clinical staging and management of gynecological tumors, allowing excellent morphological characterization of the lesion, its topography and relationship with adjacent structures for the investigation of disease dissemination, overcoming limitations of clinical methods, such as speculum examination, usually restricted to observation only of the superficial characteristics of these lesions. Some vaginal neoplasms have characteristic MRI patterns, which, combined with expert knowledge of anatomy, allow identification of local macroscopic details (such as the mucosal, submucosal, and muscle layers). Furthermore, the application of PET/CT, already well established for identifying systemic disease, has a large impact on patient prognosis. The objective of this work is to review the epidemiological aspects of primary vaginal cancers and the imaging patterns of their main histological subtypes based on MRI and PET/CT, with a brief discussion of the local anatomy, oncological staging, and treatment.

Reproducibility of MRI Features of Uterine Leiomyomas: A Study on Interobserver Agreement and Inter-Method Agreement With Surgery.

PURPOSE: To evaluate interobserver agreement in the interpretation of different MRI features of uterine leiomyomas (UL) according to observers' experience, and to assess the inter-method reproducibility (MRI versus surgery) regarding the International Federation of Gynecology and Obstetrics (FIGO) classification. METHODS: Retrospective study including UL patients who underwent MRI and surgical treatment. Four blinded observers (2 vs >10 years of experience) assessed UL regarding dimensions and volume; inner and outer mantles; FIGO classification; vascularization; degeneration; and diffusion-weighted imaging features. Uterine dimensions and volume were calculated. FIGO classification as ascertained by observers was compared to surgical findings. Intraclass correlation coefficient (ICC) estimates were used for interobserver comparison of numerical variables, and kappa statistic for categorical variables. RESULTS: Thirty-five patients (26y-73y) with 61 UL were included in the interobserver analyses, and 31 patients (54 UL) had available data allowing retrospective surgical FIGO classification for assessment of inter-method reproducibility. Both groups of observers had good to excellent agreement in assessing UL (ICC = 0.980-0.994) and uterine volumes (ICC = 0.857-0.914), mantles measurement (ICC = 0.797-0.920), and apparent diffusion coefficient calculation (ICC = 0.787-0.883). There was substantial agreement for both groups regarding FIGO classification (κ = 0.645-0.767). Vascularization, degeneration and restricted diffusion had lower agreement, varying from reasonable to moderate. Inter-method agreement was reasonable (κ = 0.341-0.395). CONCLUSIONS: Interobserver agreement of MRI for UL was higher for quantitative than qualitative features, with a little impact of observers' experience for most features. MRI agreement with surgery was reasonable. Further efforts should be taken to improve interobserver and inter-method reproducibility for MRI in this scenario.

GRAd-COV2, a gorilla adenovirus-based candidate vaccine against COVID-19, is safe and immunogenic in younger and older adults.

Safe and effective vaccines against coronavirus disease 2019 (COVID-19) are essential for ending the ongoing pandemic. Although impressive progress has been made with several COVID-19 vaccines already approved, it is clear that those developed so far cannot meet the global vaccine demand alone. We describe a COVID-19 vaccine based on a replication-defective gorilla adenovirus expressing the stabilized prefusion severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein named GRAd-COV2. We assessed the safety and immunogenicity of a single-dose regimen of this vaccine in healthy younger and older adults to select the appropriate dose for each age group. For this purpose, a phase 1, dose-escalation, open-labeled trial was conducted including 90 healthy participants (45 aged 18 to 55 years old and 45 aged 65 to 85 years old) who received a single intramuscular administration of GRAd-COV2 at three escalating doses. Local and systemic adverse reactions were mostly mild or moderate and of short duration, and no serious adverse events were reported. Four weeks after vaccination, seroconversion to spike protein and receptor binding domain was achieved in 43 of 44 young volunteers and in 45 of 45 older participants. Consistently, neutralizing antibodies were detected in 42 of 44 younger-age and 45 of 45 older-age volunteers. In addition, GRAd-COV2 induced a robust and T helper 1 cell (TH1)­skewed T cell response against the spike protein in 89 of 90 participants from both age groups. Overall, the safety and immunogenicity data from the phase 1 trial support the further development of this vaccine.

