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Indocyanine green (ICG) fluorescence imaging is an easy and reproducible method to detect hepatic lesions, both primary and metastatic. This review reports the potential benefits of this technique as a tactile mimicking visual tool and a navigator guide in minimally invasive liver resection of colorectal liver metastases (CRLM). PubMed and MEDLINE databases were searched for studies reporting the use of intravenous injection of ICG before minimally invasive surgery for CLRM. The search was performed for publications reported from the first study in 2014 to April 2021. The final review included 13 articles: 6 prospective cohort studies, 1 retrospective cohort study, 3 case series, 1 case report, 1 case-matched study, and 1 clinical trial registry. The administered dose ranged between 0.3 and 0.5 mg/kg, while timing ranged between 1 and 14 days before surgery. CRLM detection rate ranged between 30.3% and 100% with preoperative imaging (abdominal computed tomography/magnetic resonance imaging), between 93.3 and 100% with laparoscopic ultrasound, between 57.6% and 100% with ICG fluorescence, and was 100% with combined modalities (ICG and laparoscopic ultrasound) with weighted averages of 77.42%, 95.97%, 79.03%, and 100%, respectively. ICG fusion imaging also allowed to detect occult small-sized lesions, not diagnosed preoperatively. In addition, ICG is effective in real-time assessment of surgical margins by evaluating the integrity of the fluorescent rim around the CRLM.

PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Regulatory T (Treg) cells are a barrier for tumor immunity and a target for immunotherapy. Using single-cell transcriptomics, we found that CD4+ T cells infiltrating primary and metastatic colorectal cancer and non-small-cell lung cancer are highly enriched for two subsets of comparable size and suppressor function comprising forkhead box protein P3+ Treg and eomesodermin homolog (EOMES)+ type 1 regulatory T (Tr1)-like cells also expressing granzyme K and chitinase-3-like protein 2. EOMES+ Tr1-like cells, but not Treg cells, were clonally related to effector T cells and were clonally expanded in primary and metastatic tumors, which is consistent with their proliferation and differentiation in situ. Using chitinase-3-like protein 2 as a subset signature, we found that the EOMES+ Tr1-like subset correlates with disease progression but is also associated with response to programmed cell death protein 1–targeted immunotherapy. Collectively, these findings highlight the heterogeneity of Treg cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy. Human primary and metastatic tumors harbor CD4+ Treg cells that can suppress antitumor immune responses. Bonnal et al. identify an intratumoral type 1 Treg-like CD4+ T cell subset that expresses the transcription factor EOMES, granzyme K and CHI3L2. This EOMES+ T cell subset correlates with disease progression but is responsive to PD-1 checkpoint blockade immunotherapy.

Background: Indocyanine green (ICG) fluorescence imaging has been extensively used in a variety of applications in visceral surgery. In minimally invasive liver resections, the detection of small s...

Microinvasion (MI), defined as infiltration of the portal or hepatic vein or bile duct and intrahepatic metastasis are accurate indicators of a poor prognosis for mall hepatocellular carcinomas (HCC). A previous study showed that intraoperative ultrasound (IOUS) definition of MI-HCC had a high concordance with histological findings. Aim of this study is to evaluate overall survival and recurrence patterns of patients with MI-HCC submitted to hepatic resection (HR) or laparoscopic ablation therapies (LAT). A total of 171 consecutive patients (78 h; 93 LAT) with single, small HCC (

Background This study compared patients undergoing colorectal cancer surgery in 20 hospitals of northern Italy in 2019 versus 2020, in order to evaluate whether COVID-19-related delays of colorectal cancer screening resulted in more advanced cancers at diagnosis and worse clinical outcomes. Method This was a retrospective multicentre cohort analysis of patients undergoing colorectal cancer surgery in March to December 2019 versus March to December 2020. Independent predictors of disease stage (oncological stage, associated symptoms, clinical T4 stage, metastasis) and outcome (surgical complications, palliative surgery, 30-day death) were evaluated using logistic regression. Results The sample consisted of 1755 patients operated in 2019, and 1481 in 2020 (both mean age 69.6 years). The proportion of cancers with symptoms, clinical T4 stage, liver and lung metastases in 2019 and 2020 were respectively: 80.8 versus 84.5 per cent; 6.2 versus 8.7 per cent; 10.2 versus 10.3 per cent; and 3.0 versus 4.4 per cent. The proportions of surgical complications, palliative surgery and death in 2019 and 2020 were, respectively: 34.4 versus 31.9 per cent; 5.0 versus 7.5 per cent; and 1.7 versus 2.4 per cent. Cancers in 2020 (versus 2019) were more likely to be symptomatic (odds ratio 1.36 (95 per cent c.i. 1.09 to 1.69)), clinical T4 stage (odds ratio 1.38 (95 per cent c.i. 1.03 to 1.85)) and have multiple liver metastases (odds ratio 2.21 (95 per cent c.i. 1.24 to 3.94)), but were not more likely to be associated with surgical complications (odds ratio 0.79 (95 per cent c.i. 0.68 to 0.93)). Conclusion Colorectal cancer patients who had surgery between March and December 2020 had an increased risk of advanced disease in terms of associated symptoms, cancer location, clinical T4 stage and number of liver metastases.

BACKGROUND Genomic alterations and dysregulation of RAF are the main oncogenic driver in almost all pediatric low-grade gliomas (pLGGs). About 50%‒60% of pLGGs harbor KIAA1549-BRAF fusion and 5%‒15% BRAF V600E mutation. No targeted therapy has received regulatory approval for either relapsed or newly diagnosed pLGG to date. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II panRAF inhibitor. The registrational, phase 2 FIREFLY-1 (NCT04775485) study with tovorafenib in pediatric patients with recurrent/progressive LGG is currently ongoing. METHODS LOGGIC/FIREFLY-2 (EudraCT 2022-001363-27) is a registrational, randomized, multicenter, global (~100 sites across Australia, Canada, Egypt, Europe, New Zealand, Singapore, South Korea, Taiwan, and USA), phase 3 trial evaluating the efficacy, safety, and tolerability of tovorafenib vs. standard of care (SoC) chemotherapy in patients < 25 years old with LGG harboring a RAF-alteration and requiring first-line systemic therapy. Approximately 400 patients will be randomized 1:1 to receive oral tovorafenib, 420 mg/m2 ( ≤ 600 mg) weekly (tablet or liquid suspension for 26, 28-day cycles), or an investigator’s choice of SoC chemotherapy: COG-V/C regimen (60 weeks), SIOPe-LGG-V/C (81 weeks) regimen, or single-agent vinblastine (70 weeks). After completing 26 cycles tovorafenib, patients may continue tovorafenib or opt to enter a drug holiday at any point. Patients who progress in the SoC arm may receive tovorafenib. Patients who progress after stopping tovorafenib may be re-challenged. Primary endpoint is ORR based on RANO criteria, as determined by an independent radiology committee. Key secondary endpoints are progression-free survival and duration of response per RANO criteria, and ORR per RAPNO criteria. Other secondary endpoints include changes in neurological and visual function, and safety and tolerability. Exploratory objectives include quality of life and health utilization measures, molecular biomarker evaluation for treatment response and resistance, efficacy of tovorafenib after progression on chemotherapy and retreatment upon progression during drug holiday.

