Multiple Liver Research Articles

Dual Inhibition of CDK4/6 and XPO1 Induces Senescence With Acquired Vulnerability to CRBN-Based PROTAC Drugs

Background and aimsDespite the increasing number of treatment options available for liver cancer, only a small proportion of patients achieve long-term clinical benefits. Herein, we aim to develop new therapeutic approaches for liver cancer. MethodsA compound screen was conducted to identify inhibitors that could synergistically induce senescence when combined with CDK4/6 inhibitor. The combination effects of CDK4/6 inhibitor and XPO1 inhibitor on cellular senescence were investigated in a panel of human liver cancer cell lines and multiple liver cancer models. A senolytic-drug screen was performed to identify drugs that selectively killed senescent liver cancer cells. ResultsThe combination of CDK4/6 inhibitor and XPO1 inhibitor synergistically induces senescence of liver cancer cells in vitro and in vivo. The XPO1 inhibitor acts by causing accumulation of RB1 in the nucleus, leading to decreased E2F signaling and promoting senescence induction by the CDK4/6 inhibitor. Through a senolytic-drug screen, CRBN-based PROTAC ARV-825 was identified as an agent that can selectively kill senescent liver cancer cells. Upregulation of CRBN was a vulnerability of senescent liver cancer cells, making them sensitive to CRBN-based PROTAC drugs. Mechanistically, we find that USP2 directly interacts with CRBN, leading to the deubiquitination and stabilization of CRBN in senescent liver cancer cells. ConclusionOur study demonstrates a striking synergy in senescence induction of liver cancer cells through the combination of CDK4/6 inhibitor and XPO1 inhibitor. These findings also shed light on the molecular processes underlying the vulnerability of senescent liver cancer cells to CRBN-based PROTAC therapy.

Predictors for early recurrence beyond up-to-7 or distant metastasis after hepatocellular carcinoma resection: proposal for borderline resectable HCC.

The recurrence rate after curative resection for hepatocellular carcinoma (HCC) reaches over 70% after 5years and early recurrence (within 1year) is now recognized as having a poor prognosis and has limited treatment options. We retrospectively reviewed 184 consecutive patients who underwent curative hepatic resection for HCC. Severe early recurrence was defined as multiple (beyond up-to-7) liver recurrence or distant metastasis after hepatic resection within 1year. We divided the participants into two groups according to severe early recurrence and analyzed clinicopathological and long-term outcomes. Among the patients with multiple or distant metastasis (n = 59), 49 patients (83%) had recurrence within 1year. Overall survival (OS) and recurrence-free survival (RFS) were significantly worse in the severe early recurrence group than in the others group. Logistic regression analysis revealed that severe early recurrence was significantly associated with macroscopic vascular invasion (MVI), tumor burden score (TBS) > 4.70, and ALBI grade 2. In patients with scores of 2 and 3 (the sum of the three factors), OS and RFS rates were significantly poorer than those of patients with scores of 0 or 1. Positive predictive value and negative predictive value for severe early recurrence was 68.4% and 84.2%, respectively. Furthermore, a validation study demonstrated that cases with these factors were at high risk of severe early recurrence and had poor prognosis. In this retrospective analysis, MVI, TBS, and ALBI could predict severe early recurrence after hepatic resection for HCC, and patients with these risk factors had a poor prognosis.

O-06 Efficacy of Lutetium-Peptide Receptor Radionuclide Therapy and osilodrostat treatment at achiving eucortisolism and tumour stabilization in a patient with metastatic ectopic ACTH-syndrome

Abstract Introduction Ectopic ACTH syndrome (EAS) is a rare cause of endogenous hypercortisolism. We present a case of a patient diagnosed with severe EAS, achieving eucortisolism and a favorable outcome of ACTH-producing metastatic pancreatic neuroendocrine tumor (NET) after 177Lu-DOTATATE and osilodrostat treatment. Clinical Case A female patient was admitted to our clinic at the age of 55 complaining of severe fatigue, facial and leg edema. Laboratory tests revealed a significant degree of ACTH-dependent hypercortisolemia (late-night serum cortisol 1856 nmol/L (64–327), late-night salivary cortisol (LNSC) 387.7 nmol/L (0.5–9.65), 24hUFC 8561 nmol/L (100–379), ACTH 332.8 pg/mL (7.2–63.3)), hypokalemia (1.88 mmol/L), increased liver enzymes (alanine aminotransferase (ALT) 303.2 U/L (0–55), aspartate aminotransferase (AST) 94.3 U/L (5–34)). MRI of the brain was negative for pituitary abnormalities. CT and somatostatin receptor scintigraphy with 99mTc-Tektrotyd revealed NET of the pancreas and multiple liver metastases. Subsequent biopsy confirmed NET grade 2, Ki67 – 7%. Treatment with lanreotide 120 mg every four weeks was initiated. In order to control hypercortisolism the patient received osilodrostat at a dose of 10 mg daily, which improved the patient's general condition in the first days of therapy. After 1 month of treatment, her hypercortisolism symptoms improved, LNSC dropped to 0.54 nmol/L and morning cortisol dropped from 1451 nmol/L (101–535) to 60.7 nmol/L, which could suggest adrenal insufficiency. She also had normalization of potassium and liver enzymes (ALT 18.4 U/L, AST 23 U/L). The dose of osilodrostat was firstly reduced and then discontinued. 177Lu-DOTATATE treatment was offered with four doses (7.4 GBq (200 mCi) every 8 weeks). The first dose was administered in January 2023. The SPECT-CT performed after the second dose demonstrated disease stabilization. At the time of writing, the patient remains in eucortisolism (LNSC 5,36 nmol/L, morning cortisol 140 nmol/L, ACTH 36.4 pg/ml) with tumor stabilisation after 4 doses of 177Lu-DOTATATE. However, the most recent routine blood test revealed thrombocytopenia (platelets 44×109/μl (150–400)), decreased white blood cell count (3.24×109/μl (4.5–11)), lymphocytes (0.71×109/μl (1.18–1.34)) and hemoglobin 98 g/L (117–160). Nevertheless, her general condition remains stable and significantly improved versus the initial investigation. Conclusion This observation highlights the feasibility and efficacy of a combined approach using osilodrostat and 177Lu-DOTATATE in the management of patients with metastatic ACTH-producing NET. This approach resulted in a substantially improved patient quality of life. Funding Russian Scientific Foundation 19-15-00398

