Vessel-Guided Mesohepatectomy for Liver Partition and Staged Major Parenchyma-Sparing Hepatectomies with Super-Selective Portal Vein Embolization or Enhanced ALPPS to Achieve R0 Resection for Colorectal Liver Metastases at the Hepatocaval Confluence.

Background. R0 minor parenchyma-sparing hepatectomy (PSH) is feasible for colorectal liver metastases (CRLM) in contact with hepatic veins (HV) at hepatocaval confluence since HV can be reconstructed, but in the case of contact with the first-order glissonean pedicle (GP), major hepatectomy is mandatory. To pursue an R0 parenchyma-sparing policy, we proposed vessel-guided mesohepatectomy for liver partition (MLP) and eventually combination with liver augmentation techniques for staged major PSH. Methods. We analyzed 15 consecutive vessel-guided MLPs for CRLM at the hepatocaval confluence. Patients had a median of 11 (range: 0-67) lesions with a median diameter of 3.5 cm (range: 0.0-8.0), bilateral in 73% of cases. Results. Grade IIIb or more complications occurred in 13%, median hospital stay was 14 (range: 6-62) days, 90-day mortality was 0%. After a median follow-up of 17.5 months, 1-year OS and RFS were 92% and 62%. In nine (64%) patients, MLP was combined with portal vein embolization (PVE) or ALPPS to perform staged R0 major PSH. Future liver remnant (FLR) volume increased from a median of 15% (range: 7-20%) up to 41% (range: 37-69%). Super-selective PVE was performed in three (33%) patients and enhanced ALPPS (e-ALPPS) in six (66%). In two e-ALPPS an intermediate stage of deportalized liver PSH was necessary to achieve adequate FLR volume. Conclusions. Vessel-guided MLP may transform the liver in a paired organ. In selected cases of multiple bilobar CRLM, to guarantee oncological radicality (R0), major PSH is feasible combining advanced surgical parenchyma sparing with liver augmentation techniques when FLR volume is insufficient.

Exploring the Outcome of Disappearance or Small Remnants of Colorectal Liver Metastases during First-Line Chemotherapy on Hepatobiliary Contrast-Enhanced and Diffusion-Weighted MR Imaging.

We aimed to evaluate the outcome of the disappearance or small remnants of colorectal liver metastases during first-line chemotherapy assessed by hepatobiliary contrast-enhanced and diffusion-weighted MR imaging (DW-MRI). Consecutive patients with at least one disappearing liver metastasis (DLM) or small residual liver metastases (≤10 mm) assessed by hepatobiliary contrast-enhanced and DW-MRI during first-line chemotherapy were included. Liver lesions were categorized into three groups: DLM; residual tiny liver metastases (RTLM) when ≤5 mm; small residual liver metastases (SRLM) when >5mm and ≤10 mm. The outcome of resected liver metastases was assessed in terms of pathological response, whereas lesions left in situ were evaluated in terms of local relapse or progression. Fifty-two outpatients with 265 liver lesions were radiologically reviewed; 185 metastases fulfilled the inclusion criteria: 40 DLM, 82 RTLM and 60 SRLM. We observed a pCR rate of 75% (3/4) in resected DLM and 33% (12/36) of local relapse for DLM left in situ. We observed a risk of relapse of 29% and 57% for RTLM and SRLM left in situ, respectively, and a pCR rate of about 40% overall for resected lesions. DLM assessed via hepatobiliary contrast-enhanced and DW-MRI very probably indicates a complete response. The surgical removal of small remnants of liver metastases should always be advocated whenever technically possible.

Impact of baseline gadoxetic acid-enhanced liver magnetic resonance and diffusion-weighted imaging in resectable colorectal liver metastases: A prospective, monocentric study.

