Assessing the safety and activity of cabozantinib combined with lanreotide in gastroenteropancreatic and thoracic neuroendocrine tumors: rationale and protocol of the phase II LOLA trial.

BACKGROUND: Well-differentiated (WD) neuroendocrine tumors (NETs) are a group of rare neoplasms with limited therapeutic options. Cabozantinib is an inhibitor of multiple tyrosine kinases with a pivotal role in NET pathogenesis, including c-MET and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2). LOLA is the first prospective phase II trial aiming to assess the safety and activity of cabozantinib combined with lanreotide in WD NETs of gastroenteropancreatic (GEP), thoracic and of unknown origin. METHODS: This is a multicenter, open-label, double-cohort, non comparative, non-randomized, three-stage phase II trial. Eligible patients have to meet the following inclusion criteria: diagnosis of advanced or metastatic, progressive, non-functioning WD thoracic NETs, GEP-NETs or NETs of unknown origin with Ki67 ≥ 10%; positive 68 Ga-PET uptake or somatostatin receptor 2 immunohistochemical (IHC) stain; maximum 1 prior systemic regimen for metastatic disease. Two cohorts will be considered: pNETs and carcinoids (typical or atypical lung and thymus NETs, gastro-intestinal NETs or NETs of unknown origin). In stage I, the primary objective is to find the optimal dose of cabozantinib in combination with lanreotide and to evaluate the safety of the combination (percentage of patients experiencing grade 3-5 toxicities according to NCI-CTCAE version 5.0). Starting dose of cabozantinib is 60 mg/day continuously, plus lanreotide 120 mg every 28 days. In stage II and III, co-primary endpoints are safety and overall response rate (ORR) according to RECIST version 1.1. The uninteresting antitumor activity is fixed in ORR ≤ 5%. Secondary endpoints are progression-free survival and overall survival. Exploratory objectives include the assessment of c-MET, AXL and VEGFR2 IHC expression, to identify predictive or prognostic tissue biomarkers. Enrolment started in July 2020, with an expected trial duration of 42 months comprehensive of accrual, treatment and follow-up. Considering a drop-out rate of 5%, the maximum number of enrolled patients will be 69. DISCUSSION: Supported by a solid rationale, the trial has the potential to generate milestone data about the synergistic effects of cabozantinib plus lanreotide in a group of NET patients with relatively aggressive disease and limited therapeutic options. TRIAL REGISTRATION: LOLA is registered at ClinicalTrials.gov (NCT04427787) and EudraCT (2019-004506-10).

Hepatocellular Carcinoma Recurrence After Liver Transplantation.

Key Points • Recurrent HCC after OLT management is challenging and notoriously difficult. • High oncologic-risk patient identification and close follow-up are essential. • Recurrences diagnosed within the first 2 years after OLT can be classified as early-onset and are associated with poor prognosis. • Surgical resection should be the first curative attempt when it is technically feasible. • TACE in patients who have undergone OLT appears to be effective and safe. • Sorafenib can be used as systemic therapy in cases with multi-organ recurrence; newer therapies are emerging. • The benefit of immunosuppression with an mTOR inhibitor has not been established. • In the posttransplant setting, a combination treatment approach is warranted.

Contrast-Enhanced Ultrasound-Guided Percutaneous Biopsy of the Peritoneum: A Series of 3 Cases.

In the presence of peritoneal disease, patients often should undergo biopsy of the peritoneum for acquiring a specific pathologic diagnosis. Ultrasound is ideal for guiding peritoneal biopsy, although in some situations, it can be technically challenging. The addition of a contrast agent can improve the visualization of lesions and adjacent organs, providing radiologists increased confidence. A contrast agent can identify perfused areas within the target lesion, improving diagnostic accuracy. We present 3 cases of contrast-enhanced ultrasound-guided peritoneal biopsy. In all cases, we gained a specific diagnosis. No immediate or delayed complications occurred. Contrast-enhanced ultrasound-guided biopsy proved to be a simple, safe, and accurate diagnostic method.

Development of a prognostic score to predict response to Yttrium-90 radioembolization for hepatocellular carcinoma with portal vein invasion.

