Distant supervision for imaging-based cancer sub-typing in Intrahepatic Cholangiocarcinoma.

Finding effective ways to perform cancer sub-typing is currently a trending research topic for therapy opti-mization and personalized medicine. Stemming from genomic field, several algorithms have been proposed. In the context of texture analysis, limited efforts have been attempted, yet imaging information is known to entail useful knowledge for clinical practice. We propose a distant supervision model for imaging-based cancer sub-typing in Intrahepatic Cholangiocar-cinoma patients. A clinically informed stratification of patients is built and homogeneous groups of patients are characterized in terms of survival probabilities, qualitative cancer variables and radiomic feature description. Moreover, the contributions of the information derived from the ICC area and from the peri tumoral area are evaluated. The findings suggest the reliability of the proposed model in the context of cancer research and testify the importance of accounting for data coming from both the tumour and the tumour-tissue interface. Clinical relevance - In order to accurately predict cancer prognosis for patients affected by ICC, radiomic variables of both core cancer and surrounding area should be exploited and employed in a model able to manage complex information.

The Histopathological Growth Pattern of Colorectal Liver Metastases Impacts Local Recurrence Risk and the Adequate Width of the Surgical Margin.

BACKGROUND: The histopathological growth pattern (HGP) of colorectal liver metastases (CLM) has been associated with prognosis. This study was designed to elucidate if the HGP is associated with local recurrence risk and impacts the adequate width of surgical margin. METHODS: All consecutive patients resected for CLM in 2018-2019 were considered. HGP was prospectively classified as follows: desmoplastic, pushing, and replacement. Surgical margin was classified as follows: R0 (margin ≥ 1 mm), R1vasc (0-mm margin, tumor detachment from intrahepatic vessels), and R1par (tumor exposure along transection plane). R0 resections were further distinguished in R0min (1-mm margin) and R0wide (> 1-mm margin). RESULTS: A total of 340 resection areas in 136 patients were analyzed (70 R0min, 143 R0wide, 31 R1vasc, 96 R1par). HGP was desmoplastic in 26 cases, pushing in 221, and replacement in 93. Thirty-six local recurrences occurred (11%, median follow-up 21 months): 1 after R0wide, 4 after R0min, 3 after R1vasc, and 28 after R1par resection. In R1par group, local recurrence rate was high independently of HGP (29%). In R1vasc and R0min groups, local recurrence risk was higher in the replacement group (R1vasc: 29% vs. 4% if pushing/desmoplastic; R0min: 11% vs. 4%). In R0wide group, local recurrence risk was low for all HGP ( < 1%). Independent predictors of local recurrence were replacement HGP (odds ratio = 1.654, P = 0.036), and R1par resection (odds ratio = 57.209, P < 0.001 vs. R0). CONCLUSIONS: Replacement HGP is associated with an increased risk of local recurrence. In these patients, a wide surgical margin should be pursued, because R1vasc and R0min resections could be insufficient. R1par resection is inadequate, independently of the HGP.

Laparoscopic and open liver resection for hepatocellular carcinoma with Child-Pugh B cirrhosis: multicentre propensity score-matched study.

BACKGROUND: Laparoscopic liver resection for hepatocellular carcinoma (HCC) in Child-Pugh A cirrhosis has been demonstrated as beneficial. However, the role of laparoscopy in Child-Pugh B cirrhosis is undetermined. The aim of this retrospective cohort study was to compare open and laparoscopic resection for HCC with Child-Pugh B cirrhosis. METHODS: Data on liver resections were gathered from 17 centres. A 1 : 1 propensity score matching was performed according to 17 predefined variables. RESULTS: Of 382 available liver resections, 100 laparoscopic and 100 open resections were matched and analysed. The 90-day postoperative mortality rate was similar in open and laparoscopic groups (4.0 versus 2.0 per cent respectively; P = 0.687). Laparoscopy was associated with lower blood loss (median 110 ml versus 400 ml in the open group; P = 0.004), less morbidity (38.0 versus 51.0 per cent respectively; P = 0.041) and fewer major complications (7.0 versus 21.0 per cent; P = 0.010), and ascites was lower on postoperative days 1, 3 and 5. For laparoscopic resections, patients with portal hypertension developed more complications than those without (26 versus 12 per cent respectively; P = 0.002), and patients with a Child-Pugh B9 score had higher morbidity rates than those with B8 and B7 (7 of 8, 10 of 16 and 21 of 76 respectively; P < 0.001). Median hospital stay was 7.5 (range 2-243) days for laparoscopic liver resection and 18 (3-104) days for the open approach (P = 0.058). The 5-year overall survival rate was 47 per cent for open and 65 per cent for laparoscopic resection (P = 0.142). The 5-year disease-free survival rate was 32 and 37 per cent respectively (P = 0.742). CONCLUSION: Patients without preoperative portal hypertension and Child-Pugh B7 cirrhosis may benefit most from laparoscopic liver surgery.

