Background: The aim of the present study was to analyze the long-term outcomes of laparoscopic and open surgery for intrahepatic cholangiocarcinoma (iCCA) in a series, collected in a tertiary ...referral center with a high annual volume of laparoscopic activity. Methods: Between January 2004 and June 2020, 446 liver resections (LR) were performed for iCCA: of these, 179 were performed by laparoscopic surgery (LS) and 267 with the open approach. The two groups were matched through a 1:1 propensity score using covariates representative of patient and disease characteristics. The study and control groups were compared, with specific attention given to oncological outcomes (rate of R0, depth of resection margins, overall and disease-free survival, rate, and site of recurrence). Results: The number of retrieved nodes, rate, and depth of negative resection margins were comparable between the two groups. The interval time between surgery and subsequent adjuvant treatments was significantly shorter in LS patients. No differences were shown even in the comparison between the LS and the open group in terms of median disease-free and overall survival. Moreover, the disease recurrence rate was comparable between the LS and the open groups (45.2% versus 56.7%), and the recurrence pattern was similar. Conclusions: The minimally invasive approach for iCCA was once again confirmed to be associated with advantages in terms of intraoperative and short-term outcomes, but was also proven to be oncologically non-inferior to the open counterpart. In the present study, overall and disease-free survival were found to be similar between the two approaches.
Purpose: Among liver hypertrophy technics, liver venous deprivation (LVD) has been recently introduced as an effective procedure to combine simultaneous portal inflow and hepatic outflow abrogation, ...raising growing clinical interest. The aim of this study is to investigate the role of LVD for preoperative optimization of future liver remnant (FLR) in perihilar cholangiocarcinoma (PHC), especially when compared with portal vein embolization (PVE). Methods: Between January 2013 and July 2022, all patients diagnosed with PHC and scheduled for preoperative optimization of FTR, through radiological hypertrophy techniques, prior to liver resection, were included. FTR volumetric assessment was evaluated at two distinct timepoints to track the progression of both early (T1, 10 days post-procedural) and late (T2, 21 days post-procedural) efficacy indicators. Post-procedural outcomes, including functional and volumetric analyses, were compared between the LVD and the PVE cohorts. Results: A total of 12 patients underwent LVD while 19 underwent PVE. No significant differences in either post-procedural or post-operative complications were found. Post-procedural FLR function, calculated with (99m) Tc-Mebrofenin hepatobiliary scintigraphy, and kinetic growth rate, at both timepoints, were greater in the LVD cohort (3.12 ± 0.55%/min/m2 vs. 2.46 ± 0.64%/min/m2, p = 0.041; 27.32 ± 16.86%/week (T1) vs. 15.71 ± 9.82%/week (T1) p < 0.001; 17.19 ± 9.88%/week (T2) vs. 9.89 ± 14.62%/week (T2) p = 0.034) when compared with the PVE cohort. Post-procedural FTR volumes were similar for both hypertrophy techniques. Conclusions: LVD is an effective procedure to effectively optimize FLR before liver resection for PHC. The faster growth rate combined with the improved FLR function, when compared to PVE alone, could maximize surgical outcomes by lowering post-hepatectomy liver failure rates.
Neuroendocrine carcinomas of the cervix are very rare, accounting for only 1–2% of all cervical cancers and <1% of all neuroendocrine tumors. Small-cell carcinoma of the cervix is associated with ...poor prognosis, even in early stages. Despite their neuroendocrine origin, tumors presenting with syndromes due to secreted neuroendocrine hormones are extremely rare. To date, only seven cases of cervical small-cell carcinoma associated with Cushing’s syndrome due to ectopic ACTH secretion have been described. In most reports, Cushing’s syndrome associated with these tumors occurred only in association with liver or lung metastasis. Only one single case of primary uterine cervix carcinoma secreting enough ACTH to induce Cushing’s syndrome in the absence of metastatic disease has been described in 1994. Here, we describe a case of cervical small-cell carcinoma presenting with an acute onset of severe hypokalemia in Cushing’s syndrome without metastatic disease to distant organs.
Purpose To evaluate the long-term results of cheekbone augmentation using porous hydroxyapatite granules mixed with microfibrillar collagen in a large group of patients. Materials and Methods Four ...hundred thirty patients who underwent zygomatic augmentation and intermaxillary osteotomy were evaluated clinically, radiologically, and histologically. Results Complications were found in 13 patients (1.56%). There were no relevant radiologic differences in prosthesis volume after 1 month (T1) or after 24 months (T2) in any patient; there were no clinically relevant differences in 110 patients after 36 months. At T1, the prosthesis had a granular structure and the granules had not migrated; at T2, the prosthesis was staunchly adhering to the underlying bone. Over time, the radiopacity of the material increased. Histologic results of 19 biopsy specimens obtained from 8 patients 2 years after the procedure showed prominent ossification with low inflammation, confirming new bone formation over time. According to the visual analog scale, the patients were generally satisfied with the aspects that were considered. Conclusion Hydroxyapatite and collagen composite used during malarplasty produced a successful outcome. Its main drawback is a learning curve that is longer than for more frequently used implantable biomaterials.