Background: Natural killer (NK) cells play a key role in immune surveillance and response to tumors, their function regulated by NK cell receptors and their ligands. The DNAM-1 activating receptor recognizes the CD155 molecule expressed in several tumor cells, such as hepatocellular carcinoma (HCC). This study aims to investigate the role of the DNAM-1/CD155 axis in mediating the NK cell response in patients with HCC. Methods: Soluble CD155 was measured by ELISA. CD155 expression was sought in HCC cells by immunohistochemistry, qPCR, and flow cytometry. DNAM-1 modulation in NK cells was evaluated in transwell experiments and by a siRNA-mediated knockdown. NK cell functions were examined by direct DNAM-1 triggering. Results: sCD155 was increased in sera from HCC patients and correlated with the parameters of an advanced disease. The expression of CD155 in HCC showed a positive trend toward better overall survival. DNAM-1 downmodulation was induced by CD155-expressing HCC cells, in agreement with lower DNAM-1 expressions in tumor-infiltrating NK (NK-TIL) cells. DNAM-1-mediated cytotoxicity was defective both in circulating NK cells and in NK-TIL of HCC patients. Conclusions: We provide evidence of alterations in the DNAM-1/CD155 axis in HCC, suggesting a possible mechanism of tumor resistance to innate immune surveillance.

Background Bevacizumab is increasingly used in children with pediatric low-grade glioma (PLGG) despite limited evidence. A nationwide UK service evaluation was conducted to provide larger cohort “real life” safety and efficacy data including functional visual outcomes. Methods Children receiving bevacizumab-based treatments (BBT) for PLGG (2009–2020) from 11 centers were included. Standardized neuro-radiological (RANO-LGG) and visual (logMAR visual acuity) criteria were used to assess clinical–radiological correlation, survival outcomes and multivariate prognostic analysis. Results Eighty-eight children with PLGG received BBT either as 3rd line with irinotecan (85%) or alongside 1st/2nd line chemotherapies (15%). Toxicity was limited and minimal. Partial response (PR, 40%), stable disease (SD, 49%), and progressive disease (PD, 11%) were seen during BBT. However, 65% progressed at 8 months (median) from BBT cessation, leading to a radiology-based 3 yr-progression-free survival (PFS) of 29%. Diencephalic syndrome (P = .03) was associated with adverse PFS. Pre-existing visual morbidity included unilateral (25%) or bilateral (11%) blindness. Improvement (29%) or stabilization (49%) of visual acuity was achieved, more often in patients’ best eyes. Vision deteriorated during BBT in 14 (22%), with 3-year visual-PFS of 53%; more often in patients’ worst eyes. A superior visual outcome (P = .023) was seen in neurofibromatosis type 1-associated optic pathway glioma (OPG). Concordance between visual and radiological responses was 36%; optimized to 48% using only best eye responses. Conclusions BBTs provide effective short-term PLGG control and delay further progression, with a better sustained visual (best > worst eye) than radiological response. Further research could optimize the role of BBT toward a potentially sight-saving strategy in OPG.

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair–deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. Significance: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction. This article is highlighted in the In This Issue feature, p. 995

Background The aim of the project was to identify risk factors associated with visual progression and treatment indications in pediatric patients with neurofibromatosis type 1 associated optic pathway glioma (NF1-OPG). Methods A multidisciplinary expert group consisting of ophthalmologists, pediatric neuro-oncologists, neurofibromatosis specialists, and neuro-radiologists involved in therapy trials assembled a cohort of children with NF1-OPG from 6 European countries with complete clinical, imaging, and visual outcome datasets. Using methods developed during a consensus workshop, visual and imaging data were reviewed by the expert team and analyzed to identify associations between factors at diagnosis with visual and imaging outcomes. Results Eighty-three patients (37 males, 46 females, mean age 5.1 ± 2.6 y; 1–13.1 y) registered in the European treatment trial SIOP LGG-2004 (recruited 2004–2012) were included. They were either observed or treated (at diagnosis/after follow-up). In multivariable analysis, factors present at diagnosis associated with adverse visual outcomes included: multiple visual signs and symptoms (adjusted odds ratio [adjOR]: 8.33; 95% CI: 1.9–36.45), abnormal visual behavior (adjOR: 4.15; 95% CI: 1.20–14.34), new onset of visual symptoms (adjOR: 4.04; 95% CI: 1.26–12.95), and optic atrophy (adjOR: 3.73; 95% CI: 1.13–12.53). Squint, posterior visual pathway tumor involvement, and bilateral pathway tumor involvement showed borderline significance. Treatment appeared to reduce tumor size but improved vision in only 10/45 treated patients. Children with visual deterioration after primary observation are more likely to improve with treatment than children treated at diagnosis. Conclusions The analysis identified the importance of symptomatology, optic atrophy, and history of vision loss as predictive factors for poor visual outcomes in children with NF1-OPG.

To determine the effectiveness of liver reporting and data system (LI-RADS) to diagnose hepatocellular carcinoma (HCC) and to retrospectively evaluate its impact on the adopted therapeutic strategy. Preoperative imaging of 40 of 350 patients (median age 66, 31 M/9 F) submitted to liver resection for suspected HCC, between January 2008 and August 2019, has been retrospectively analyzed by two radiologists with different expertise, according to CT/MRI LI-RADS® v2018, both blinded to clinical and pathological results and untrained to using aforementioned scoring system. The perfect agreement between the readers was about 62.5% (25/40) (Cohen k: 0.41), better for LR-5 category (16/25) and higher in magnetic resonance imaging (MRI) investigations (68%; 13/19), which has been demonstrated the modality of choice for diagnosis of high probable and certain HCC, with arterial phase hyperenhancement as the most sensitive and accurate major feature. Compared to final histology, LR4 and LR5 scores assigned by senior radiologist reached sensitivity, specificity, positive and negative predictive values (PPV, PNV) and diagnostic accuracy of 90,9%, 29,0%, 93,8%, 62,5% and 87,5%, respectively, slightly higher than junior’s ones. Misdiagnosis of HCC was done by both radiologists in the same two patients: 1 primary hepatic lymphoma (PHL) and 1 regenerative liver nodule (RLN). If LI-RADS would have been applied at the time of pre-surgical imaging, treatment planning would be modified in 10% of patients (4/40); the patient scheduled as LR-3 and finally resulted a focal nodular hyperplasia would have avoided liver resection. Application of LI-RADS, especially on MRI, may provide a more accurate evaluation of suspected HCC. PHL and RLN are the Achille’s heels according to our experience.

The major histocompatibility complex-class I chain related proteins A and B (MICA/B) is upregulated because of cellular stress and MICA/B shedding by cancer cells causes escape from NKG2D recognition favoring the emergence of cancers. Cholangiocarcinoma (CCA) is a relatively rare, though increasingly prevalent, primary liver cancer characterized by a late clinical presentation and a dismal prognosis. We explored the NKG2D-MICA/B axis in NK cells from 41 patients with intrahepatic cholangiocarcinoma (iCCA). The MICA/B-specific 7C6 mAb was used for