Multicentre evaluation of case volume in minimally invasive hepatectomy.

BACKGROUND: Surgical outcomes may be associated with hospital volume and the influence of volume on minimally invasive liver surgery (MILS) is not known. METHODS: Patients entered into the prospective registry of the Italian Group of MILS from 2014 to 2018 were considered. Only centres with an accrual period of at least 12 months and stable MILS activity during the enrolment period were included. Case volume was defined by the mean number of minimally invasive liver resections performed per month (MILS/month). RESULTS: A total of 2225 MILS operations were undertaken by 46 centres; nine centres performed more than two MILS/month (1376 patients) and 37 centres carried out two or fewer MILS/month (849 patients). The proportion of resections of anterolateral segments decreased with case volume, whereas that of major hepatectomies increased. Left lateral sectionectomies and resections of anterolateral segments had similar outcome in the two groups. Resections of posterosuperior segments and major hepatectomies had higher overall and severe morbidity rates in centres performing two or fewer MILS/month than in those undertaking a larger number (posterosuperior segments resections: overall morbidity 30·4 versus 18·7 per cent respectively, and severe morbidity 9·9 versus 4·0 per cent; left hepatectomy: 46 versus 22 per cent, and 19 versus 5 per cent; right hepatectomy: 42 versus 34 per cent, and 25 versus 15 per cent). CONCLUSION: A volume-outcome association existed for minimally invasive hepatectomy. Complex and major resections may be best managed in high-volume centres.

ANTECEDENTES: Los resultados quirúrgicos pueden estar relacionados con el volumen de casos del hospital, pero no se conoce la influencia en la cirugía mínimamente invasiva del hígado (minimally­invasive liver surgery, MILS). MÉTODOS: Se incluyeron los pacientes registrados en el registro prospectivo del grupo italiano de MILS desde 2014 a 2018. Solo se consideraron centros con extensión de ≥ 12 meses y actividad estable de MILS durante el periodo de reclutamiento. El volumen de casos se definió como el número de MILS efectuado por mes. RESULTADOS: Se llevaron a cabo un total de 2.225 MILS en 46 centros, 9 de ellos con > 2 MILS/mes (n = 1.376 pacientes) y 37 centros con ≤ 2 MILS/mes (n = 849). La proporción de resecciones de segmentos anterolaterales disminuyó con el volumen de casos, mientras que la proporción de hepatectomías mayores aumentó. Los resultados para ambos grupos fueron similares en las seccionectomías lateral izquierda y en las resecciones del segmento anterolateral. Las resecciones del segmento posterosuperior y las hepatectomías mayores presentaron tasas más altas de morbilidad global y morbilidad grave en centros que realizaban ≤ 2 MILS/mes que en los que realizaban > 2 MILS/mes (resecciones del segmento posterosuperior, morbilidad global 30,4 versus 18,7%, morbilidad grave 9,9 versus 4,0%; hepatectomía izquierda, 46,2 versus 22,0%, 19,2 versus 5,5%; hepatectomía derecha, 41,7 versus 33,8%, 25,0 versus 14.9%). CONCLUSIÓN: Se observó una asociación volumen­resultado para la resección hepática mínimamente invasiva. Las resecciones complejas y mayores se pueden manejar mejor en centros de gran volumen.

Drop-out between the two liver resections of two-stage hepatectomy. Patient selection or loss of chance?