BACKGROUND & AIMS: Yttrium-90 transarterial radioembolization (TARE) has shown promising efficacy in the treatment of patients with hepatocellular carcinoma (HCC), associated with portal vein tumor thrombus (PVTT). The aim of this study is to identify prognostic factors for survival in patients with HCC and PVTT undergoing TARE, and build a prognostic classification for these patients. METHODS: This is a single center retrospective study conducted over six years (2010-2015), on consecutive patients undergoing TARE. Patients were included if they met the following criteria: presence of at least one measurable HCC, presence of PVTT not occluding the main portal trunk, absence of extrahepatic metastases, Child-Pugh score within B7, Eastern Cooperative Oncology Group performance status 0-1. Uni- and multivariable analysis was used to explore the variables that showed an independent relationship with survival. A prognostic score was then derived, and three prognostic categories were identified. RESULTS: A total of 120 patients were included in the study. Median overall survival (OS) was 14.1 months (95% CI 10.7-17.5) and median progression-free survival (PFS) was 6.5 months (95% CI 3.8-9.2). The only variables independently correlated with OS were bilirubin, extension of PVTT and tumor burden. Three prognostic categories were identified: favourable prognosis (0 points), intermediate prognosis (2-3 points) and dismal prognosis (>3 points). Median OS in the three categories was 32.2 months, 14.9 months and 7.8 months respectively (p <0.0001). PFS (p = 0.045) and the risk of liver decompensation (p <0.0001) also significantly differed along the same prognostic categories. CONCLUSIONS: Radioembolization with Yttrium-90 is an effective therapy for patients with HCC and PVTT. The proposed prognostic stratification may help to better identify good candidates for the treatment, and those for whom TARE may be futile. LAY SUMMARY: Yttrium-90 transarterial radioembolization (TARE) is a microembolic procedure that minimizes alterations to hepatic arterial flow, and thus can be safely performed in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). In this study, we retrospectively evaluated the independent predictors of long-term outcomes in patients with HCC and PVTT treated with TARE. Bilirubin level, extension of PVTT and tumor burden were independently related to post-treatment survival: the combination of these factors allowed us to build a prognostic stratification that may help to better identify good candidates for the treatment, and those for whom TARE may be futile.

Drug-eluting beads versus conventional chemoembolization for the treatment of unresectable hepatocellular carcinoma.

BACKGROUND AND AIM: Solid demonstrations of superior efficacy of drug-eluting beads transarterial chemoembolization with respect to conventional chemoembolization in hepatocellular carcinoma patients are lacking. The aim of the study was to compare these two techniques in two large cohorts of unresectable hepatocellular carcinoma patients. METHODS: A single center series of 249 early/intermediate hepatocellular carcinoma patients who underwent "on demand" chemoembolization in the period 2007-2011 was analyzed. Overall survival, time to progression, tumor response rate, and safety were compared between 104 patients who underwent conventional chemoembolization and 145 who underwent drug-eluting beads chemoembolization. Time-to-event data were analyzed using the Cox univariate and multivariate regression. RESULTS: The two cohorts resulted balanced for liver function and tumor stages. Objective response rate was 85.3% after conventional and 74.8% after drug-eluting beads chemoembolization (P = 0.039), and median time to progression was 17 (95% confidence interval: 14-21) versus 11 months (9-12), respectively (P < 0.001). Treatment regimen was the sole independent predictor of progression at multivariate analysis (hazard ratio = 2.01; 1.45-2.80; P < 0.001). Median survival was 39 (32-47) and 32 (24-39) months in the two groups, respectively (hazard ratio = 1.33; 0.94-1.87; P = 0.10), but conventional chemoembolization was significantly associated with a survival advantage in patients with bilobar neoplasia, portal hypertension and alpha fetoprotein above normal limits. No significant differences in severe adverse events were found. CONCLUSION: In a large series of Western hepatocellular carcinoma patients, drug-eluting beads chemoembolization with 100-300 µm particles did not seem to improve survival in comparison with conventional chemoembolization, which in turn provided better tumor responses and time to progression.

The role of CEUS in the management of biloma.