Background. Most of the available evidence on the use of indocyanine green (ICG) fluorescence in clinical practice consists of articles published by surgeons of the Asian-Pacific area. We performed a prospective cohort study to assess the patterns of ICG fluorescence in Western hepatocellular carcinoma (HCC) counterparts. Methods. From April 2019 to January 2022, a total of 31 consecutive patients who underwent laparoscopic liver resection (LLR) for superficial HCC were enrolled in this prospective study. All patients underwent laparoscopic staging with both laparoscopic ultrasound (LUS) and ICG fluorescence imaging. Results. A total of 38 hepatocellular carcinomas (HCCs) were enrolled: 23 superficial (surfacing at the liver’s Glissonian capsule), 5 exophytic, 5 shallow (10 mm from the hepatic surface). The detection rate with preoperative imaging (abdominal CT/MRI), LUS, ICG fluorescence and combined modalities (ICG and LUS) was 97.4%, 94.9%, 89.7% and 100%, respectively. The five deep seated lesions underwent ultrasound-guided laparoscopic thermal ablation. The other 33 HCCs were treated with minimally invasive liver resection. Intraoperative ultrasound patterns were registered for each single nodule resected. The ICG fluorescence pattern was classified in two types: total fluorescence (all the tumoral tissue showed strong and homogeneous fluorescence), n = 9/33 (27.3%), and non-total fluorescence (partial and rim fluorescence), n = 24/33 (72.7%). There was a statistical correlation between ICG patterns and grade of differentiation. Almost all lesions with uniform fluorescence pattern were well-differentiated HCCs (G1-G2), while partial and rim-type fluorescence pattern were more common among moderately and poorly differentiated HCCs (G3-G4) (88.9% vs 11.1%, 37.5% vs 62.5%, P = .025, respectively). Conclusions. ICG fluorescence imaging could be used to identify early the grade of HCC, ie intraoperatively, thus influencing the intraoperative treatment.

People with HIV are at increased risk of human papillomavirus (HPV) disease progression, given the persistence of immune activation and residual inflammation despite effective combination antiretroviral therapy (cART). Whether a low CD4:CD8 T-cell ratio, known to mirror peripheral immune dysfunction, is associated with squamous intraepithelial lesions (SILs) is unknown.This was a retrospective cohort study on cART-treated HIV-positive subjects undergoing screening for HPV-related dysplasia (anal/cervical cytology and HPV genotyping). SIL was defined as the presence of either atypical squamous cells of undetermined significance (ASCUS), low-grade SILs, or high-grade SILs. Demographic and viro-immunological parameters (T-cell count, CD4:CD8 T-cell ratio, CD8+ CD38+ T-cell percentage) at the time of screening were analyzed by the chi-square test, Mann-Whitney test, and multivariate logistic regression analysis.A total of 419 cART-treated subjects were included. Half of the patients had cervical/anal SIL. Individuals with SIL were more commonly males, were men who have sex with men, were coinfected withHPV infection is the major driver of dysplasia in the setting of HIV infection. In this study, CD8+ CD38+ T cells were an independent predictor of dysplasia in cART-treated subjects, while CD4:CD8 T-cell ratio was not. In the setting of HIV-HPV coinfection, CD4:CD8 T-cell ratio may not fully capture the alterations of HPV-specific immunity.

INTRODUCTION: Whilst most patients with PLGG will survive, varying morbidities derived from patient,tumour & treatment characteristics can afflict life-long disabling functional impairments. No PLGG studies have evaluated potential prognostic factors for important functional outcomes. METHODS: We performed retrospective analysis of all children diagnosed with PLGG at GOSH 1980-2021.Review of medical notes recorded patient demographics,tumour characteristics & treatment data.Functional outcomes included endocrine,educational,visual (in OPG),auditory & physical function.Multivariate regression analysis(p

Simple Summary The features of preoperative systemic anticancer therapy associated with best outcomes after resection of initially-irresectable liver metastases from colorectal cancer are yet to be identified. We harnessed data from a prospective international surgical database (LiverMetSurvey) to explore the duration and modalities of preoperative systemic anticancer therapy associated with longer overall survival in this clinical setting. Our study included 2793 patients having undergone liver surgery after preoperative systemic anticancer treatment for initially irresectable disease. We found that short (

Rectal prolapse is a condition that can cause significant social impairment and negatively affects quality of life. Surgery is the mainstay of treatment, with the aim of restoring the anatomy and correcting the associated functional disorders. During recent decades, laparoscopic abdominal procedures have emerged as effective tools for the treatment of rectal prolapse, with the advantages of faster recovery, lower morbidity, and shorter length of stay. Robotic surgery represents the latest evolution in the field of minimally invasive surgery, with the benefits of enhanced dexterity in deep narrow fields such as the pelvis, and may potentially overcome the technical limitations of conventional laparoscopy. Robotic surgery for the treatment of rectal prolapse is feasible and safe. It could reduce complication rates and length of hospital stay, as well as shorten the learning curve, when compared to conventional laparoscopy. Further prospectively maintained or randomized data are still required on long-term functional outcomes and recurrence rates.

ObjectiveThis study compared all patients undergoing surgery for colorectal cancer in 20 hospitals of Northern Italy in 2019 versus 2020, in order to evaluate whether COVID-19-related delays in the execution of colorectal cancer screening resulted in more advanced cancers at diagnosis and worse clinical outcomes.DesignA retrospective multicentric cohort analysis of patients who underwent surgery for colorectal cancer in March-December 2019 (2019) versus March-December 2020 (2020). The independent predictors of disease stage (oncologic stage, associated symptoms, clinical T4 stage, metastasis) and postoperative outcome (surgical complications, palliative surgery, 30-day death) were evaluated using logistic regression.ResultsThe sample consisted of 1755 patients operated in 2019, and 1481 in 2020 (both mean ages 69.6 years). The proportions of cancers with symptoms, clinical T4 stage, liver and lung metastases in 2019 and 2020 were, respectively: 80.8% vs 84.5%; 6.2% vs 8.7%; 10.2% vs 10.3%; and 3.0% vs 4.4%. The proportions of surgical complications, palliative surgery, and death in 2019 and 2020 were, respectively: 34.4%vs 31.9%; 5.0% vs 7.5%; and 1.7% vs 2.4%. At multivariate analysis, as compared with 2019, cancers in 2020 were significantly more likely to be symptomatic (Odds Ratio - OR: 1.36, 95% Confidence Interval - CI: 1.09-1.69), in clinical T4 stage (OR: 1.38; 1.03-1.85), with multiple liver metastases (OR: 2.21; 1.24-3.94), but less likely to cause surgical complications (OR: 0.79; 0.68-0.93).ConclusionsColorectal cancer patients who had surgery between March and December 2020 had an increased risk of more advanced disease in terms of associated symptoms, cancer location, clinical T4 stage, and number of liver metastases.SHORT SUMMARY BOXWhat is already known about this subject?A specific search regarding the correlation between colorectal cancer oncologic outcomes and COVID-19 showed a few modeling studies which reported the predictions of the potential impact of the diagnostic delays (due to the reduction of the screening programs) on the survival of patients affected by colorectal cancer. However, no study reported any real-life evidence regarding the correlation between the COVID-19 outbreak and the deteriorations of the oncologic outcomes of patients with colorectal cancer.What are the new findings?The present study showed that patients who had surgery for colorectal cancer between March and December 2020 had an increased risk of more advanced disease in terms of associated symptoms, cancer location, clinical T4 stage, and number of liver metastases, than patients who had surgery between March and December 2019.How might it impact on clinical practice in the foreseeable future?The present study confirmed that the backlogs of the screening programs have had, and probably will have, detrimental effects on the oncologic outcomes of patients affected by colorectal cancer. Increased resources should be placed in order to reactivate and enhance the screening programs, and to reduce the risk of colorectal cancer patients to be diagnosed with advanced cancer in the next future.

Chemotherapy; Childhood cancer; Radiotherapy Quimioterapia; Cáncer infantil; Radioterapia Quimioteràpia; Càncer infantil; Radioteràpia Introduction Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment. Method Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication. Results Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy. Conclusion Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers. Open access funding enabled and organized by Projekt DEAL.