BACKGROUND: Liver magnetic resonance imaging (MRI) utilizing hepatocyte-specific contrast agent and diffusion-weighted imaging (DWI) is currently used to properly stage colorectal liver metastases (CRLM) in patients candidate to liver surgery. However, the added value of liver MRI in choosing the treatment strategy in resectable CRLM over computed tomography (CT)-scan is not clear. PATIENTS AND METHODS: This is a prospective monocentric collection of consecutive cases of patients with CRLM conceived with the aim to assess the added value of liver MRI in changing the initial treatment strategy planned according to CT-scan. Potential changes in the initially planned strategy were defined as: - from upfront surgery to perioperative chemotherapy (fluoropyrimidine and oxaliplatin) - from upfront surgery to first-line systemic therapy (doublet or triplet plus a biological agent) - from perioperative chemotherapy to first-line systemic therapy. Hypothesising that MRI may induce a change in the choice of the treatment strategy in the 20% of cases (alternative hypothesis), against a null hypothesis of 5%, with one-tailed alpha and beta errors of 0.05 and 0.20 respectively, 27 patients were needed. The added value of liver MRI would have been considered clinically meaningful if at least 4 changes in the treatment strategy were observed. RESULTS: Among 27 enrolled patients, upfront surgery and perioperative chemotherapy strategies were chosen in 17 (63%) and 10 (37%) cases, respectively, based on CT-scan. After liver MRI, additional liver lesions were found in 8 patients (30%) and the initial strategy was changed in 7 patients (26%) (4 initially deemed candidate to upfront surgery and 3 initially sent to perioperative chemotherapy) that were treated with first-line systemic therapy. CONCLUSIONS: Our results support the indication of the current guidelines on the routine use of liver MRI in the initial workup of patients with resectable CRLM with an MRI-driven changes of initial treatment plan in a relevant percentage of cases.

The management of colorectal liver metastases amenable of surgical resection: How to shape treatment strategies according to clinical, radiological, pathological and molecular features.

Metastatic colorectal cancer (mCRC) patients have poor chances of long term survival, being < 15% of them still alive after 5 years from diagnosis. Nonetheless, patients with colorectal liver metastases (CRLM) may be eligible for metastases resection thus being able to achieve long-term disease remission and survival. The likelihood for patients with CRLM of being or becoming eligible for liver metastasectomy is increasing, thanks to the evolution of surgical techniques, the availability of active systemic treatments and the widespread diffusion of experienced multidisciplinary boards to manage these patients. However, disease relapse after liver surgery is common and occurs in two-thirds of resected patients. Therefore, adequate radiological staging and risk stratification is crucial for the optimal selection of patients candidate to surgery in order to maximize the benefit-risk ratio of liver metastasectomy and to individualize the treatment strategy. Based on the multidimensional assessment, three possible approaches are available: upfront liver surgery followed by adjuvant chemotherapy, perioperative chemotherapy preceding and following liver surgery, and an upfront systemic treatment including chemotherapy plus a targeted agent, both chosen according to patients' and tumours' characteristics, then followed by liver surgery if indicated. In this review, we describe the most important factors impacting the therapeutic choices in patients with resectable and potentially resectable CRLM, and we discuss the most promising factors that may reshape the future decision-making process of these patients.

Upper transversal hepatectomy with double hepatic vein resection and reconstruction to treat colorectal cancer liver metastases at the hepatocaval confluence: a strategy to achieve R0 liver-sparing resection.

BACKGROUND: Repeated hepatectomies in the therapeutic route of patients with colorectal liver metastases (CRLM) may improve their long term survival. Hepatic vein (HV) resection and reconstruction allows parenchyma-sparing hepatectomy (PSH) and R0 resections for CRLM in contact with one HV. We aimed at verifying the feasibility of PSH with double HV resection and direct reconstruction for CRLM in contact with two HVs at the hepatocaval confluence. METHODS: Out of 106 consecutive PSH performed for CRLM deep-located in segments I-IVa-VII-VIII, four (3.7%) PSH were performed with resection of CRLM en bloc with two adjacent HVs which were both reconstructed with double direct HV anastomosis: 3 cases between right-HV and middle-HV and 1 case between middle-HV and left-HV. Two patients had previously undergone liver resection. Three patients had one single lesion and one had 5 CRLMs. RESULTS: Median size of CRLMs in contact with HVs was 25 mm (range 22-30 mm). At histological examination, all resections were R0 except one R1-vascular (detachment from glissonean pedicle): in all cases at least one HV and in 1 case both HVs were infiltrated by the tumor cells. After median follow-up of 18 (range 3.5-41.2) months, all HVs were patent. All patients were alive and in good general conditions, and 3 patients were disease free (one of them following a liver re-resection). One patient experienced a grade IIIa complication. Median hospital-stay was 11 (range 9-13) days. CONCLUSION: In patients with CRLMs involving two adjacent HVs at the hepatocaval confluence, liver resection with double HV resection and direct reconstruction is feasible and may be considered to guarantee oncological radicality (R0) and spare health parenchyma.