BACKGROUND: A biloma refers to an abnormal, well-defined accumulation of bile outside the biliary tree within the abdomen, which can be either intra- or extra-hepatic in nature. It can result from traumatic or iatrogenic causes, leading to a disruption in the biliary system. Without prompt diagnosis and appropriate management, it can result in significant morbidity and mortality. While magnetic resonance cholangiopancreatography (MRCP) is the typical diagnostic method, there are instances where it may not provide conclusive results. CASE PRESENTATION: We present the case of a 72-year-old woman who underwent an hepatic resection of the seventh segment after recurrence of hepatocellular carcinoma (HCC). During the ultrasound (US) follow-up, she developed a peri-hepatic collection which proved to be a biloma continuously refurnished by the biliary tree. Neither the MRCP nor the percutaneous transhepatic cholangiography (PTC) were able to clearly detect the exact site of the bile leak. While awaiting the Endoscopic Retrograde Cholangio-Pancreatography (ERCP), a Contrast-Enhanced Ultrasound (CEUS) was conducted administering the contrast agent directly through the percutaneous drainage catheter placed in the biloma. This revealed the presence of contrast flow from the collection to a peripheral right bile duct, confirming the intra-hepatic leak communication. CONCLUSIONS: This case demonstrates that Contrast-Enhanced Ultrasound (CEUS) presents a straightforward, secure, and precise approach to detect biliary leakage responsible for the formation of a biloma. Additionally, the adoption of CEUS offers the dual benefit of minimizing radiation exposure for the patient and obviating the requirement for anesthesia. In summary, CEUS emerges as a compelling alternative to conventional diagnostic methods for effectively managing a biloma.

Stripping the catheter: A new device for an old technique.

Fibroblastic sleeve is a common pathophysiological phenomenon characterized by the formation of a mixed fibrous-collagen tissue encasing the outside of venous access devices. Although it nearly always presents asymptomatically, this catheter-related complication represents one of the leading culprits of venous catheters malfunction. Several techniques have been described for the management of dysfunctional catheters secondary to fibroblastic sleeve, including medical therapy, catheter exchange, balloon angioplasty, and percutaneous stripping. However, there is no common consensus for the treatment management in patients who present contraindications to surgical port removal. This report illustrates the case of a port catheter malfunction due to a fibroblastic sleeve in an oncological patient with a high risk of bleeding. This was effectively treated with a minimally invasive stripping technique using an off-label device for mechanical thrombectomy, namely the ClotTriever system (Inari Medical, Irvine, CA).

Surveillance or Dynamic Sentinel Lymph-Node Biopsy in Low-Risk Clinically N0 Penile Squamous Cell Carcinoma: Single-Institution Real World Data.

INTRODUCTION: Surveillance is the standard management in low-risk cN0 penile squamous cell carcinoma (peSCC) patients. However, no previous analysis focused on early and long-term outcomes of these patients. We report on main oncological outcomes of a large series of low-risk cN0 peSCC patients. PATIENTS AND METHODS: Between 1980 and 2017 included, 93 evaluable consecutive low-risk (ie, pT1a G1 cN0M0) peSCC patients underwent primary tumor surgery and either observation (74) or dynamic sentinel node biopsy (DSNB) (19) following a clinical diagnosis of T1 in 66 (71%), T2 in 15 (16.1%) and Tx in 12 (12.9%) patients, respectively. The statistical significance of differences in medians and proportions was tested with the Kruskal-Wallis and chi-square tests. Kaplan-Meier plots illustrated 5-year inguinal relapse (IR)-free survival rates. RESULTS: Median age was 60 years (IQR: 50-69 years). Median follow-up was 92 months (IQR 54-133 months). Surveillance was more frequently adopted in clinical (c)T1 than in cT2 tumors (79.7% vs. 36.8%). None of 19 patients who had DSNB had nodal metastasis. Overall, 7 (7.5%) out of 93 pT1aG1cN0 peSCC patients had IR after a median interval of 9 months. Of note, 1 patient only relapsed after 12 months of surveillance. After stratification according to IR, relapses occurred more frequently in younger patients (59 vs. 64 years, P < .001). The 5-year IR-free survival rates for the entire cohort was 92% (95% Confidence interval [CI] 87-98%). CONCLUSIONS: Observation is a safe and effective management for low-risk peSCC patients. Younger patients may be offered a mini-invasive staging as an alternative.