Treatment of hepatocellular carcinoma (HCC) is rapidly evolving, with many new therapeutic options; in particular, immunotherapy (IT) is acquiring a major role, even in combination regimens. Despite ...these promising results, an important limitation is the lack of prognostic and predictive factors that prevent provision of a tool for patient stratification in order to select the most appropriate strategy. Furthermore, response assessment can be challenging with IT due to peculiar patterns such as mixed responses or pseudoprogression. We analyzed biological and clinical features from the first 10 HCC patients treated with nivolumab in our institution. Analysis of patterns of response in CT assessment revealed complete response in pulmonary lesions, along with heterogeneous behavior in the liver and other organ lesions. Peripheral blood mononuclear cells (PBMC) analysis in the first four patients showed unique alterations in a patient with poor prognosis, both at baseline (lower percentage of effector T cells, higher percentage of natural killer T NK/T cells) and during treatment with nivolumab (decrease in nonclassical monocytes, increase in monocytic myeloid-derived suppressor cells MO-MDSC), suggesting a possible prognostic role for these features. Although obtained in a small cohort of patients, our results open a new perspective for understanding mechanisms underlying IT outcomes in HCC patients.
BackgroundAdoptive transfer of CAR T cells demonstrated impressive results against B-cell malignancies, but still limited efficacy against solid tumors. In this context, multiple challenges need to ...be overcome, including poor tumor recognition and strong immunosuppression within the tumor microenvironment (TME). Our Unit has recently reported that pharmacological inhibition of N-glycan synthesis in cancer cells increases CAR T cell efficacy by improving tumor recognition and preventing T cell exhaustion. In this project, we investigated the role of N-glycosylation blockade on TME cells in the context of colorectal cancer (CRC) and pancreatic adenocarcinoma (PDAC)-derived liver metastases and CEA-specific CAR T cell therapy.MethodsTo understand the effect of N-glycosylation blockade on TME cells (both M2-macrophages, M2-M and Hepatic stellate cells, HepSCs), we analyzed the phenotypic and transcriptional profile and we performed in vitro functional assays, such as tripartite co-cultures, suppressive assays and released-cytokines analysis. Moreover, to evaluate the effect of N-glycosylation inhibition on TME cells in vivo, we exploited immunodeficient mice reconstituted with a human immune system (huSGM3), engrafted intra-hepatically with tumor cells and treated with CEA CAR T cells.ResultsIn vitro studies revealed that N-glycosylation inhibition abolishes the ability of both TME cells to restrain T cell proliferation and increases the elimination of cancer cell lines and patient-derived tumor organoids (PDOs from CRC-liver metastases). Interestingly, these effects were associated with profound phenotypic and transcriptional changes in M2-M and HepSCs. In particular, the treatment was able to inhibit M2-polarization in terms of surface markers expression, IL-10 secretion and gene expression profile, and was shown to hinder the activation of HepSCs and inhibit the PD- 1/PDL-1 axis. Interestingly, in the in vivo model, the presence of human immune cells supports CAR T cell responses and helps recreate an immune TME more representative of the human disease. Importantly, using these mice we observed that N-glycosylation inhibition increases CEA CAR T cell antitumor activity, in terms of survival, and this is associated with the downregulation of immunosuppressive genes in tumor-infiltrating human immune cells.ConclusionsOverall, these data suggest that blocking N-glycosylation can help overcome multiple barriers that currently limit CAR T cell efficacy in solid tumors, acting not only on tumor cells, but also on immunosuppressive tumor microenvironment cells.
Obesity is characterized by the accumulation of T cells in insulin-sensitive tissues, including the visceral adipose tissue (VAT), that can interfere with the insulin signaling pathway eventually ...leading to insulin resistance (IR) and type 2 diabetes. Here, we found that PD-1+CD4 conventional T (Tconv) cells, endowed with a transcriptomic and functional profile of partially dysfunctional cells, are diminished in VAT of obese patients with dysglycemia (OB-Dys), without a concomitant increase in apoptosis. These cells showed enhanced capacity to recirculate into the bloodstream and had a non-restricted TCRβ repertoire divergent from that of normoglycemic obese and lean individuals. PD-1+CD4 Tconv were reduced in the circulation of OB-Dys, exhibited an altered migration potential, and were detected in the liver of patients with non-alcoholic steatohepatitis. The findings suggest a potential role for partially dysfunctional PD-1+CD4 Tconv cells as inter-organ mediators of IR in obese patients with dysglycemic.