T-cell immune response after mRNA SARS-CoV-2 vaccines is frequently detected also in the absence of seroconversion in patients with lymphoid malignancies.

Patients affected by lymphoid malignancies (LM) are frequently immune-compromised, suffering increased mortality from COVID-19. This prospective study evaluated serological and T-cell responses after complete mRNA vaccination in 263 patients affected by chronic lymphocytic leukaemia, B- and T-cell lymphomas and multiple myeloma. Results were compared with those of 167 healthy subjects matched for age and sex. Overall, patient seroconversion rate was 64·6%: serological response was lower in those receiving anti-cancer treatments in the 12 months before vaccination: 55% vs 81·9% (P < 0·001). Anti-CD20 antibody plus chemotherapy treatment was associated with the lowest seroconversion rate: 17·6% vs. 71·2% (P < 0·001). In the multivariate analysis conducted in the subgroup of patients on active treatment, independent predictors for seroconversion were: anti-CD20 treatment (P < 0·001), aggressive B-cell lymphoma diagnosis (P = 0·002), and immunoglobulin M levels <40 mg/dl (P = 0·030). The T-cell response was evaluated in 99 patients and detected in 85 of them (86%). Of note, 74% of seronegative patients had a T-cell response, but both cellular and humoral responses were absent in 13·1% of cases. Our findings raise some concerns about the protection that patients with LM, particularly those receiving anti-CD20 antibodies, may gain from vaccination. These patients should strictly maintain all the protective measures.

Predicting respiratory failure in patients infected by SARS-CoV-2 by admission sex-specific biomarkers.

BACKGROUND: Several biomarkers have been identified to predict the outcome of COVID-19 severity, but few data are available regarding sex differences in their predictive role. Aim of this study was to identify sex-specific biomarkers of severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19. METHODS: Plasma levels of sex hormones (testosterone and 17ß-estradiol), sex-hormone dependent circulating molecules (ACE2 and Angiotensin1-7) and other known biomarkers for COVID-19 severity were measured in male and female COVID-19 patients at admission to hospital. The association of plasma biomarker levels with ARDS severity at admission and with the occurrence of respiratory deterioration during hospitalization was analysed in aggregated and sex disaggregated form. RESULTS: Our data show that some biomarkers could be predictive both for males and female patients and others only for one sex. Angiotensin1-7 plasma levels and neutrophil count predicted the outcome of ARDS only in females, whereas testosterone plasma levels and lymphocytes counts only in males. CONCLUSIONS: Sex is a biological variable affecting the choice of the correct biomarker that might predict worsening of COVID-19 to severe respiratory failure. The definition of sex specific biomarkers can be useful to alert patients to be safely discharged versus those who need respiratory monitoring.

Neuropathology and Inflammatory Cell Characterization in 10 Autoptic COVID-19 Brains.

COVID-19 presents with a wide range of clinical neurological manifestations. It has been recognized that SARS-CoV-2 infection affects both the central and peripheral nervous system, leading to smell and taste disturbances; acute ischemic and hemorrhagic cerebrovascular disease; encephalopathies and seizures; and causes most surviving patients to have long lasting neurological symptoms. Despite this, typical neuropathological features associated with the infection have still not been identified. Studies of post-mortem examinations of the cerebral cortex are obtained with difficulty due to laboratory safety concerns. In addition, they represent cases with different neurological symptoms, age or comorbidities, thus a larger number of brain autoptic data from multiple institutions would be crucial. Histopathological findings described here are aimed to increase the current knowledge on neuropathology of COVID-19 patients. We report post-mortem neuropathological findings of ten COVID-19 patients. A wide range of neuropathological lesions were seen. The cerebral cortex of all patients showed vascular changes, hyperemia of the meninges and perivascular inflammation in the cerebral parenchyma with hypoxic neuronal injury. Perivascular lymphocytic inflammation of predominantly CD8-positive T cells mixed with CD68-positive macrophages, targeting the disrupted vascular wall in the cerebral cortex, cerebellum and pons were seen. Our findings support recent reports highlighting a role of microvascular injury in COVID-19 neurological manifestations.