Bilateral inguinal lymph-node dissection vs. unilateral inguinal lymph-node dissection and dynamic sentinel node biopsy in clinical N1 squamous cell carcinoma of the penis.

INTRODUCTION: To evaluate the role of unilateral inguinal lymph-node dissection (ILND) plus contralateral dynamic sentinel node biopsy (DSNB) vs. bilateral ILND in clinical N1 (cN1) penile squamous cell carcinoma (peSCC) patients. MATERIAL AND METHODS: Within our institutional database (1980-2020, included), we identified 61 consecutive cT1-4 cN1 cM0 patients with histological confirmed peSCC who underwent either unilateral ILND plus DSNB (26) or bilateral ILND (35). RESULTS: Median age was 54 years (Interquartile range [IQR]: 48-60 years). Median follow-up was 68 months (IQR 21-105 months). Most patients had pT1 (23 %) or pT2 (54.1%), as well as G2 (47.5%) or G3 (23%) tumors, while lymphovascular invasion (LVI) was present in 67.1% of cases. Considering a cN1 and a cN0 groin, overall 57 out of 61 patients (93.5%) had nodal disease in the cN1 groin. Conversely, only 14 out of 61 patients (22.9%) had nodal disease in the cN0 groin. 5-year IR-free survival was 91% (Confidence interval [CI] 80%-100%) for bilateral ILND group and 88% (CI 73%-100%) for the ipsilateral ILND plus DSNB group (P-value 0.8). Conversely, 5-year CSS was 76% (CI 62%-92%) for bilateral ILND group and 78% (CI 63%-97%) for the ipsilateral ILND plus contralateral DSNB group (P-value 0.9). CONCLUSIONS: In patients with cN1 peSCC the risk of occult contralateral nodal disease is comparable to cN0 high risk peSCC and the gold standard, namely bilateral ILND, may be replaced by unilateral ILND and contralateral DSNB without affecting positive node detection, IRRs and CSS.

Laparoscopic retroperitoneal lymph-node dissection in metastatic nonseminomatous germ-cell tumors.

OBJECTIVES: To support laparoscopic post-chemotherapy retroperitoneal lymph-node dissection (L-PC-RPLND) as a potential new standard, we report on a large dataset of patients systematically undergoing L-PC-RPLND. PATIENTS AND METHODS: Patients with unilateral residual mass (≥1 cm), normalized markers, limited encasement (<30%) of gross retroperitoneal vessels underwent unilateral L-PC-RPLND with no adjuvant chemotherapy. Surgical performances, histology, hospital stay, complications within 30 days and follow-up visits were recorded. Multivariable linear and logistic regression models were used. RESULTS: Between February 2011 and January 2021, 151 consecutive patients underwent L-PC-RPLND. Median size of the residual mass was 25 mm (interquartile range [IQR] 20-35 mm). Overall median operative time was 208 min (IQR 177-241) and was 51 min longer (p-value <0.001) for right L-PC-RPLNDs. Eleven procedures were converted to open surgery. Median number of removed and positive nodes was 11 (IQR 8-16) and 1 (IQR 1-2), respectively. Mean hospital stay was 2 days (IQR 2-3). Nine complications (6%) occurred: two were Clavien-Dindo grade III. Definitive pathology revealed post-pubertal teratoma in 65.6%, fibro-necrotic tissue in 23.8%, teratoma with malignant somatic component in 6.6% and viable tumour in 4.0% patients. In multivariable linear regression models, fibro-necrotic tissue (32 min, CI 8.5-55.5; p < 0.01) and residual volume (1.05 min, CI 0.24-1.85; p < 0.01) achieved independent predictor status for longer operative time. All patients, but one, are alive and disease-free after a median follow-up of 22 months (IQR 10, 48). CONCLUSION: L-PC-RPLND, when adequately planned, is safe and effective for most patients with low to medium volume residual masses.