Cancers arising from germline DNA mismatch-repair or polymerase-proofreading deficiencies (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion/deletion (MS-indel) burden in humans and are lethal due to inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICI) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI in these patients. ICI treatment of 45 progressive/recurrent tumours from 38 patients revealed durable objective responses in the majority, culminating in 3-year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations/Mb) enriched for combined MMRD+PPD, while MS-indels predicted response in MMRD tumours with lower mutation burden (10-100 mutations/Mb). Further, both mechanisms were associated with increased immune infiltration even in “immunologically-cold” tumours such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and associated with immune activation in both the tumour microenvironment and systemically. Further, patients with flare continuing ICI treatment achieved durable responses. Our study demonstrates improved survival for patients with tumours not previously known to respond to ICI, including CNS and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained responses to immunotherapy.

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy., Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.

Background Complete mesocolic excision (CME) for right colectomy increase the technical complexity of a laparoscopic approach especially when an intracorporeal anastomosis (IA) is associated. The robotic platform, with its intrinsic technical advantages, could potentially overcome the limitations of conventional laparoscopy. This study aimed to describe the robotic bottom-up technique and to evaluate short-terms outcomes of robotic right colectomy (RRC) with CME and IA. Methods Data from patients who underwent RRC for cancer with bottom-up suprapubic approach from October 2016 to April 2020 were prospectively collected and retrospectively analyzed. Intraoperative outcomes and complications, conversion rate, 30-day postoperative outcomes, incisional hernia rate and pathological outcomes were the variables assessed. Results A total of 109 patients were submitted to bottom-up suprapubic approach for RRC with CME and IA during the study period. Mean operative time was 179 min, no intraoperative complications were observed, and the conversion rate was 3.6%. Mean postoperative stay was 4.6 days and the overall 30-day complication rate was 15.6%. Thirteen patients (12%) had minor complications, while major postoperative complications occurred in 4 patients (3.6%). Anastomotic leak was recorded in 1 patient (0.9%) and the 30-day re-admission rate was 0.9%. Mean number of harvested lymph nodes was 22.6. Incisional hernia rate at the specimen extraction site was 0.9%. Conclusions Bottom-up approach for RRC with CME and IA carries a low rate of conversions, intraoperative and short-term postoperative complications.

INTRODUCTION: Bevacizumab/Irinotecan is currently 3rd-line treatment in the UK for progressive Paediatric Low-Grade Glioma (PLGG) based on limited evidence. A nationwide service evaluation was conducted to review its safety and efficacy amongst a larger cohort. METHODS: Data from children with PLGG receiving Bevacizumab-based Treatments (BBT) from 11 UK Centres (2009-2020) were reviewed. Radiological and visual outcomes were based on standardized measurements. Clinical-radiological correlation was investigated. Time to progression from BBT stop, progression free-survival (PFS) curves and multivariate analysis of prognostic factors (p 0.05) were performed. RESULTS: 88 children with PLGG (88% OPG, 24% NF1) had BBT for radiological (43%), visual (20%) or combined (27%) progression, after 40 months (median) from diagnosis. Amongst OPG cases, visual acuity (VA) per eye (better/worse) before BBT was logMAR 0.0-0.3 (23/7) 0.3 - 1.0 (27/20), > 1.0 (14/18) and LP/NLP (8/27), with 19/8 children respectively blind (LP/NLP) in one or both eyes. Bevacizumab 10 mg/kg every 14 days (median 24 doses) was given as 3rd line+ with Irinotecan (85%) or alongside 1st/2nd line chemo (15%) leading to remarkable radiological (88%) and visual (74%) responses (stable or improved) within 3-6 months, with limited toxicity. 12% progressed on treatment, and 8% died unrelated to BBT. After initial response 65% progressed at a median of 8 months (4 - 23) after BBT, resulting in 3-year-all-causes-PFS of 16% and 3-yr-visual-PFS of 45% from start of BBT. Visual concordance with MRI was poor (36%) but increases (47%) when better-eye determines visual outcome. Lack of NF1 and diencephalic syndrome (DS) at presentation were independent negative prognostic factors for PFS. CONCLUSIONS: A remarkable but transient effect of BBT has been confirmed. Visual > radiological responses can be sustained after BBT. Variations in current BBT strategies justifies further research, including the potential upfront use alongside conventional first-line chemotherapy as sight-saving strategy.

INTRODUCTION: The treatment aim of childhood optic pathway glioma (OPG) is visual preservation. However, long-term outcomes and prognostic factors implicated remain largely unknown. METHODS: We undertook a retrospective study of infants and young children (IYC) ≤3 years with OPG and logMAR visual acuity (VA) at baseline/follow-up. We derived Overall- (OS), Progression-free (PFS), Radiotherapy-free (RTFS) and Visual event-free survival (vEFS) curves and analysed prognostic factors for visual deterioration and WHO defined blindness (>1.3 logMAR both eyes). RESULTS: Of 81 IYC-OPG (147 evaluable eyes) baseline vision was below 5%ile for age in 33 (41%) and 27 (33%) in one or both eyes respectively, within normal range in 21 (26%). After observation (11), chemotherapy (66) or RT (4), radiological progression occurred in 47 (58%), multiple times in 34.6% (range 2 - 8) and 10yr-PFS was 39.8%. Twenty had RT after 4.2 years from diagnosis (10yr-RTFS 72.4%) and 12% died (10yr-OS 89%). After 8.9 years VA was better/stable/ worse in 36%/32%/32% of subjects, with median time to visual event of 1.7 years (range 0.16 - 12) and 10yr-vEFS 41.3%. Final VA was reduced (>0.2 logMAR) in 23 (28.4%) and 43 (53.1%) in only one or both eyes respectively. Amongst those with unilateral impairment 13/23 affected eyes had no useful vision (light/no light perception). Amongst those with bilateral impairment best eye VA was > 1.0 log MAR in 22/43 (LP/NLP in 10). Infants < 1 year had significantly inferior 10-yrPFS (5.6%), post-chiasmatic involvement was associated with visual deterioration (HR 2.91, 95%CI=1.1- 7.7), and baseline bilateral abnormal for age vision predicted WHO blindness at follow-up (OR 17.9, 95%CI=3.2 – 101.1). CONCLUSIONS: Many IYC-OPG suffer multiple progressions with significant long-term visual morbidity. Predictive factors such as age, tumor location and baseline age-adjusted vision allow patients’ selection for early sight rehabilitation and consideration for experimental strategies preventing visual loss.

BACKGROUND: Despite high survival, paediatric optic pathway hypothalamic gliomas are associated with significant morbidity and late mortality. Those youngest at presentation have the worst outcomes. METHODS: We aimed to assess presenting disease, tumour location and treatment factors implicated in the evolution of neuroendocrine, metabolic and neuro-behavioural morbidity in children diagnosed before their 3rd birthday and followed over four decades (1981- 2020). RESULTS: Ninety infants/young children followed-up for 9.5 years (range 0.5-25.0) were included in the study. Fifty-two (57.8%) patients experienced endo-metabolic dysfunction (EMD), the large majority (46) had hypothalamic involvement (H+) and lower endocrine event free survival (EEFS) rates. Median time to first endocrine event was 3.4 years, with EEFS declining up to 13.6 years after diagnosis. EMD was greatly increased by a diencephalic syndrome presentation (85.2% vs 46%, p=0.001), H+ (OR 6.1 95% CI 1.7 – 21.7, p 0.005), radiotherapy (OR 16.2, 95% CI 1.7 – 158.6, p=0.017) and surgery (OR 4.8 95% CI 1.3- 17.2, p=0.015), all associated with anterior pituitary disorders. Obesity occurred in 25% of cases and clustered with the endocrinopathies. Posterior pituitary disorders were recorded in 15 subjects (16.7%), only after surgery and/or as a consequence of hydrocephalus in those with suprasellar tumours and hypothalamic disease. Neuro-behavioural deficits occurred in over half (52) of the cohort and were associated with H+ (OR 2.5 95% C.I. 1.1 – 5.9, p=0.043) and radiotherapy (OR 23.1 C.I. 2.9 – 182, p=0.003). CONCLUSIONS: Very young children with OPHG carry a high risk of endo-metabolic and neuro-behavioural comorbidities which deserve better understanding and timely/parallel support from diagnosis to improve outcomes. These evolve in a complex hierarchical pattern overtime whose aetiology appears predominantly determined by injury from the hypothalamic tumour location alongside adjuvant treatment strategies.

