Primary Resistance to Immunotherapy-Based Regimens in First Line Hepatocellular Carcinoma: Perspectives on Jumping the Hurdle

Simple Summary Immune checkpoint inhibitors (ICIs) had been explored extensively in patients affected by unresectable hepatocellular carcinoma. These agents were expected to be the keystones of the disease's first-line treatment because they were theoretically able to revert the immune suppressive tumor microenvironment of the cancerous liver, and because of their manageable safety profile. However, when used as monotherapies, they showed important activity and efficacy limitations. In this mini-review, we summarize the characteristics of the different ICIs-based regimens which constitute the present gold standard of first-line treatment, then, moving from their shortcomings, we discuss the rationale supporting the strategies currently under investigation: systemic triplets and new paradigms of immune-therapeutic agents such as CAR-T and vaccines. Immune checkpoint inhibitors (ICIs) are a key component of different stages of hepatocellular carcinoma (HCC) treatment, particularly in the first line of treatment. A lesson on the primary resistance which hampers their efficacy and activity was learned from the failure of the trials which tested them as first-line mono-therapies. Despite the combination of anti-PD(L)1 agents with anti-VEGF, anti CTLA4, or TKIs demonstrating relevant improvements in efficacy, the "doublets strategy" still shows room for improvement, due to a limited overall survival benefit and a high rate of progressive disease as best response. In this review, we discuss the results from the currently tested doublet strategies (i.e., atezolizumab+bevacizumab, durvalumab+tremelimumab with a mention to the newly presented ICIs/TKIs combinations), which highlight the need for therapeutic improvement. Furthermore, we examine the rationale and provide an overview of the ongoing trials testing the treatment intensification strategy with triplet drugs: anti-PD1+anti-CTLA4+anti-VEGF/TKIs and anti-PD1+anti-VEGF+alternative immunity targets. Lastly, we report on the alternative strategy to integrate ICIs into the new paradigm of immune therapeutics constituted by CAR-T and anti-cancer vaccines. This review provides up-to-date knowledge of ongoing clinical trials of the aforementioned strategies and critical insight into their mechanistic premises

Circulating hematopoietic stem cells and putative intestinal stem cells in coeliac disease

Background: The intestinal stem cells (ISC) modulation and the role of circulating hematopoietic stem cells (HSC) in coeliac disease (CD) are poorly understood. Our aim was to investigate the longitudinal modifications in peripheral blood HSC traffic and putative ISC density induced by gluten-free diet (GFD) in CD. Methods: Thirty-one CD patients and 7 controls were enrolled. Circulating CD133+ and CD34+ HSC were measured by flow cytometry, at enrolment and after 7 days and 1, 3, 6, 12, and 24 months of GFD. Endoscopy was performed at diagnosis and repeated at 6, 12, and 24 months following GFD. We used the Marsh-Oberhuber score to evaluate the histological severity of duodenal damage; immunohistochemistry was employed to measure the intraepithelial lymphoid infiltrate (IEL, CD3+ lymphoid cells) and the putative ISC compartment (CD133+ and Lgr5+ epithelial cells). Results: At enrolment, circulating HSCs were significantly increased in CD patients and they further augmented during the first week of GFD, but progressively decreased afterwards. CD patients presented with villous atrophy, abundant IEL and rare ISC residing at the crypt base. Upon GFD, IEL progressively decreased, while ISC density increased, peaking at 12 months. After 24 months of GFD, all patients were asymptomatic and their duodenal mucosa was macroscopically and histologically normal. Conclusions: In active CD patients, the ISC niche is depleted and there is an increased traffic of circulating HSC versus non-coeliac subjects. GFD induces a precocious mobilization of circulating HSC, which is followed by the expansion of the local ISC compartment, leading to mucosal healing and clinical remission

Percutaneous real-time sonoelastography as a non-invasive tool for the characterization of solid focal liver lesions: A prospective study

Real-time sonoelastography is currently used for the characterization of superficial solid lesions such as thyroid and breast masses. This study evaluates the usefulness of percutaneous sonoelastography for the characterization of solid focal liver lesions

Suggestive Seizure Induction technique in a pediatric PNES population related to neurocognitive and psychological profile: a pilot study.