Safety and antitumor activity of metformin plus lanreotide in patients with advanced gastro-intestinal or lung neuroendocrine tumors: the phase Ib trial MetNET2.

In retrospective studies, metformin use has been associated with better clinical outcomes in diabetic patients with advanced, well-differentiated neuroendocrine tumors (WDNETs). However, prospective evidence of metformin safety and activity is lacking. Here, we conducted the first-in-human phase Ib MetNET2 trial to investigate the safety and antitumor activity of metformin in combination with the somatostatin analog lanreotide autogel (ATG) in both diabetic and non-diabetic patients with advanced WDNETs of the gastrointestinal (GI) or thoracic tract. Enrolled patients received lanreotide ATG 120 mg plus oral metformin, up to a maximum dosage of 2550 mg/day. We enrolled 20 patients, of whom 18 (90%) and 2 (10%) had WDNETs of the GI and thoracic tract, respectively. Fourteen patients (70%) were non-diabetic. With a 5% incidence of SAEs, the study met its primary objective of demonstrating treatment safety. With a median follow-up of 39 months (95% CI 28-NE), median PFS was 24 months (95% CI 16-NE), with 12-month and 24-month PFS probability of 75% (95% CI 58-97) and 49% (95% CI 31-77), respectively. We found no statistically significant PFS differences between diabetic and non-diabetic patients. Among exploratory analyses, the presence of tumor genomic alterations in DNA damage pathways was associated with trend towards worse PFS, whereas a precocious reduction of HOMA-IR index and plasma cholesterol concentration showed a trend towards an association with better PFS. In conclusion, metformin plus lanreotide ATG is a safe and well tolerated combination treatment that is associated with promising antitumor activity in both non-diabetic and diabetic patients with WDNETs, and that warrants further investigation in larger clinical trials.

A "blood theft" after liver transplantation: the role of interventional radiology in the management and treatment of splenic artery steal syndrome.

Splenic artery steal syndrome is a rare complication after liver transplant. It could lead to rapidly evolving major issues such as ischemic cholangiopathy and acute graft failure. Although the pathophysiology is not yet well understood, if diagnosed in time it could be easily managed with interventional radiology treatments. We present a case of a 47-year-old man presented to our institute with radiological findings typical for multifocal hepatocellular carcinoma in a cirrhotic liver. After therapy he underwent transplant. Some days after surgery he developed signs of acute liver failure. Steal syndrome was suspected by laboratory tests and radiology exams. The syndrome was confirmed by angiography and treated. The graft was saved, and the patient is still alive and free of disease. The purpose of this paper is to explain the importance of radiology exams in the diagnosis of splenic steal syndrome, explain its pathogenesis and describe the interventional management of this complication.

Long Term Survival Analysis in a Cohort of 125 Patients with Hepatocellular Carcinoma Treated with Transarterial Chemoembolization Using Small Drug Eluting Beads.

PURPOSE: Different types of drug-eluting beads have been proposed for hepatocellular carcinoma (HCC) treatment, but long-term results are not well known. We report safety, efficacy and long-term overall survival of HCC patients not amenable of curative therapies treated with transcatheter arterial chemoembolization (TACE) using drug-eluting beads sized 70-150 micron. MATERIALS AND METHODS: This single-center retrospective study included 125 patients with Barcelona Clinic Liver Cancer stage A (80), B (45) and compensated cirrhosis. TACE was executed injecting drug-elutings microparticles loaded with 75 mg of Doxorubicine and was repeated in patients with partial response or stable disease after one month. Adverse events, response according to modified Response Evaluation Criteria in Solid Tumors and overall survival were assessed. RESULTS: Chemoembolization with 70-150 micron beads revealed an objective response rate of 88% according to mRECIST criteria and complete response was 60%. After a median follow-up of 53.3 months, overall survival was 36.6 months. Data were censored at the date of liver transplantation in 35 patients. 33 on 125 patients (26,4%) experienced at least one adverse event. We recorded a total of 102 adverse events and 18 were of a high grade (G3-G4). 30 day mortality was 0%. CONCLUSION: Chemoembolization with very small particles (70-150 µm) is an effective and safe treatment in unresectable HCC both as a primary therapy or as bridge to transplantation.