BACKGROUND: Two-stage hepatectomy (TSH) is the present standard for multiple bilobar colorectal liver metastases (CLM), but 25-35% of patients fail to complete the scheduled procedure (drop-out). To elucidate if drop-out of TSH is a patient selection (as usually considered) or a loss of chance. METHODS: All the consecutive patients scheduled for a TSH at the Paul Brousse Hospital between 2000 and 2012 were considered. TSH patients were matched 1:1 with patients receiving a one-stage ultrasound-guided hepatectomy (OSH) at the Humanitas Research Hospital in the same period. Matching criteria were: primary tumor N status; timing of CLM diagnosis; CLM number and distribution into the liver. RESULTS: Sixty-three pairs of patients were analyzed. Demographic and tumor characteristics were similar (median 7 CLM), except for more chemotherapy lines and adjuvant chemotherapy in TSH. Drop-out rate of TSH was 38.1% (0% of OSH). The two groups had similar R0 resection rate (19.0% OSH vs. 15.9% TSH). OSH and completed TSH had similar five-year survival (from CLM diagnosis 49.8% vs. 49.7%, from liver resection 36.1% vs. 44.3%), superior to drop-out (10% three-year survival, p < 0.001). OSH and completed TSH had similar recurrence-free survival (at three years 21.7% vs. 20.5%) and recurrence sites. The completion of resection (drop-out vs. OSH/completed TSH) was the only independent prognostic factor (p = 0.003). CONCLUSIONS: Drop-out of TSH could be a loss of chance rather than a criteria for patient selection. "Unselected" OSH patients had the same outcomes of selected patients who completed TSH. A complete resection is the main determinant of prognosis.

Serum microRNAs as novel biomarkers for primary sclerosing cholangitis and cholangiocarcinoma.

The diagnosis of primary sclerosing cholangitis (PSC) is difficult due to the lack of sensitive and specific biomarkers, as is the early diagnosis of cholangiocarcinoma (CC), a complication of PSC. The aim of this study was to identify specific serum miRNAs as diagnostic biomarkers for PSC and CC. The levels of 667 miRNAs were evaluated in 90 human serum samples (30 PSC, 30 CC and 30 control subjects) to identify disease-associated candidate miRNAs (discovery phase). The deregulated miRNAs were validated in an independent cohort of 140 samples [40 PSC, 40 CC, 20 primary biliary cirrhosis (PBC) and 40 controls]. Receiver operating characteristic (ROC) curves were established and only miRNAs with an area under the curve (AUC) > 0·70 were considered useful as biomarkers. In the discovery phase we identified the following: 21 miRNAs expressed differentially in PSC, 33 in CC and 26 in both in comparison to control subjects as well as 24 miRNAs expressed differentially between PSC and CC. After the validation phase, miR-200c was found to be expressed differentially in PSC versus controls, whereas miR-483-5p and miR-194 showed deregulated expression in CC compared with controls. We also demonstrate a difference in the expression of miR-222 and miR-483-5p in CC versus PSC. Combination of these specific miRNAs further improved the specificity and accuracy of diagnosis. This study provides a basis for the use of miRNAs as biomarkers for the diagnosis of PSC and CC.

State of the art of intraoperative ultrasound in liver surgery: current use for staging and resection guidance.

The performance of hepatic surgery without a parenchyma-sparing strategy carries significant risks for patient survival because of the not negligible occurrence of postoperative liver failure. In modern liver surgery the use of intraoperative ultrasound (IOUS) includes staging of the liver disease and more importantly resection guidance. IOUS allows the performance of so-called "radical but conservative surgery", which is pivotal in offering a chance of a cure to an increasing number of patients who until a few years ago were considered only for palliative care. The present article details the rationale of IOUS for staging and for resection guidance in liver surgery.

Organ targeted mini-invasive approach in the treatment of colorectal cancer liver metastases: role of intraoperative ultrasonography as guidance in liver resection.

Surgery is still considered the gold standard therapy for patient carries of colorectal liver metastases (CLM) because related to more chance of long-term survival. The major limitation of surgical approach is its technical feasibility because of the inability to completely clear the metastatic disease in a single operation while preserving enough future liver remnant. Thus, the two-stage hepatectomy is generally recommended for these patients. We have shown how with an extensive use of intraoperative ultrasonography based on strict criteria is possible performing curative resection in a single stage despite complex tumor presentation as in multifocal and bilateral spread. This strategy aims to keep the liver skeleton although allowing the radical tumor clearance: as consequence it is minimized the need for a multistep surgical strategy, and is enhanced the feasibility of repeated hepatectomies in the event of recurrent disease.

Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis.