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•Dysglycemic obesity associates with reduced partially dysfunctional PD-1+CD4 Tconv in VAT•Dysglycemia induces alterations in the TCRβ repertoire of CD4 Tconv cells in obese VAT•Dysglycemia prompts an increased recirculation of PD-1+CD4 Tconv cells to the bloodstream•PD-1+CD4 Tconv cells accumulate in the liver of patients with dysglycemic
Health sciences; Obesity medicine
Abstract Background and study aims Besides increasing adequacy, rapid on-site evaluation (ROSE) during endoscopic ultrasound (EUS) or endoscopic retrograde cholangiopancreatography (ERCP) may impact ...choices and timing of subsequent therapeutic procedures, yet has been unexplored. Patients and methods This was a retrospective evaluation of a prospectively maintained database of a tertiary, academic centre with availability of ROSE and hybrid EUS-ERCP suites. All consecutive patients referred for pathological confirmation of suspected malignancy and jaundice or gastric outlet obstruction (GOO) between Jan-2020 and Sep-2022 were included. Results Of 541 patients with underlying malignancy, 323 (59.7%) required same-session pathological diagnosis (male: 54.8%; age 70 interquartile range 63–78; pancreatic cancer: 76.8%, biliary tract adenocarcinoma 16.1%). ROSE adequacy was 96.6%, higher for EUS versus ERCP. Among 302 patients with jaundice, ERCP-guided stenting was successful in 83.1%, but final drainage was completed in 97.4% thanks to 43 EUS-guided biliary drainage procedures. Twenty-one patients with GOO were treated with 15 EUS-gastroenterostomies and six duodenal stents. All 58 therapeutic EUS procedures occurred after adequate ROSE. With ERCP-guided placement of stents, the use of plastic stents was significantly higher among patients with inadequate ROSE (10/11; 90.9%) versus adequate sampling (14/240; 5.8%) P <0.0001; OR 161; 95%CI 19–1352). Median hospital stay for diagnosis and palliation was 3 days (range, 2–7) and median time to chemotherapy was 33 days (range, 24–47). Conclusions Nearly two-thirds of oncological candidates for endoscopic palliation require contemporary pathological diagnosis. ROSE adequacy allows, since the index procedure, state-of-the-art therapeutics standardly restricted to pathologically confirmed malignancies (e.g. uncovered SEMS or therapeutic EUS), potentially reducing hospitalization and time to oncological treatments.
18FFluorodeoxyglucose (18F-FDG) PET/CT is increasingly used to assess organ involvement and response to treatment in IgG4-related disease (IgG4-RD), but clear correlations between 18F-FDG uptake and ...disease activity have not been established yet. We aimed to correlate the intensity and distribution of 18F-FDG uptake with validated clinical, serological and immunological parameters of IgG4-RD activity.
Twenty patients with active IgG4-RD underwent a baseline 18F-FDG PET/CT. Ten patients repeated 18F-FDG PET/CT after immunosuppressive treatments. 18F-FDG tissue uptake was measured using the standardized uptake value corrected for the partial volume effect (PVC-SUV) and the total lesion glycolysis (TLG) with (TLGtot+ln) and without (TLGtot-ln) lymph nodes. Disease activity was assessed by means of clinical parameters IgG4-RD Responder Index (RI), serological (ESR and CRP) and immunological (serum IgG4 and circulating plasmablasts) biomarkers. The enhanced liver fibrosis score was exploited as a biomarker for fibroblast activation.
Thirteen (65%) patients had two or more organs affected by IgG4-RD. All patients had active IgG4-RD as defined by a median IgG4-RD RI value of 9 (range 6-15; normal < 3). Serum IgG4 and plasmablasts were elevated in 85% of patients. Circulating plasmablasts positively correlated with PVC-SUV (P = 0.027), inversely correlated with TLGtot-ln (P = 0.023) and did not correlate with TLGtot+ln (P > 0.05). No statistically significant correlation was found between PVC-SUV or TLG and IgG4-RD RI, ESR, CRP, serum IgG4 or enhanced liver fibrosis score (P > 0.05). Clinical response to immunosuppressive therapies was associated with a consensual reduction of circulating plasmablasts, PVC-SUV, TLGtot+ln and TLGtot-ln values (P < 0.05 for all comparisons).
18F-FDG uptake of IgG4-RD lesions reflects immunological perturbations of the B cell compartment rather than fibroblast activation and extracellular matrix deposition. Conventional biomarkers of disease activity, namely IgG4-RD RI, ESR, CRP and serum IgG4 levels, do not appear to correlate with the radiometabolic activity of IgG4-RD lesions. In light of our results PET/CT represents a reliable instrument for assessing IgG4-RD activity, although lymph-node uptake deserves careful interpretation.
AbstractSystemic symptoms such as fever and fatigue are non-specific manifestations spanning from inflammation to neoplasia. Here we report the case of a 34 year-old man who presented with systemic ...symptoms for four months. CT-scan and MRI revealed a 3.4 cm arterialized hepatic lesion and a 7 cm paraduodenal mass. Surgical resection of both lesions and histological examination revealed an inflammatory hepatocellular adenoma and a unicentric plasma cell type of Castleman disease. Moreover, a diffuse AA amyloid deposition in the liver was observed. Resection of both lesions was associated with an improvement of the symptoms. To our knowledge, this is the first report of a synchronous presentation of a unicentric plasma cell type of Castleman disease, inflammatory hepatocellular adenoma and AA amyloidosis.
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