BACKGROUND: High-grade gliomas (HGG) with replication-repair deficiency (RRD) harbour high mutation burden (TMB) and are rapidly fatal following chemo-radiation approaches. Although hypermutation results in objective responses and prolonged survival in >30% of patients undergoing PD1-blockade, salvage following failure of PD1-inhibition remains a challenge. METHODS: We performed a real-world study of Ipilimumab (anti-CTLA4) in combination with Nivolumab/Pembrolizumab for patients failing single-agent PD1-inhibition. RESULTS: Among 68 consortium patients with relapsed HGG treated with single-agent PD1-inhibitors, progression was observed in 43 (63%). Ipilimumab was added to 20/43 (46.5%), 14 (32.5%) received best supportive care (BSC), and 9 (21%) received miscellaneous therapies. For patients receiving CTLA4/PD1-inhibition, median age at progression was 12.3-years (IQR: 9; 15.6). Time from anti-PD1 initiation to progression was 8-months (IQR: 3.8; 18.5). Germline predisposition was observed in all patients (CMMRD: 70%, Lynch: 25%, polymerase-proofreading deficiency: 5%). All HGG were hypermutant (median TMB: 182 mutations/Mb; IQR: 15.6; 369.4). Centralized radiology review revealed objective responses in 3/20 (15%, all ultra-hypermutant: 320, 496, 834 mutations/Mb), stable disease in 5 (25%), and 12 (60%) eventually progressed (iRANO). Following failure of PD1-blockade, estimated progression-free and overall survival at 18-months for patients receiving CTLA4/PD1-inhibition were 11% and 25%, respectively. Importantly, survival was superior to patients receiving BSC (median OS 1-year on the anti-CTLA4/PD1combination (range:1-48 months). The combinational immunotherapy resulted in significant autoimmune toxicity in 11/20 (55%), warranting immunosuppressive therapy in all, and treatment abandonment in 6 patients. CONCLUSION: Combined CTLA4/PD1-blockade after failure of single-agent PD1-inhibition revealed objective responses and prolonged survival in an otherwise rapidly-fatal disease. This needs to be assessed in the context of significant autoimmunity, supporting the need for the current prospective trial (NCT04500548), and novel strategies to limit treatment-related toxicity.

Background Indocyanine green fluorescence (ICG) is one of the first fluorophore that found a clinical application in medicine. In the liver, ICG fluorescence is due to the preserved uptake but impaired washout of the dye from hepatocellular cells into the bile ducts. Therefore, some hepatobiliary surgeons proposed the technique of intravenous ICG injection before surgery for the detection of superficial hepatocarcinomas (HCCs) and colorectal liver metastases (CRLMs). Little evidence exists regarding the use of ICG to identify other hepatic tumors, such as intrahepatic cholangiocarcinoma (ICC). We report two patients affected by ICC who underwent laparoscopic liver resection with lymphadenectomy, the ICG staining was routinely performed not only to evaluate the site of the hepatic lesions but also to guide the extension of liver resection. Methods It was injected intravenously a single dose of ICG dye (0.5 mg/kg) during liver function tests 5 days before scheduled surgery. All patients underwent laparoscopic staging with both laparoscopic ultrasound and ICG fluorescence imaging. Results It was identified two different patter of ICG imaging: rim and segmental fluorescence for mass forming and mixed ICC subtype respectively. Conclusions Identification of the ICC subtype before definitive histological examination may have an impact on the surgical plan.

Background COVID-19 pandemic has impacted the Italian National Health Care system at many different levels, causing a complete reorganization of surgical wards. In this context, our study retrospectively analysed the management strategy for patients with acute cholecystitis. Methods We analysed all patients admitted to our Emergency Department for acute cholecystitis between February and April 2020 and we graded each case according to 2018 Tokyo Guidelines. All patients were tested for positivity to SARS-CoV-2 and received an initial conservative treatment. We focused on patients submitted to cholecystostomy during the acute phase of pandemic and their subsequent disease evolution. Results Thirty-seven patients were admitted for acute cholecystitis (13 grade I, 16 grade II, 8 grade III). According to Tokyo Guidelines (2018), patients were successfully treated with antibiotic only, bedside percutaneous transhepatic gallbladder drainage (PC) and laparoscopic cholecystectomy (LC) in 29.7%, 21.6% and 48.7% of cases respectively. Therapeutic strategy of three out of 8 cases, otherwise fit for surgery, submitted to bedside percutaneous transhepatic gallbladder drainage (37.5%), were directly modified by COVID-19 pandemic: one due to the SARS-CoV-2 positivity, while two others due to unavailability of operating room and intensive care unit for post-operative monitoring respectively. Overall success rate of percutaneous cholecystostomy was of 87.5%. The mean post-procedural hospitalization length was 9 days, and no related adverse events were observed apart from transient parietal bleeding, conservatively treated. Once discharged, two patients required readmission because of acute biliary symptoms. Median time of drainage removal was 43 days and only 50% patients thereafter underwent cholecystectomy. Conclusions Percutaneous cholecystostomy has shown to be an effective and safe treatment thus acquiring an increased relevance in the first phase of the pandemic. Nowadays, considering we are forced to live with the SARS-CoV-2 virus, PC should be considered as a virtuous, alternative tool for potentially all COVID-19 positive patients and selectively for negative cases unresponsive to conservative therapy and unfit for surgery.

Regulatory T (T

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Replication repair deficiency (RRD) leading to hypermutation is an important driving mechanism of high-grade glioma (HGG) occurring predominantly in the context of germline mutations in RRD-associated genes. Although HGG presents specific patterns of DNA methylation corresponding to oncogenic mutations, this has not been well studied in replication repair-deficient tumors. We analyzed 51 HGG arising in the background of gene mutations in RRD utilizing either 450 k or 850 k methylation arrays. These were compared with HGG not known to be from patients with RRD. RRD HGG harboring secondary mutations in glioma genes such as IDH1 and H3F3A displayed a methylation pattern corresponding to these methylation subgroups. Strikingly, RRD HGG lacking these known secondary mutations clustered together with an incompletely described group of HGG previously labeled “Wild type-C” or “Paediatric RTK 1”. Independent analysis of two comparator HGG cohorts showed that other RRD/hypermutant tumors clustered within these subgroups, suggesting that undiagnosed RRD may be driving some HGG clustering in this location. RRD HGG displayed a unique CpG Island Demethylator Phenotype in contrast to the CpG Island Methylator Phenotype described in other cancers. Hypomethylation was enriched at gene promoters with prominent demethylation in genes and pathways critical to cellular survival including cell cycle, gene expression, cellular metabolism, and organization. These data suggest that methylation arrays may provide diagnostic information for the detection of RRD HGG. Furthermore, our findings highlight the unique natural selection pressures in these highly dysregulated, hypermutant cancers and provide the novel impact of hypermutation and RRD on the cancer epigenome.