BACKGROUND: Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with HCC and CP class B. PATIENTS AND METHODS: A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily. [Results of this study were presented in part at the ASCO 2012 Gastrointestinal Cancers Symposium, 19-21 January 2012. J Clin Oncol 2012; 30 (Suppl 4): abstract 306.] RESULTS: Overall progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 3.9, 4.1 and 9.1 months, respectively. For patients with CP class A versus B status, PFS was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar. CONCLUSION: Although patients with HCC and CP class B liver function have poorer outcomes than those with CP class A function, data suggest that patients with CP class B liver function can tolerate treatment and may still benefit from sorafenib.

Complete response in 5 out of 38 patients with advanced hepatocellular carcinoma treated with stem cell differentiation stage factors: case reports from a single centre.

Hepatocellular carcinoma (HCC) represents the third cause of cancer-related death. Because HCC is multi-centric with time, excluding the few transplanted patients, sooner or later it becomes untreatable with loco-regional therapies and, until some years ago, it was not responsive to systemic therapies. In 2005 a randomized trial indicated the efficacy of a product containing stem cell differentiation stage factors (SCDSF) taken from zebra fish embryos during the stage in which the totipotent stem cells are differentiating into the pluripotent adult stem cells. In such a trial the patients, with "intermediate" and "advanced" HCC according to BCLC/AASLD guidelines, presented benefit in terms of performance status (PS) and objective tumoral response, with some cases (2.4%) of complete response (CR). The aim of this cohort study is to report the experience of a tertiary referral center on the evidence of cases of CR in patients with "advanced" stage HCC treated with SCDSF as supportive care. CR was regarded as sustained disappearance of the neoplastic areas or blood supply therein, accompanied by normalization of AFP levels. Out of 49 patients consecutively recruited and retrospectively evaluated, 38 had "advanced" stage and 11 "terminal" stage. In 5 patients with "advanced" stage a sustained CR was reported (13.1%). Improvement on PS was obtained in 17 patients (34.6%). No side effects occurred. SCDSF treatment confirmed its efficacy in patients with "advanced" HCC, in terms of PS and tumoral response.

Intraoperative ultrasonographic detection of communicating veins between adjacent hepatic veins during hepatectomy for tumours at the hepatocaval confluence.

BACKGROUND: The presence of communicating veins between adjacent hepatic veins may allow parenchyma-sparing hepatectomy. Taking advantage of improvements in ultrasound technology, such as e-flow modality, a study of the presence of communicating veins was conducted in patients with hepatic tumours at the caval confluence. METHODS: Consecutive patients undergoing surgery between October 2007 and December 2009 for hepatic tumours in contact with or invading a hepatic vein at its caval confluence were included. Communicating vein mapping by means of e-flow intraoperative ultrasonography (EF-IOUS) was carried out. RESULTS: A total of 20 patients were enrolled. Communicating veins between adjacent hepatic veins or with the inferior vena cava were detected in 16 patients. The median number of communicating veins was 1 (range 0-5). The total number of lesions removed was 126 (range 1-46). In 11 of 12 patients requiring resection of a hepatic vein, communicating veins enabled a parenchyma-sparing procedure to be performed. No patient had a formal major hepatectomy. There was no postoperative mortality or major morbidity. CONCLUSION: EF-IOUS estimation of the frequency of communicating veins between adjacent hepatic veins suggests that such veins are common. This may facilitate parenchyma-sparing procedures in patients with hepatic tumours encroaching on major hepatic veins.

[Surgical treatment of liver metastases from colorectal carcinoma]. / Il trattamento chirurgico delle metastasi epatiche da carcinoma del colon-retto.

In patients with colorectal liver metastases, hepatic resection is the treatment of choice, and the 5-year overall survival rate after surgery is now approaching 60%. The multidisciplinary and multimodality approaches that may include preoperative systemic chemotherapy, and the recent innovative surgical techniques that may include complex ultrasound guided hepatic resection, have enabled a large proportion of patients to undergo potentially curative treatment. The definition of resectability has shifted from a focus on tumor characteristics, such as tumor number and size, to determination whether both intrahepatic and extrahepatic disease can be completely resected, and whether such an approach is appropriate from an oncological standpoint. Hepatobiliary surgeons and medical oncologists should work together to evaluate patients with colorectal liver metastases to individualize the treatment strategy to maximize the chances of long-term survival.

Salvage hepatic resection after incomplete interstitial therapy for primary and secondary liver tumours.