Renal tumor biopsy in patients with cT1b-T4-M0 disease susceptible to radical nephrectomy: analysis of safety, accuracy and clinical impact on definitive management.

PURPOSE: Renal tumor biopsy was provided in patients candidate to radical nephrectomy for a renal mass ≥4 cm, to evaluate treatment deviation. METHODS: Between 2008 and 2017, 102 patients with a solid renal mass ≥4 cm with no distant metastases underwent preliminary renal tumor biopsy. We investigated the proportion of patients who proceeded with radical nephrectomy, variables predicting non-renal cell carcinoma (RCC) and concordance between biopsy findings and definitive pathology. RESULTS: Median tumor size was 70 mm (IQR 55-110). Clinical stage was cT1b in 41, cT2 in 33, cT3 in 25 and cT4 in three patients. A median of three (IQR 2-3) renal tumor biopsies were taken with 16/18 Gauge needles in 97% of cases. Clavien grade I complications occurred in five cases. Malignant tumors were documented in 84 patients: 78 RCCs and six non-RCCs. Fifteen biopsies documented oncocytoma and three were non-diagnostic. Grade was reported in 50 RCCs: 42 (84%) were low and eight (16%) high grade. Eighty-three patients proceeded with radical nephrectomy; six non-RCC malignant tumors underwent combined and/or intensified treatment; 13 of 15 patients with oncocytoma did not undergo radical nephrectomy (eight underwent observation). Definitive pathology confirmed diagnosis in all cases. Grade concordance was 84%, considering two tiers (high vs low grade). No preoperative clinical variable predicted definitive pathology. CONCLUSIONS: Renal tumor biopsy is a safe procedure that leads to radical nephrectomy in most tumors ≥4 cm. Nonetheless, 20% of patients exhibited non-RCC histology. Renal tumor biopsy should be considered in this setting.

Metastatic pheochromocytomas and paragangliomas: where are we?

Pheochromocytomas and paragangliomas (PPGLs) can metastasize in approximately 15-20% of cases. This review discusses the available evidence on the biology and treatment of metastatic PPGLs. Chemotherapy is the first-line treatment option for this evolving and symptomatic disease. In patients with high MIBG uptake and positive PETGa-68, radiometabolic treatment may be considered. The efficacy of sunitinib has been shown in observational studies, and pembrolizumab has been evaluated in phase II clinical studies, while other agents investigated in this setting are anti-angiogenic drugs cabozantinib, dovitinib, axitinib and lenvatinib. As these agents' efficacy and safety data, alone or in combination, are scant and based on few treated patients, enrollment in clinical trials is mandatory. Future therapeutic options may be represented by DNA repair system inhibitors (such as olaparib), HIF2 inhibitors and immunotherapy.

Radioembolization of Hepatocellular Carcinoma with 90Y Glass Microspheres: No Advantage of Voxel Dosimetry with Respect to Mean Dose in Dose-Response Analysis with Two Radiological Methods.

In this confirmatory study, we tested if a calculation that included the non-uniformity of dose deposition through a voxel-based dosimetric variable Ψ was able to improve the dose-response agreement with respect to the mean absorbed dose D. We performed dosimetry with 99mTc-MAA SPECT/CT and 90Y-PET/CT in 86 patients treated 8 instead of 4 days after the reference date with 2.8 times more 90Y glass microspheres/GBq than in our previous study. The lesion-by-lesion response was assessed with the mRECIST method and with an experimental densitometric criterion. A total of 106 lesions were studied. Considering Ψ as a prognostic response marker, having no Ψ provided a significantly higher AUC than D. The correlation, t-test, and AUC values were statistically significant only with the densitometric method and only with post-therapy dosimetry. In comparison with our previous study, the dose-response correlation and AUC values were poorer (maximum r = 0.43, R2 = 0.14, maximal AUC = 0.71), and the efficacy at a high dose did not reach 100%. The expected advantages of voxel dosimetry were nullified by the correlation between any Ψ and D due to the limited image spatial resolution. The lower AUC and efficacy may be explained by the mega-clustering effect triggered by the higher number of microspheres/GBq injected on day 8.