To determine the effectiveness of liver reporting and data system (LI-RADS) to diagnose hepatocellular carcinoma (HCC) and to retrospectively evaluate its impact on the adopted therapeutic strategy.Preoperative imaging of 40 of 350 patients (median age 66, 31 M/9 F) submitted to liver resection for suspected HCC, between January 2008 and August 2019, has been retrospectively analyzed by two radiologists with different expertise, according to CT/MRI LI-RADSThe perfect agreement between the readers was about 62.5% (25/40) (Cohen k: 0.41), better for LR-5 category (16/25) and higher in magnetic resonance imaging (MRI) investigations (68%; 13/19), which has been demonstrated the modality of choice for diagnosis of high probable and certain HCC, with arterial phase hyperenhancement as the most sensitive and accurate major feature. Compared to final histology, LR4 and LR5 scores assigned by senior radiologist reached sensitivity, specificity, positive and negative predictive values (PPV, PNV) and diagnostic accuracy of 90,9%, 29,0%, 93,8%, 62,5% and 87,5%, respectively, slightly higher than junior's ones. Misdiagnosis of HCC was done by both radiologists in the same two patients: 1 primary hepatic lymphoma (PHL) and 1 regenerative liver nodule (RLN). If LI-RADS would have been applied at the time of pre-surgical imaging, treatment planning would be modified in 10% of patients (4/40); the patient scheduled as LR-3 and finally resulted a focal nodular hyperplasia would have avoided liver resection.Application of LI-RADS, especially on MRI, may provide a more accurate evaluation of suspected HCC. PHL and RLN are the Achille's heels according to our experience.

Background & Aims: COVID-19 posed a major worldwide threat to population health as well as to patients with comorbidities, but its impact on patients with cirrhosis and hepatocellular carcinoma is currently poorly understood. This study aimed at evaluating the effects of COVID-19 outbreak both on the clinical outcome of these patients and on their follow-up. Methods: We conducted a phone survey off all patients living in Lombardy (the region with the highest incidence of Covid-19 infections in our country) included in our database and treated for hepatocellular carcinoma from January 2017 to April 2020. Results: We analyzed the database concerning 187 patients submitted to surgical treatment for HCC: 35 patients died before the pandemic. Therefore, we obtained a complete answer to the questionnaire from 131 patients while in other 7 cases we gained information by a family member because the patient had died in the meanwhile; 14 cases were unreachable (9%). We identified 7 cases of Covid-19 among the 138 patients (5%): 5 confirmed and 2 probables. One patient died for COVID-19 pneumonia. During the lockdown period (March-April 2020), we registered 7 deaths: 1 patient for Covid-19 pneumonia, 2 patients for diffuse HCC recurrence and the remnant 4 for other causes. (crude death rate: 46.4). In the same period of 2018, we registered a crude death rate of 25.6 while in the 2019 a crude death rate of 10. Conclusions: irrespective of a low rate of Covid infections in a group of frailty patients, we observed a higher rate of mortality due to other causes: the reduced access to health services due to the disruption of the normal activities and the forced reassurance of sick patients could be the primary causes of this increase. Funding Statement: None. Declaration of Interests: All authors declare that they have no conflicts of interest or financial ties to disclose. Ethics Approval Statement: This retrospective study protocol was approved by our Institutional Review Board and waived the requirement for informed consent. Research involving human participants and/or animals Institutional review research board approval was granted by ASST Fatebenefratelli Sacco, and appropriate good clinical and research practices were followed.

When compatible with the liver functional reserve, laparoscopic hepatic resection remains the treatment of choice for hepatocellular carcinoma while laparoscopic ablation therapies appear as a promising less invasive alternative. The aim of the study is to compare two homogeneous groups of patients submitted to either hepatic resection or thermoablation for the treatment of single hepatocellular carcinoma (≤ 3 cm). We enrolled 264 cirrhotic patients out of 905 cases consecutively evaluated for hepatocellular carcinoma. We performed 59 hepatic resections and 205 thermoablations through a laparoscopic approach, and they were then followed for similar follow-up (41.7 ± 31.5 months for laparoscopic hepatic resection vs. 38.7±32.3 for laparoscopic ablation therapy). Outcomes included short- and long-term morbidities, tumoral recurrence, and overall survival. Short-term morbidity was significantly higher in the resection group (but the two groups had similar rates for severe complications) while, during follow-up, recurrence was more frequent in patients treated with thermoablation, with a clear disadvantage in terms of survival. At multivariate analysis, only the type of surgical treatment was an independent predictor of disease recurrence, while plasmatic alpha-fetoprotein and Hb values, model for end-stage liver disease score, time to recurrence, and the type of surgical treatment were independent predictors of overall survival. Our data ultimately support some therapeutic advantages for hepatic resection in patients with a single nodule and preserved liver function. However, thermoablation is an adequate alternative in patients with nodules that would require complex surgical resections or imply a poor prognosis that might therefore better tolerate a less invasive procedure.

Optic pathway glioma (OPG) represents the most common central nervous system tumor in children with Neurofibromatosis type-1 (NF1). Although overall survival is usually good, no clear prognostic factors have been identified so far. We assessed the natural history of OPG in a cohort of unselected patients affected by NF1. We retrospectively evaluated 414 consecutive patients affected by NF1 and referred to our NF1 clinic before age 6. Average follow-up was 11.9 years: 52 out of 414 patients had OPG with a total cumulative incidence of 15.4% at age 15 (Kaplan-Meier estimate) and a statistically significant difference according to sex. Brain and orbit MRI was performed in 44.7% of patients: 34.6% for screening purposes and 65.4% because of the presence of neurological, ocular or other symptoms. OPG was diagnosed in 12.5% of cases in the first group, whereas in 36.4% in the latter group (p = 0.001). Clinical management was conservative in most patients, while 8 of them underwent therapy mainly because of visual deterioration. OPG was diagnosed earlier in treated patients, but the difference was not statistically significant. Conversely, all patients who underwent screening MRI had normal visual outcome. In conclusion, OPG location does not correlate with need for treatment; female patients were more frequently affected by OPG but not more frequently treated. OPG diagnosis by screening MRI does not affect the natural history of the tumor.

The optimal treatment for hepatocellular carcinoma (HCC) is surgical resection. However, only a small percentage of patients are amenable to this option. Percutaneous radiofrequency interstitial thermal ablation (TA) proved to be effective in the treatment of unresectable HCC. Recent advances in laparoscopic ultrasound have improved the accuracy in detecting small intrahepatic HCC nodules missed by pre-operative imaging techniques. Our objective was to evaluate an operative combination of laparoscopic ultrasound with laparoscopic thermoablation (LTA) in the treatment of HCC not amenable to liver resection. The aim of our review was to evaluate the advantages and limits of the laparoscopic approach according the criteria of the evidence-based medicine. LTA of HCC proved to be a safe and effective technique both in the short- and long-term follow-up period. This technique may be indicated in selected cases when the percutaneous approach to the lesion is very difficult or contraindicated.