Modeling Hepatocellular Carcinoma Cells Dynamics by Serological and Imaging Biomarkers to Explain the Different Responses to Sorafenib and Regorafenib.

In advanced HCC, tyrosine-kinase inhibitors obtain partial responses (PR) in some patients and complete responses (CR) in a few. Better understanding of the mechanism of response could be achieved by the radiomic approach combining digital imaging and serological biomarkers (α-fetoprotein, AFP and protein induced by vitamin K absence-II, PIVKA-II) kinetics. A physic-mathematical model was developed to investigate cancer cells and vasculature dynamics in three prototype patients receiving sorafenib and/or regorafenib and applied in seven others for validation. Overall four patients showed CR, two PR, two stable-disease (SD) and two progressive-disease (PD). The rate constant of cancer cells production was higher in PD than in PR-SD and CR (median: 0.398 vs. 0.325 vs. 0.316 C × day-1). Therapy induced reduction of neo-angiogenesis was greater in CR than in PR-SD and PD (median: 83.2% vs. 29.4% and 2.0%), as the reduction of cell-proliferation (55.2% vs. 7.6% and 0.7%). An additional dose-dependent acceleration of tumor vasculature decay was also observed in CR. AFP and cancer cells followed the same kinetics, whereas PIVKA-II time/dose dependent fluctuations were influenced also by tissue ischemia. In conclusion, pending confirmation in a larger HCC cohort, modeling serological and imaging biomarkers could be a new tool for systemic therapy personalization.

Colorectal liver metastases: ADC as an imaging biomarker of tumor behavior and therapeutic response.

PURPOSE: To correlate the ADC values of colorectal liver metastases, evaluated before (preADC) and after (postADC) neoadjuvant chemotherapy (ChT), as well as their difference (ΔADC), with the histological tumor regression grade (TRG) and to determine whether the preADC value can be predictive of the lesion ChT response. METHOD: Twenty-four patients with colorectal liver metastases, who had undergone 3 T-MRI before and after ChT and were subsequently treated by parenchymal-spearing surgery, were retrospectively included. Diffusion-weighted MRI (DW-MRI) was performed using a spin-echo echo-planar sequence with multiple b values, obtaining an ADC map. Fitted ADC values were calculated for each lesion before and after ChT. The maximum diameter of each lesion in both examinations was recorded. Diameter variations and RECIST1.1 criteria were assessed. All MRI findings were histopathologically correlated to TRG of resected liver metastases. Statistical analysis was performed on a per-lesion basis. RESULTS: A total of 58 colorectal liver metastases were analysed; after ChT, 8 out of 58 lesions disappeared. TRG1, TRG2, TRG3, TRG4 and TRG5 were observed in 6, 12, 12, 13 and 7 lesions, respectively. The preADC values showed a different distribution according to the TRG scores (p = 0.0027), even though the distribution was not linear. The postADC and ΔADC values were significant different based on the TRG system (both p < 0.0001). A significant correlation between the lesion TRG and the evaluation according to RECIST1.1 criteria was observed by a per-lesion analysis (p = 0.0009). CONCLUSIONS: PostADC and ΔADC could be proposed as reliable biomarkers to assess tumor treatment response after preoperative ChT in patients with colorectal liver metastases.

Stratification of Major Hepatectomies According to Their Outcome: Analysis of 2212 Consecutive Open Resections in Patients Without Cirrhosis.