BACKGROUND: When the response to percutaneous ablation therapy (PAT) of liver tumours is incomplete, surgery may be undertaken as a salvage therapy. To validate the safety and effectiveness of salvage hepatectomy, patients who had undergone PAT or no treatment before hepatectomy were compared. METHODS: Of 137 patients who had hepatectomy for primary and secondary tumours, 21 had undergone PAT and 116 had surgery as primary treatment. Tumour features and the incidence of liver cirrhosis were similar in the two groups. RESULTS: Peroperative mortality and major morbidity rates were zero and 5 per cent (one of 21) respectively among patients who had PAT before surgery, and 0.9 per cent (one of 116) and zero in those who did not. Duration of operation (mean 495 versus 336 min; P<0.001), clamping time (mean 81 versus 53 min; P<0.001), blood loss (mean 519 versus 286 ml; P=0.004), need for blood transfusion (six of 21 patients versus nine of 116; P=0.001), and rates of thoracophrenolaparotomy (eight of 21 versus 14 of 116; P<0.001) and resection of other tissues (six of 21 versus nine of 116; P<0.001) were significantly higher in the PAT group. CONCLUSION: Hepatectomy after incomplete PAT is safe and effective, but more extensive procedures are necessary. The effect of salvage hepatectomy on long-term outcome is still unclear.

Ultrasonographically guided surgical approach to liver tumours involving the hepatic veins close to the caval confluence.

BACKGROUND: Intraoperative ultrasonography (IOUS) may allow a more conservative procedure in patients with liver tumours involving a hepatic vein at the caval confluence. The aim of this study was to determine whether IOUS and colour Doppler IOUS might reduce the rate of major hepatectomy and vascular reconstruction in patients with such tumours. METHODS: Of 133 consecutive patients with a liver tumour who underwent hepatectomy, 22 had involvement of a hepatic vein at the caval confluence. The surgical strategy employed was determined by IOUS findings of the relationship between the tumour and hepatic vein, the presence of accessory veins, and portal flow as measured by colour Doppler IOUS following clamping of the hepatic vein to be resected. Mortality, morbidity, major resection, hepatic vein reconstruction and local recurrence rates were evaluated. RESULTS: There were no hospital deaths and only one patient suffered major morbidity. Although hepatic vein resection was performed in 15 patients, only two underwent major hepatectomy and none had vascular reconstruction. No patients had tumour recurrence at a mean follow-up of 23 months. CONCLUSION: IOUS allowed sparing of the liver parenchyma without tumour recurrence in most patients with a tumour involving a hepatic vein at the caval confluence, avoiding more extensive hepatectomy or vascular reconstruction.

Liver resection for primary hepatic neuroendocrine tumours: report of three cases and review of the literature.

Primary neuroendocrine tumours are rare especially in the liver, which is more often site of metastatic tumours. We report three cases of primary hepatic neuroendocrine tumours, which underwent hepatic resection. Review of the diagnostic and therapeutic approaches to these tumours are discussed.

Utility of the hooking technique for cases of major hepatectomy.

Currently, resective hepatic surgery should be considered an echoguided surgical procedure to guarantee conservative but radical resections. A simple and original technique guided by intraoperative ultrasonography, termed the "hooking technique," had been described previously. It enables the ligation sites of the intrahepatic vessels during systematic segmentectomy to be chosen precisely. This report describes a further application of this technique to allow safe ligation of portal vein main branches invaded by tumor thrombi during major hepatectomies.

Technical tricks for radical but conservative liver resection. The ultrasound guidance.

Rate of major resection is still high in most surgical institutions due to fear of incomplete tumor removal: this is in spite mortality and major morbidity of major hepatectomies, particularly in cirrhotic are still not negligible. Intraoperative ultrasonography (IOUS), when used not only for tumor staging but also for resection guidance, minimises the rate of major hepatectomies maintaining treatment radicality. Maintaining this policy, the rate of major resection in our experience is 15% if major hepatectomy is classified as removal of at least 1 sector or 2 adjacent segments, and 5% if we consider major resections only those which include at least 3 segments. This policy has allowed us a safe surgical approach with no mortality and minimal major morbidity and effective local treatment with no tumor relapses at the site of the resection after a mean follow-up of 18 months. Tricks for safe and radical IOUS-guided liver resections are here discussed.