Target therapies plus somatostatin analogs in NETs: a network meta-analysis.

Although combination therapy is not recommended in patients with gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs), this strategy is widely used in clinical practice. This network meta-analysis of randomized trials evaluates targeted therapies and somatostatin analogues in GEP-advanced NETs, either alone or in combination, comparing the efficacy of different, single or combined treatment strategies in terms of progression-free survival (PFS). Interventions were grouped as analogs, everolimus, everolimus plus SSAs, sunitinib and placebo. In a secondary analysis, we also assessed the efficacy of individual-specific pharmacological treatments vs placebo or each other. From 83 studies identified, 8 randomized controlled trials were selected, with a total of 1849 patients with either functioning or non-functioning NETs. The analysis confirmed the superiority of all treatments over placebo (HR ranging from 0.34, 95% CI: 0.24-0.37 with the combination of everolimus plus SSAs to 0.42, 0.31-0.57 with the analogs; moderate quality of evidence). On ranking analysis, the combination of everolimus plus SSA (P score = 0.86) and then everolimus alone (P score = 0.65) ranked highest in increasing PFS. On comparative evaluation of different interventions, pasireotide (P score = 0.96) and everolimus + octreotide (P score = 0.82) ranked as the best pharmacological treatment options. Our findings support the use of combination therapy in the treatment of functioning and non-functioning GEP NETs. The role of pasireotide should be explored in selected subgroups of patients. Lastly, the combination of everolimus and octreotide appears promising and should be more widely considered in clinical practice.

Local therapies for liver metastases of rare head and neck cancers: a monoinstitutional case series.

INTRODUCTION: Transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) are established procedures for treating hepatocellular cancer and selected malignancies with liver metastasis. The aim of this study is to describe a monoinstitutional case series of local approaches in patients with liver metastases from rare head and neck cancers (HNCs). METHODS: This is a retrospective series of adult patients with HNC treated with liver locoregional approaches (TACE or RFA) at our institution from 2007 to 2018. In case of chemoembolization, the preferred chemotherapeutic drug was doxorubicin. Response according to RECIST (Response Evaluation Criteria in Solid Tumors) was assessed with contrast-enhanced computed tomography scans. RESULTS: Thirty-four patients were treated (20 men, median age 58 years) with TACE (27), transarterial embolization (2), or RFA (7). Primary tumours were salivary gland (21), thyroid (6), nasopharyngeal (5), and sinonasal cancers (2). Seventeen patients (50%) had a single metastatic liver nodule; 70% of the remaining 17 patients had at least three liver metastases. The median diameter of the metastatic liver mass undergoing treatment was 39 mm (range 11-100 mm). Median follow-up was 27.6 months. Response rate was 35% (3% complete, 32% partial response). Median progression-free survival and overall survival were 6.9 and 19.6 months, respectively. Treatment-related adverse events occurred in 59% of patients (21% grade ⩾ 3; no grade 5). DISCUSSION: This retrospective case series demonstrates that locoregional radiologic approaches for rare HNCs with liver metastases are feasible. These procedures deserve further prospective studies before being considered safe and active in these malignancies where the availability of effective systemic treatments is lacking.

Recent Advances in the Management of Typical and Atypical Lung Carcinoids.

Neuroendocrine neoplasms of the lung represent about 20% to 30% of all neuroendocrine tumors. On the basis of clinical and pathologic characteristics, 2 different categories of tumors may be defined: poorly differentiated neuroendocrine neoplasms, characterized by a high rate of recurrences and poor prognosis, and well-differentiated neuroendocrine neoplasms (typical carcinoids and atypical carcinoids), which generally display an indolent course. Lung carcinoids represent only 1% to 5% of all lung malignancies, but their incidence has significantly increased over the past 30 years. Surgery is the reference standard of treatment for lung carcinoids with locoregional disease. For advanced or unresectable lung carcinoids, several therapeutic options are available, but the choice should be shared within a multidisciplinary team to ensure optimal therapeutic outcomes. We describe the current management of these rare neoplasms.