OBJECTIVE: To stratify major hepatectomies (MajHs) according to their outcomes. SUMMARY OF BACKGROUND DATA: MajHs are associated with non-negligible operative risks, but they include a wide range of procedures. Detailed depiction of the outcomes of different MajHs is the basis for a new classification of liver resections. METHODS: We retrospectively considered patients that underwent hepatectomy in 17 high-volume centers. Patients with an associated digestive/biliary resection were excluded. We analyzed open MajHs in non-cirrhotic patients. MajHs were classified according to the Brisbane nomenclature. Right hepatectomies (RHs) were reference standards. Outcomes were adjusted for potential confounders, including indication, liver function, preoperative portal vein embolization, and enrolling center. RESULTS: We analyzed a series of 2212 patients. In comparison with RH, left hepatectomy had lower mortality [0.6% vs 2.2%, odds ratio (OR) = 0.25], severe morbidity (11.7% vs 14.4%, OR = 0.62), and liver failure rates (2.1% vs 11.6%, OR = 0.16). Left hepatectomy+Sg1 and mesohepatectomy+/-Sg1 had outcomes similar to RH, except for higher bile leak rate (31.3% and 13.5% vs 6.7%, OR = 4.36 and OR = 2.29). RH + Sg1 had slightly worse outcomes than RH. Right and left trisectionectomies had higher mortality (5.0% and 7.3% vs 2.2%, OR = 2.07 and OR = 2.71) and liver failure rates than RH (19.0% and 22.0% vs 11.6%, OR = 2.03 and OR = 2.21). Left trisectionectomy had even higher severe morbidity (25.6% vs 14.4%, OR = 2.07) and bile leak rates (14.6% vs 6.7%, OR = 2.31). CONCLUSIONS: The term "major hepatectomy" includes resections having heterogeneous outcome. Different MajHs can be stratified according to their mortality, severe morbidity, liver failure, and bile leak rates.

Prognostic impact of immune-microenvironment in colorectal liver metastases resected after triplets plus a biologic agent: A pooled analysis of five prospective trials.

BACKGROUND: Immune-contexture of tumour microenvironment (TME) influences prognosis of colorectal cancer (CRC) patients and can be altered by cytotoxic and targeted agents. Limited data are available regarding the immune-TME of CRC after treatment. METHODS: An extensive immunohistochemistry evaluation of immunological parameters on tumour cells and TME of colorectal liver metastases from 106 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (5-fluorouracil, oxaliplatin and irinotecan) or COI (capecitabine, oxaliplatin and irinotecan) plus bevacizumab (N = 59) or cetuximab (N = 47) in five first-line no-profit clinical trials was performed. RESULTS: No substantial differences were reported in immunological parameters according to administered targeted agent, RAS/BRAF mutational status and histopathological or Response Evaluation Criteria in Solid Tumours response. Stromal expression of Cyclooxygenase-2 (COX-2) (p = 0.002), Human leukocyte antigen (HLA) (p = 0.003) and Programmed cell death protein 1 (PD1) (p = 0.002) were independent prognostic factors for longer relapse-free survival (RFS) at multivariate analysis with a positive trend for post-resection overall survival (OS). Patients whose metastases expressed stromal COX-2, HLA and PD1 (inflamed-score positive) reported longer RFS (25.5 versus 9.8 months; p < 0.001) and post-resection OS (64.3 versus 37.7 months; p = 0.003) as compared with others. In addition, patients with higher expression of CD4 and CD8 T-cells in tumour core and invasive margin (CD4/CD8-score) showed a better post-resection OS (not-reached versus 41.6 months; p = 0.032). A combined score of inflamed-score and CD4/CD8-score (combo-score) showed a clear prognostic role. CONCLUSIONS: The present study emphasises the role of immune-TME as independent predictor of survival in patients resected after triplets plus biologic. Inflamed-, CD4/C8- and combo-scores should be confirmed as prognostic factors in further studies.

Minor Hepatectomies: Focusing a Blurred Picture: Analysis of the Outcome of 4471 Open Resections in Patients Without Cirrhosis.