Type 1 neurofibromatosis (NF1) is a dominantly inherited condition predisposing to tumor development. Optic pathway glioma (OPG) is the most frequent central nervous system tumor in children with NF1, affecting approximately 15–20% of patients. The lack of well-established prognostic markers and the wide clinical variability with respect to tumor progression and visual outcome make the clinical management of these tumors challenging, with significant differences among distinct centers. We reviewed published articles on OPG diagnostic protocol, follow-up and treatment in NF1. Cohorts of NF1 children with OPG reported in the literature and patients prospectively collected in our center were analyzed with regard to clinical data, tumor anatomical site, diagnostic workflow, treatment and outcome. In addition, we discussed the recent findings on the pathophysiology of OPG development in NF1. This review provides a comprehensive overview about the clinical management of NF1-associated OPG, focusing on the most recent advances from preclinical studies with genetically engineered models and the ongoing clinical trials.

Low grade gliomas (LGGs) constitute the largest, yet clinically and (molecular-) histologically heterogeneous group of pediatric brain tumors of WHO grades I and II occurring throughout all pediatric age groups and at all central nervous system (CNS) sites. The tumors are characterized by a slow growth rate and may show periods of growth arrest. Around 40% of all LGG patients can be cured by complete neurosurgical resection and are followed by close observation. In case of relapse, second resection often is possible. Following incomplete resection observation is recommended, as long as there is no radiologic tumor growth and the patient does not suffer from significant, tumor-related symptoms. This also applies to patients with a diagnosis of LGG on the basis of radiological criteria. By contrast, clinical worsening and / or radiologic progression are an indication to treatment with either chemo- or radiotherapy. Overall survival is around 90%, and many patients survive with residual tumor, i. e. they suffer from chronic disease. All patients need comprehensive neuro-oncological care, the principles and details of which are summarized in the current guidelines. These represent standard of care for diagnostic work-up (including neuroimaging and neuropathology), and for therapeutic decisions (including the indications to non-surgical treatment) as well as concepts for neurosurgical intervention, chemotherapy and radiotherapy as well as surveillance and rehabilitation. The current treatment algorithm was compiled by members of the LGG working group of the SIOP-E brain tumor group (SIOP-E-BTG) and is based upon the results of previous European LGG studies and international reports.

Background Malignant brain tumors (BT) are among the cancers most frequently associated with constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations in mismatch repair genes. This study analyzed data from the European “Care for CMMRD” (C4CMMRD) database to describe their clinical characteristics, treatments, and outcome with the aim of improving its diagnosis/treatment. Methods Retrospective analysis of data on patients with CMMRD and malignant BT from the C4CMMRD database up to July 2017. Results Among the 87 registered patients, 49 developed 56 malignant BTs: 50 high-grade gliomas (HGG) (with giant multinucleated cells in 16/21 histologically reviewed tumors) and 6 embryonal tumors. The median age at first BT was 9.2 years [1.1–40.6], with nine patients older than 18. Twenty-seven patients developed multiple malignancies (including16 before the BT). Most patients received standard treatment, and eight patients immunotherapy for relapsed HGG. The 3- and 5-year overall survival (OS) rates were 30% (95% CI: 19–45) and 22% (95% CI: 12–37) after the first BT, with worse prognosis for HGG (3-year OS = 20.5%). Six patients were alive (median follow-up 2.5 years) and 43 dead (38 deaths, 88%, were BT-related). Other CMMRD-specific features were café-au-lait macules (40/41), multiple BTs (5/15), developmental brain anomalies (11/15), and consanguinity (20/38 families). Conclusions Several characteristics could help suspecting CMMRD in pediatric malignant BTs: giant cells on histology, previous malignancies, parental consanguinity, café-au-lait macules, multiple BTs, and developmental brain anomalies. The prognosis of CMMRD-associated BT treated with standard therapies is poor requiring new therapeutic up-front approaches.

Laparoscopic thermal ablation is a common alternative to surgical resection in treating hepatic tumors, particularly in those located in difficult-to-reach locations. The aim of this study was to compare the safety and long-term efficacy of laparoscopic radiofrequency ablation (RFA) and microwave ablation (MWA) in treating hepatocellular carcinoma (HCC). From February 2009 to May 2015, data from patients with HCC nodules who had undergone either laparoscopic MWA or laparoscopic RFA were examined. Complications, complete ablation rates, local tumor progression (LTP) rates, and disease-free and cumulative survival rates were compared between the two treatment groups. A total of 154 patients with HCC (60 MWA and 94 RFA) were treated via the laparoscopic approach. Major complication rates were identified as 1 and 2 % in the RFA and MWA groups, respectively (p = 0.747). Complete ablation rates were 95 % for both treatment groups (p = 0.931), and LTP rates were 21.2 % for RFA and 8.3 % for MWA (p = 0.034). Disease-free survival rates at 5 years were 19 % in the RFA group and 12 % in the MWA group (p = 0.434), while cumulative survival rates at 5 years were 50 % in the RFA group and 37 % in the MWA group (p = 0.185). Laparoscopic RFA and MWA appear to be safe in the treatment of early-stage HCC. The LTP rates were lower in the laparoscopic MWA group compared with the laparoscopic RFA group, but their respective overall and disease-free survival rates remained similar.

Summary Tumor-infiltrating regulatory T lymphocytes (Treg) can suppress effector T cells specific for tumor antigens. Deeper molecular definitions of tumor-infiltrating-lymphocytes could thus offer therapeutic opportunities. Transcriptomes of T helper 1 (Th1), Th17, and Treg cells infiltrating colorectal or non-small-cell lung cancers were compared to transcriptomes of the same subsets from normal tissues and validated at the single-cell level. We found that tumor-infiltrating Treg cells were highly suppressive, upregulated several immune-checkpoints, and expressed on the cell surfaces specific signature molecules such as interleukin-1 receptor 2 (IL1R2), programmed death (PD)-1 Ligand1, PD-1 Ligand2, and CCR8 chemokine, which were not previously described on Treg cells. Remarkably, high expression in whole-tumor samples of Treg cell signature genes, such as LAYN, MAGEH1, or CCR8, correlated with poor prognosis. Our findings provide insights into the molecular identity and functions of human tumor-infiltrating Treg cells and define potential targets for tumor immunotherapy., Highlights • Transcriptome analysis performed on tumor-resident CD4+ Th1, Th17, and Treg cells • Tumor-infiltrating Treg cells are defined by the expression of signature genes • Treg-specific signature genes correlate with patients’ survival in both CRC and NSCLC, Tumor-infiltrating regulatory T cells can suppress effector T cells specific for tumor antigens. De Simone et al. (2016) demonstrate that tumor-infiltrating Treg cells display specific gene signatures that were also validated at the single-cell level. These data can contribute to dissect the molecular networks underlying the biology of tumor-infiltrating Treg cells. As part of the IHEC consortium, this study integrates genetic, epigenetic, and transcriptomic profiling in three immune cell types from nearly 200 people to characterize the distinct and cooperative contributions of diverse genomic inputs to transcriptional variation. Explore the Cell Press IHEC webportal at www.cell.com/consortium/IHEC.