Objective: To investigate seizures induction techniques response in a pediatric population affected by psychogenic non epileptic seizures (PNES) and the relationship between neurocognitive and psychological profiles. Methods: We recruited patients referred to our Unit who received a diagnosis of clinically established PNES in the last year. Enrolled patients underwent video-EEG recording that included a seizures induction standardized protocol:bitemporal compression, verbal suggestion, diapason stimulation,saline buffer,hyperpnea and intermittent light stimulation (ILS).Patients also carried out neuropsychiatric evaluation. Results: The sample consisted of 12 patients (9 females and 3 males) aged between 12 and 17 years old (mean 15.08).Seizure phenotype was mostly generalized tonic-clonic seizures with loss of consciousness (7/12 patients, 58,3%).7 patients (GROUP A, 58.3%) presented seizures during induction tests and seizures were inducted by two techniques in three of them. In particular,bitemporal compression activated seizures in a patient (8.3%),verbal suggestion in 4 patients(33,3%),saline buffer in 5 patients (41,6%), ILS in 2 patients.Patients who did not present seizures (GROUP B, 41,7%) during the test reported somatic complaints in each technique (headache, paresthesias, visual impairment, chest pain). Neuropsychological tests showed a mild intellectual disability in one patient (8,3%), borderline intellectual functioning in two patients (16,6%) and 4 patients (33,3%) received diagnosis of Learning Disorder.Regarding cognitive profiles, GROUP A had a mean IQ of 85 (versus a mean of 94 in GROUP B) and lower verbal comprehension index compared to perceptual reasoning index (mean VCI=90 vs mean PRI=102,28).Psychopatological evaluation showed higher scores in the Dissociation Questionnaire in GROUP A compared to GROUP B. Conclusions: Results showed a possible role of lower verbal ability and a higher dissociation proneness in young PNES patients who respond to suggestion techniques

Percutaneous real-time sonoelastography as a non-invasive tool for the characterization of solid focal liver lesions: A prospective study

Background: Real-time sonoelastography is currently used for the characterization of superficial solid lesions such as thyroid and breast masses. This study evaluates the usefulness of percutaneous sonoelastography for the characterization of solid focal liver lesions. Methods: 30 out of 43 patients with 38 known liver lesions were included in a prospective, diagnostic study. Qualitative analysis (pattern of deformation, elasticity type of liver tumour) and semi-quantitative measurements (strain ratio, hardness percentage, histogram) were evaluated. Sensitivity, specificity, positive and negative predictive values were calculated and the area under the receiver operating characteristics curve was constructed. Results: Patterns A and C-D are specific of benign lesions and metastases respectively. The patterns for haemangiomas, focal nodular hyperplasia and metastases were significantly different to each other in terms of strain ratio, hardness percentage and histogram (p < 0.05). A statistically significant difference (p < 0.001) was observed between the median values of the 3 measured parameters for benign (1.02; 12%; 47) and malignant lesions (1.66; 65%; 20.5) respectively. The area under the receiver operating characteristics curve values for strain ratio, hardness percentage and histogram were 0.88, 0.89, and 0.86 respectively for cut-off values of 1.2, 45, and 30. Conclusions: By percutaneous sonoelastography it is possible to differentiate benign versus malignant focal liver lesions, metastases in particular, with good diagnostic performance

Rationale and clinical benefits of an intensive long-term pulmonary rehabilitation program after oesophagectomy: preliminary report

Abstract Patients who undergo oesophagectomy for oesophagealcancer (OC) usually have an overall poor prognosis and, still more preoccupying, an unsatisfactory quality of life (QoL). Considering that, as already noted, post-operative pulmonary function has a strong correlation with the long-term outcome and QoL after surgery, we have assumed and speculated on the clinical benefits of an intensive long-term pulmonary post-operative rehabilitation program in this particular subset of patients. Herein, we report the preliminary results of a comparative retrospective analysis in a series of 58 patients who underwent radical oesophagectomy and post-operative chest physical therapy (CPT) under two different protocols, from October 2006 to January 2011. Finally, we discuss on the time-trend analysis of pulmonary function and the potential role of post-operative pulmonary rehabilitation.</p