OBJECTIVE: To elucidate minor hepatectomy (MiH) outcomes. SUMMARY BACKGROUND DATA: Liver surgery has moved toward a parenchyma-sparing approach, favoring MiHs over major resections. MiHs encompass a wide range of procedures. METHODS: We retrospectively evaluated consecutive patients who underwent open liver resections in 17 high-volume centers. EXCLUSION CRITERIA: cirrhosis and associated digestive/biliary resections. Resections were classified as (Brisbane nomenclature): limited resections (LR); (mono)segmentectomies/bisegmentectomies (Segm/Bisegm); right anterior and right posterior sectionectomies (RightAnteriorSect/RightPosteriorSect). Additionally, we defined: complex LRs (ComplexLR = LRs with exposed vessels); postero-superior segmentectomies (PosteroSuperiorSegm = segment (Sg)7, Sg8, and Sg7+Sg8 segmentectomies); and complex core hepatectomies (ComplexCoreHeps = Sg1 segmentectomies and combined resections of Sg4s+Sg8+Sg1). Left lateral sectionectomies (LLSs, n = 442) and right hepatectomies (RHs, n = 1042) were reference standards. Outcomes were adjusted for potential confounders. RESULTS: Four thousand four hundred seventy-one MiHs were analyzed. Compared with RHs, MiHs had lower 90-day mortality (0.5%/2.2%), severe morbidity (8.6%/14.4%), and liver failure rates (2.4%/11.6%, P < 0.001), but similar bile leak rates. LR and LLS had similar outcomes. ComplexLR and Segm/Bisegm of anterolateral segments had higher bile leak rates than LLS rates (OR = 2.35 and OR = 3.24), but similar severe morbidity rates. ComplexCoreHeps had higher bile leak rates than RH rates (OR = 1.94); the severe morbidity rate approached that of RH. PosteroSuperiorSegm, RightAnteriorSect, and RightPosteriorSect had severe morbidity and bile leak rates similar to RH rates. MiHs had low liver failure rates, except RightAnteriorSect (vs LLS OR = 4.02). CONCLUSIONS: MiHs had heterogeneous outcomes. Mortality was low, but MiHs could be stratified according to severe morbidity, bile leak, and liver failure rates. Some MiHs had postoperative outcomes similar to RH.

Clinical and molecular determinants of extrahepatic disease progression in patients with metastatic colorectal cancer with liver-limited metastases deemed initially unresectable.

BACKGROUND: No tools to predict the probability of extrahepatic disease progression (ePD) of initially unresectable, liver-limited metastatic colorectal cancer (mCRC) are currently available. To estimate the likelihood to develop ePD and to identify clinical and molecular factors that could predict extrahepatic progression-free survival (ePFS), we conducted an observational, retrospective, multicentre cohort study. METHODS: We retrospectively identified a cohort of 225 patients with initially unresectable liver-limited disease (LLD), treated from January 2004 to December 2017 with first-line doublets or triplet plus a biological agent at two Italian institutions. RESULTS: 173 (77%) patients experienced ePD which occurred within 1, 2 or 3 years from the diagnosis of mCRC in 15%, 49% and 66% of patients, respectively. Globally, 164 (73%) patients underwent a liver resection at some point of their disease history, and 54 (33%) of them underwent a subsequent locoregional treatment. Age > 70 years, locoregional nodal involvement at diagnosis of colorectal cancer and ≥4 liver metastases were significantly associated with higher risk of ePD while liver resections were associated with reduced risk of ePD. In the multivariable model, number of liver metastases (subdistribution HR, SHR 1.63, 95% CI 1.12 to 2.36; p = 0.01) and liver resections (SHR 0.43, 95% CI 0.29 to 0.63; p = 0.001) were still associated with ePD. Number of liver metastases < 4, no nodal involvement at diagnosis and liver resections were also associated with prolonged ePFS. CONCLUSIONS: The identified clinical factors could help physicians in personalising the intensity and aggressiveness of liver-directed treatments in patients with mCRC with initially unresectable LLD.

Total neoadjuvant approach with FOLFOXIRI plus bevacizumab followed by chemoradiotherapy plus bevacizumab in locally advanced rectal cancer: the TRUST trial.

BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC) does not achieve effective control of distant metastases. Induction chemotherapy is a promising strategy, and bevacizumab (BV) could improve the results of CRT. 5-Fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI) plus BV is a treatment option in metastatic colorectal cancer. We evaluate feasibility and efficacy of neoadjuvant treatment comprising induction FOLFOXIRI plus BV followed by CRT with fluoropyrimidines plus BV. METHODS: In this phase II single-arm trial, patients node-positive or clinical T4 or high-risk T3 LARC underwent 6 cycles of induction FOLFOXIRI plus BV, followed by CRT (50.4 Gy plus concomitant capecitabine) and BV (5 mg/kg on days 1, 15 and 28). Surgery was planned 8 weeks after completion of CRT. Primary end-point was 2-year disease-free survival (DFS). RESULTS: We enrolled 49 patients: All but one (withdrewing consent after enrolment) were included in the per-protocol analyses. The study met its primary end-point: 36 patients were free of recurrence at 2 years (2-y DFS: 80.45%, 95% confidence interval [CI]: 78.79-82.10). Forty-four patients underwent surgery; pathologic complete response rate was 36.4%. Forty-six patients completed induction: neutropenia (41.6%) and diarrhoea (12.5%) were main G3/4 toxicities. Forty-five patients received CRT, but the protocol was amended and the capecitabine schedule during CRT was slightly modified after 13 patients due to the incidence of G3 hand-foot syndrome and proctitis (23.1%). After amendment, no severe events during CRT were reported. CONCLUSIONS: FOLFOXIRI plus BV followed by CRT plus BV is feasible and active. Results in terms of DFS suggest that this strategy may improve distant disease control in LARC.