COVID-19 Vaccination in Fragile Patients: Current Evidence and an Harmonized Transdisease Trial.

Patients diagnosed with malignancy, neurological and immunological disorders, i.e., fragile patients, have been excluded from COVID-19 vaccine trials. However, this population may present immune response abnormalities, and relative reduced vaccine responsiveness. Here we review the limited current evidence on the immune responses to vaccination of patients with different underlying diseases. To address open questions we present the VAX4FRAIL study aimed at assessing immune responses to vaccination in a large transdisease cohort of patients with cancer, neurological and rheumatological diseases.

Influence of 5-Alpha Reductase Inhibitors on Prostate Cancer Detection with Magnetic Resonance Imaging: A Matched Cohort Study.

PURPOSE: We evaluated the influence of 5-alpha reductase inhibitors (5-ARIs) on the performance of magnetic resonance imaging (MRI) for detection of Gleason grade group (GG) ≥2 prostate cancer, and on apparent diffusion coefficient (ADC) maps. MATERIALS AND METHODS: This single center, retrospective study included men who had MRI for initial detection or active surveillance of prostate cancer. The study group included 59 men who used for 5-ARIs for ≥12 months, and the control group included 59 men who were matched for both MRI indication and biopsy results. DeLong's test was used to compare the area under the receiver operating characteristic curve (AUC) for detection of GG ≥2 cancer between the groups. Wilcoxon rank sum test was used for comparison of lesions apparent diffusion coefficient (ADC) metrics between the groups. RESULTS: MRI accuracy in the study group (AUC=0.778) was not significantly different compared to the control group (AUC=0.821; 95% CI for difference 0.22-0.13; p=0.636). In the control group, all ADC metrics were lower in lesions with GG ≥2 cancer on biopsy than in those with GG 1 cancer or negative results (p=0.001-0.01). In the study group, this difference was significant only when the mean ADC of the lesions was normalized by the ADC of urine (p=0.044). CONCLUSIONS: Long-term exposure to 5-ARIs does not seem to impair the detection of significant cancer on MRI but may affect the ability of ADC metrics to discriminate between lesions that harbor significant cancer and those that harbor insignificant cancer or benign tissue.

Prolonged SARS-CoV-2 RNA virus shedding and lymphopenia are hallmarks of COVID-19 in cancer patients with poor prognosis.

Patients with cancer are at higher risk of severe coronavirus infectious disease 2019 (COVID-19), but the mechanisms underlying virus-host interactions during cancer therapies remain elusive. When comparing nasopharyngeal swabs from cancer and noncancer patients for RT-qPCR cycle thresholds measuring acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 1063 patients (58% with cancer), we found that malignant disease favors the magnitude and duration of viral RNA shedding concomitant with prolonged serum elevations of type 1 IFN that anticorrelated with anti-RBD IgG antibodies. Cancer patients with a prolonged SARS-CoV-2 RNA detection exhibited the typical immunopathology of severe COVID-19 at the early phase of infection including circulation of immature neutrophils, depletion of nonconventional monocytes, and a general lymphopenia that, however, was accompanied by a rise in plasmablasts, activated follicular T-helper cells, and non-naive Granzyme B+FasL+, EomeshighTCF-1high, PD-1+CD8+ Tc1 cells. Virus-induced lymphopenia worsened cancer-associated lymphocyte loss, and low lymphocyte counts correlated with chronic SARS-CoV-2 RNA shedding, COVID-19 severity, and a higher risk of cancer-related death in the first and second surge of the pandemic. Lymphocyte loss correlated with significant changes in metabolites from the polyamine and biliary salt pathways as well as increased blood DNA from Enterobacteriaceae and Micrococcaceae gut family members in long-term viral carriers. We surmise that cancer therapies may exacerbate the paradoxical association between lymphopenia and COVID-19-related immunopathology, and that the prevention of COVID-19-induced lymphocyte loss may reduce cancer-associated death.