Barrett’s esophagus is a condition in which the normal squamous lining of the esophagus has been replaced by columnar epithelium containing intestinal metaplasia induced by recurrent mucosal injury related to gastroesophageal reflux disease. Barrett’s esophagus is a premalignant condition that can progress through a dysplasia-carcinoma sequence to esophageal adenocarcinoma. Multiple endoscopic ablative techniques have been developed with the goal of eradicating Barrett’s esophagus and preventing neoplastic progression to esophageal adenocarcinoma. For patients with high-grade dysplasia or intramucosal neoplasia, radiofrequency ablation with or without endoscopic resection for visible lesions is currently the most effective and safe treatment available. Recent data demonstrate that, in patients with Barrett’s esophagus and low-grade dysplasia confirmed by a second pathologist, ablative therapy results in a statistically significant reduction in progression to high-grade dysplasia and esophageal adenocarcinoma. Treatment of dysplastic Barrett’s esophagus with radiofrequency ablation results in complete eradication of both dysplasia and of intestinal metaplasia in a high proportion of patients with a low incidence of adverse events. A high proportion of treated patients maintain the neosquamous epithelium after successful treatment without recurrence of intestinal metaplasia. Following successful endoscopic treatment, endoscopic surveillance should be continued to detect any recurrent intestinal metaplasia and/or dysplasia. This paper reviews all relevant publications on the endoscopic management of Barrett’s esophagus using radiofrequency ablation.

PURPOSE Prolonged Postoperative Ileus (PPOI) after abdominal surgery may affect unfavourably the patient recovery. The aim of this study was to estimate the incidence of PPOI in patients elective for colorectal resection and investigate perioperative variables associated with PPOI. METHODS A consecutive series of 428 patients undergoing colorectal resection (median age 72, range 24-92, years; men/women ratio 1.14) were analyzed. Data were extracted retrospectively throughout a five-year period from an electronic prospectively maintained database. PPOI was defined as the need for postoperative insertion of a nasogastric tube in a patient experiencing nausea and two episodes of vomiting and further showing absence of adequate bowel function (absence of flatus/stool) with lack of bowel sounds and abdominal distension. RESULTS Incidence of PPOI was 7% [95% confidence interval (95%CI), 4.8-9.9%]. Mean hospital stay was 8 days longer in patients with PPOI. Male gender, cancer, cardiac and respiratory co-morbidity, rectal resection, open/converted access, duration of operation, stoma formation and body mass index were associated with PPOI at univariate analysis (0.001< P< 0.048). PPOI was independently associated with male gender [adjusted odds ratio (OR), 4.2; 95%CI, 1.5-11.5], stoma formation (OR, 2.8; 95%CI, 1.2-6.8) and obesity (OR of obese vs. normal weight patients, 3.8, 95%CI, 1.2-12.0). CONCLUSION After colorectal resection, PPOI leads to a prolonged hospital stay and slower patient's recovery. An international standardized definition of PPOI is strongly needed to make comparable results from researches and to reliably identify patients with increased risk, also to improve the therapeutic preventive policies in these patients.

The activating natural cytotoxicity receptor NKp30 is critical for natural killer (NK) cell function and tumor immune surveillance. The natural cytotoxicity receptor-3 (NCR3) gene is transcribed into several splice variants whose physiological relevance is still incompletely understood. In this study, we investigated the role of NKp30 and its major ligand B7 homolog 6 (B7-H6) in patients with hepatocellular carcinoma (HCC). Peripheral blood NK cell phenotype was skewed toward a defective/exhausted immune profile with decreased frequencies of cells expressing NKp30 and natural killer group 2, member D and an increased proportion of cells expressing T-cell immunoglobulin and mucin-domain containing-3. Moreover, NKp30-positive NK cells had a reduced expression of NCR3 immunostimulatory splice variants and an increased expression of the inhibitory variant in patients with advanced tumor, resulting in deficient NKp30-mediated functionality. Tumor-infiltrating lymphocytes showed a prevalent inhibitory NKp30 isoform profile, consistent with decreased NKp30-mediated function. Of note, there were significant differences in the cytokine milieu between the neoplastic and the surrounding non-neoplastic tissue, which may have further influenced NKp30 function. Exposure of NK cells to B7-H6-expressing HCC cells significantly down-modulated NKp30, that was prevented by small interfering RNA-mediated knockdown, suggesting a role for this ligand in inhibiting NKp30-mediated responses. Interestingly, B7-H6 expression was reduced in HCC tissue and simultaneously augmented as a soluble form in HCC patients, particularly those with advanced staging or larger nodule size. Conclusion: These findings provide evidence in support of a role of NKp30 and its major ligand in HCC development and evolution.

Radiofrequency ablation (RFA) is widely used as a first-line option in patients with hepatocellular carcinoma (HCC). However, since percutaneous approach of RFA may be, in some cases, unfeasible by the tumor size and its location, laparoscopic ablation therapies (LATs) were used as an alternative. Objective of the present study was to assess the efficacy of laparoscopic ultrasound examination in addition to LATs in the treatment of HCC in patients not eligible for percutaneous RFA or surgical resection. Four hundred and twenty-six patients who underwent LATs were analyzed. Laparoscopic approach was offered to patients fulfilling at least one of the following criteria: (a) patients with a single nodule or up to three nodules smaller than 3 cm not suitable for liver transplantation or not eligible for HR because of severe portal hypertension, impaired liver function, or coexistent comorbidities; (b) patients not suitable for percutaneous RFA because of inconvenient tumor location; and (c) short-term recurrence of HCC (

The increased invasiveness of endoscopic procedures and complex surgical interventions has resulted in an increased number of gastrointestinal iatrogenic defects, such as perforations, leak and fistulas. The conventional treatment for these gastrointestinal defects is surgery, with considerable risks especially in emergency situations and in patients with comorbidities. The Ovesco over-the- scope clip (OTSC) system (Ovesco Endoscopy AG, Tübingen, Germany) and more recently, the Padlock ClipTM (Aponos Medical, Kingston, NH, United States) have shown promising results in the treatment of gastrointestinal defects. Several case reports and case series have demonstrated the efficacy of the OTSC system for the closure of full-thickness defects. Clinical success is best achieved in patients undergoing closure of a perforation or a leak. Closure of fistulas remains a clinical challenge since fibrosis or necrotic and inflamed tissue surrounding lesions may cause clip failure. Over-the-scope clips are a less invasive endoscopic option for managing patients with gastrointestinal defects before a more invasive surgical approach is attempted. Moreover, a failed attempt of OTSC deployment does not preclude subsequent surgical treatment.

Introduction Endoscopic ultrasound (EUS) guided fine needle aspiration (FNA) has a crucial role in the diagnosis of solid pancreatic lesions and rapid on-site evaluation (ROSE) can increase its diagnostic yield. Rapid on-site evaluation is not always available and after EUS-FNA provides a cytology specimen with scant cellularity. Fine needle biopsy (FNB) specimens containing core tissue may theoretically overcome the limitations of EUS-FNA sampling. It could be hypothesized that EUS-FNB without ROSE could achieve the same adequacy and accuracy of EUS-FNB with ROSE. The aim of this review is to evaluate the evidence on the role of ROSE in the setting of EUS-guided tissue acquisition with core needles in patients with solid pancreatic lesions. Evidence acquisition All relevant articles were extracted up to February 2017 based on the results of searches in PubMed, Scopus and Google Scholar. Evidence synthesis A total of 21 pertinent articles were finally included. Among the included studies, 11 were performed without ROSE, 8 with ROSE, and 2 were performed both with and without ROSE. In the ROSE group we found a sensitivity, specificity, overall diagnostic adequacy and overall diagnostic accuracy of 96%, 100%, 86.5%, 85.5%, respectively, while in the no-ROSE group 86.6%, 100%, 89.5%, 86.1% were found, respectively. Mild pancreatitis (mean rates, 3.43%) and abdominal pain (mean rates, 3.6%) were reported as most frequent adverse events. Conclusions Endoscopic ultrasound guided-FNB without ROSE offers similar results in terms of adequacy and accuracy as in the presence of an on-site cytopathologist.