Clinical outcomes with long-term sorafenib treatment of patients with hepatocellular carcinoma: a multicenter real-life study.

AIM: This multicenter field-practice study evaluates outcomes of long-term sorafenib in hepatocellular carcinoma (HCC) patients. METHODS: Consecutive HCC patients on sorafenib were enrolled. We evaluated those receiving sorafenib for ≥12 months. RESULTS: Out of 800 patients on sorafenib, 81 (10%) received long-term treatment. Median duration of treatment was 22.7 months (range: 12.3-92.6). Only 21 (26%) reported grade 3/4 adverse events. Complete response was reported in 11 patients (14%). Median overall survival was 34.8 months (95% CI: 29.9-44.3). Only baseline Child-Pugh class was associated with survival. CONCLUSION: Sorafenib could result in long-term control of HCC in a relevant proportion of patients. Given the availability of regorafenib in the second-line setting, an earlier introduction of systemic therapy may be considered according to clinical indications.

Clinical reappraisal and state of the art of nephropexy.

The diffusion of minimally invasive techniques for renal surgery has prompted a renewed interest in nephropexy which is indicated to prevent nephroptosis in symptomatic patients and to mobilize the upper ureter downward in order to bridge a ureteral defect. Recent publications have been reviewed to present the state of the art of the diagnosis and management of these two challenging conditions and to try to foresee the next steps. The evaluation of patients with mobile kidney can be made relying on diagnostic criteria such as ultrasound with color Doppler and measurement of resistive index, conventional upright X-ray frames after a supine uro-computerized tomography scan and both static and dynamic nuclear medicine scans, always with evaluation in the sitting or erect position. Laparoscopic nephropexy emerges as the current treatment option combining both objectively controlled repositioning of the kidney and resolution of symptoms with minimal invasiveness, low morbidity, and short hospital stay. The use of robotics is presently limited by its higher cost, but may increase in the future. Downward renal mobilization and nephropexy is a safe and versatile technique which has been adopted as a unique strategy or more often in combination with other surgical maneuvers in order to cope with complex ureteral reconstruction.

Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials.

BACKGROUND: Many factors, including histopathologic parameters, seem to influence the prognosis of patients undergoing resection of colorectal cancer liver metastases (CRCLM), although their relative weight is unclear. Histopathologic growth patterns (HGPs) of CRCLM may affect sensitivity to antiangiogenics. We aimed at evaluating differences in histopathologic parameters of response according to the use of bevacizumab or cetuximab as first-line targeted agents, and at exploring the prognostic and predictive role of HGPs. METHODS: We performed a comprehensive histopathologic characterisation of CRCLM from 159 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) or COI (capecitabine, oxaliplatin, and irinotecan) plus bevacizumab (N = 103) vs cetuximab (N = 56) in five first-line no-profit clinical trials. RESULTS: Both major histopathologic response (tumour regression grade TRG1-2, 32 vs 14%, p = 0.013) and infarct-like necrosis (80 vs 64%, p = 0.035) were significantly higher in the bevacizumab than in the cetuximab group. Achieving major response positively affected relapse-free survival (RFS) (p = 0.012) and overall survival (OS) (p = 0.045), also in multivariable models (RFS, p = 0.008; OS, p = 0.033). In the desmoplastic HGP (N = 28), a higher percentage of major response was reported (57 vs 17% in pushing and 22% in replacement HGP, p < 0.001) and an unsignificant advantage from cetuximab vs bevacizumab was evident in RFS (p = 0.116). In the pushing HGP (N = 66), a significant benefit from bevacizumab vs cetuximab (p = 0.017) was observed. No difference was described in the replacement HGP (N = 65, p = 0.615). CONCLUSIONS: The histopathologic response is the only independent determinant of survival in patients resected after triplets plus a biologic. When associated with triplet chemotherapy, bevacizumab induces a higher histopathologic response rate than cetuximab. The assessment of HGPs should be further explored as a predictor of benefit from available targeted agents.

3T diffusion-weighted MRI in the response assessment of colorectal liver metastases after chemotherapy: Correlation between ADC value and histological tumour regression grading.

PURPOSE: The purpose of the study was to correlate the apparent diffusion coefficient (ADC) values of diffusion-weighted MR imaging (DW-MRI) by 3T device with the histological tumour regression grading (TRG) analysis of colorectal liver metastases after preoperative chemotherapy. MATERIALS AND METHODS: Our study included thirty-five patients with colorectal liver metastases who had undergone MRI by 3T device (GE DISCOVERY MR750; GE Healthcare) after preoperative chemotherapy. DW-MRI was performed using a single-shot spin-echo echo-planar sequence with multiple b-values (0, 150, 500, 1000, 1500s/mm2), thus obtaining an ADC map. For each liver lesion (more than 1cm in diameter) the fitted ADC values were calculated by two radiologists in conference and three ROIs were drawn: around the entire tumour (ADCe), at the tumour periphery (ADCp) and at the tumour center (ADCc). All ADC values were correlated with histopathological findings after surgery. Hepatic metastases were pathologically classified into five groups on the basis of TRG. Statistical analysis was performed on a per-lesion basis utilizing the one-way analysis of variance (ANOVA). This retrospective study was approved by our institutional review board; written informed consent was obtained from all patients. RESULTS: A total of 106 colorectal liver metastases were included for image analysis. TRG1, TRG2, TRG3, TRG4 and TRG5 were observed in 4, 14, 36, 35 and 17 lesions, respectively. ADCe and ADCp values were significantly higher in lesions classified as TRG1 (2.40±0.12×10-9m2/s and 2.28±0.26×10-9m2/s, respectively) and as TRG2 (1.40±0.31×10-9m2/s and 1.44±0.35×10-9m2/s), compared to TRG3 (1.16±0.13×10-9m2/s and 1.01±0.18×10-9m2/s), TRG4 (1.10±0.26×10-9m2/s and 0.97±0.24×10-9m2/s), and TRG5 (0.93±0.17×10-9m2/s and 0.82±0.28×10-9m2/s). ADCe, ADCp and ADCc values were significantly different in TRG classes (p<0.0001). Statistical correlations were found between the ADCe, ADCp, ADCc values and the TRG classes (Spearman correlation coefficient were -0.568, -0.542 and -0.554, respectively). CONCLUSION: Our study showed a significant correlation between ADC values of 3T DW-MRI and histological TRG of colorectal liver metastases after preoperative chemotherapy.

Techniques of parenchyma-sparing hepatectomy for the treatment of tumors involving the hepatocaval confluence: A reliable way to assure an adequate future liver remnant volume.

BACKGROUND: Parenchyma-sparing hepatectomy techniques allow a lesser volume resection (<3 adjacent segments) for tumors involving the hepatic veins at the hepatocaval confluence, assuring adequate volume of the future liver remnant. We report the ability to perform parenchyma-sparing hepatectomy as planned from the preoperative imaging and the type of vascular intervention used to preserve hepatic outflow. METHODS: We analyzed 60 consecutive parenchyma-sparing hepatectomies in 54 patients for 7 primary and 53 metastatic tumors (48 colorectal), located in segments I, VII, VIII, or IVa and involving the hepatocaval confluence. Patients had a median of 2 (range: 1-18) lesions with median diameter of 4 cm (range: 1.2-16.5), which were bilateral in 43%. RESULTS: A parenchyma-sparing hepatectomy was performed in all of the 60 cases, only one case required the resection of 3 adjacent segments. In 16 (27%) hepatic veins-resections, the outflow was assured by preservation of the inferior-right-hepatic veins in 3 (5%), of the communicating-veins in 4 (7%), of the middle-hepatic veins in 3 (4%; middle-hepatic veins patch-reconstruction in 2 cases), by polytetrafluoroethylene-grafts in 4 (7%), and by hepatic veins-anastomosis in 2 (3%). In 15 (25%) cases, the hepatic veins were resected tangentially and reconstructed by direct suture venorraphy. In 29 (48%) cases, the hepatic veins were skeletonized from the tumor. Grade IIIb to IV complications occurred in 7%, median hospital-stay was 9 days, and 90-day mortality occurred in one cirrhotic patient. Median overall and disease-free survivals were 72 and 16 months (median follow-up: 34 months). CONCLUSION: A lesser volume parenchyma-sparing hepatectomy rather than a formal major hepatectomy for tumors involving the hepatocaval confluence can be performed with a low rate of major complications (7%). Parenchyma-sparing hepatectomy should be considered in highly selected patients when evaluating liver resection for tumors involving the hepatocaval confluence based on appropriate and accurate preoperative imaging.

Near total parathyroidectomy for the treatment of renal hyperparathyroidism.

BACKGROUND: Different surgical strategies are used to treat medical refractory renal hyperparathyroidism. Our preferred choice in patients with moderate secondary hyperparathyroidism (SHPT) and in patients with low compliance with medical treatment is to leave a very small parathyroid remnant in situ: we name this operation "near total parathyroidectomy" (ntPTX). We report here our results with this technique. METHODS: Retrospective study [2001-2015] of all patients submitted to ntPTX in a single centre. RESULTS: Forty-seven patients were submitted to ntPTX (32 males) aged 47.3 years. Follow-up time is 8.5 years. Thirty-five patients (74%) are alive, 12 are dead. One patient in this series had a functioning renal transplant at time of ntPTX (tertiary hyperparathyroidism), and other 27 subsequently received a renal transplantation (RTx) after ntPTX (still functioning at last follow-up or at death in 19). Amongst the 35 current survivors, the renal graft is functioning in 16 (45.7%). Parathyroid hormone (PTH) at follow-up was 116.1±135.5 pg/mL and calcium 8.6±0.9 mg/dL. Among patients with a functioning RTx PTH was 83 pg/mL and calcium 8.7 mg/dL. There was no persistent disease, and 3 patients (6.4%) had a relapse of hyperparathyroidism at follow-up. CONCLUSIONS: ntPTX is associated to very satisfying rates of normal parathyroid function and of relapse of hyperparathyroidism (6.4%) at long term, either in case of RTx or of maintenance hemodialysis: the concept of "small amount" remnant represents a valuable choice for patients undergoing PTX with a realistic chance of receiving a RTx.

Efficacy of FOLFOXIRI plus bevacizumab in liver-limited metastatic colorectal cancer: A pooled analysis of clinical studies by Gruppo Oncologico del Nord Ovest.

Secondary resection is a chance of cure for a subgroup of metastatic colorectal cancer (mCRC) patients with unresectable liver-limited disease. Medical treatment has a dual goal: to induce tumour shrinkage and to prevent disease relapse. The aims of the present analysis were to assess the efficacy of FOLFOXIRI plus bevacizumab in this setting, and to investigate whether this regimen could revert the poor prognosis of high-risk patients defined by clinical and molecular factors. We performed a pooled analysis of patients with unresectable and liver-limited mCRC, treated with first-line FOLFOXIRI plus bevacizumab in three prospective clinical trials by Gruppo Oncologico del Nord Ovest. 205 (37.9%) patients with liver-limited disease were selected, out of 541 treated patients. Liver metastases were synchronous, ≥4 and bilobar in 90%, 61%, and 79% of cases, respectively. The largest diameter was >5 cm in 42% of cases, and ≥6 segments were involved in 25%. Seventy-four patients (36.1%) underwent R0 or R1 resection of metastases. R2 resections were performed in 17 cases (8.3%). Having <6 involved segments (p < 0.001) and achieving RECIST response (p = 0.019) were associated with higher chances of resection. R0/R1 resected patients had significantly longer median progression-free survival (PFS) (18.1 versus 10.7 months, HR: 0.48 [0.35-0.66], p < 0.001) and overall survival (OS) (44.3 versus 24.4 months, HR: 0.32 [0.22-0.48], p < 0.001) compared with other patients, both in the univariate and multivariate analyses (PFS p = 0.025; OS p < 0.001). The 5-year PFS and OS rate in R0 resected patients were 12% and 43%, respectively. Neither negative baseline characteristics nor high clinical risk scores or RAS/BRAF mutations were associated with poor post-resection outcomes. In conclusion, FOLFOXIRI plus bevacizumab demonstrates efficacy in the conversion setting with considerable long-term outcome results independent of clinical and molecular prognostic factors (NCT00719797, NCT01163396 and NCT02271464).