Associations of liver function with plasma biomarkers for Alzheimer's Disease.

Blood-based biomarkers for Alzheimer's disease (AD) are promising to be used in clinical settings. The liver is an important degradation organ of the body. Whether liver function affects the levels of AD biomarkers needs to be studied. To investigate the associations between liver function and the plasma levels of AD biomarkers. We conducted an ADNI cohort-based cross-sectional study. Thirteen liver function markers commonly used in clinical settings were analyzed: total protein (TP), albumin (AL), globulin (GL), AL/GL ratio (A/G), total bilirubin (TB), direct bilirubin (DB), indirect bilirubin (IB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT ratio, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and γ-glutamyltransferase (GGT). Liquid chromatography-tandem mass spectrometry was used to detect the plasma Aβ42 and Aβ40 concentrations. Single Molecule array technique was used to measure the plasma p-tau181 and NfL concentrations. We used linear regression models to analyze the associations between liver function markers and the levels of AD plasma biomarkers. ALP was positively associated with the levels of plasma Aβ42 (β = 0.16, P = 0.018) and Aβ40 (β = 0.21, P = 0.004). LDH was positively associated with the levels of plasma p-tau181 (β = 0.09, P = 0.022). While NfL was correlated with multiple liver function markers, including AL, A/G, ALT, AST/ALT, and LDH. Liver function was associated with the plasma levels of AD biomarkers. It needs to consider the potential influence of liver function on the reference ranges and the interpretation of results for AD biomarkers before clinical use.

Response to capmatinib in a patient with neuroendocrine carcinoma of the gallbladder origin harboring MET amplification.

Neuroendocrine carcinoma (NEC) of the gallbladder origin is particularly rare, accounting for only 0.38% of primary malignancies of the gallbladder, and standard therapies are limited. The MET gene encodes the tyrosine kinase receptor, c-Met. Pathogenic variants of MET, such as MET exon 14 skipping and MET amplification, result in excessive downstream signaling that promotes tumor progression. A MET inhibitor, capmatinib, blocks signaling of c-Met and has been approved by the Food and Drug Administration for non-small cell lung cancer with MET exon 14 skipping. The effectiveness of capmatinib has been reported in other cancers with MET amplification, but NEC with MET variants has not been reported. Here, we present a case of a 72-year-old woman with NEC of the gallbladder with multiple liver and lymph node metastases, who was resistant to conventional chemotherapy including carboplatin plus etoposide as first-line treatment and irinotecan as second-line treatment, but she responded to capmatinib. After 6weeks of treatment, CT scan showed a partial response (80% reduction in size), but after 13weeks, regrowth of liver metastasis was observed. Herein, we report a meaningful efficacy of capmatinib to the patient of NEC of the gallbladder origin with MET amplification.

Cholesterol modulates type I/II TGF-β receptor complexes and alters the balance between Smad and Akt signaling in hepatocytes

Cholesterol mediates membrane compartmentalization, affecting signaling via differential distribution of receptors and signaling mediators. While excessive cholesterol and aberrant transforming growth factor-β (TGF-β) signaling characterize multiple liver diseases, their linkage to canonical vs. non-canonical TGF-β signaling remained unclear. Here, we subjected murine hepatocytes to cholesterol depletion (CD) or enrichment (CE), followed by biophysical studies on TGF-β receptor heterocomplex formation, and output to Smad2/3 vs. Akt pathways. Prior to ligand addition, raft-dependent preformed heteromeric receptor complexes were observed. Smad2/3 phosphorylation persisted following CD or CE. CD enhanced phospho-Akt (pAkt) formation by TGF-β or epidermal growth factor (EGF) at 5 min, while reducing it at later time points. Conversely, pAkt formation by TGF-β or EGF was inhibited by CE, suggesting a direct effect on the Akt pathway. The modulation of the balance between TGF-β signaling to Smad2/3 vs. pAkt (by TGF-β or EGF) has potential implications for hepatic diseases and malignancies.

Grade 3 Pancreatic Neuroendocrine Tumor Refractory to Chemotherapy Successfully Treated with Peptide Receptor Radionuclide Therapy Leading to Conversion Surgery.

A 59-year-old woman was diagnosed with a pancreatic neuroendocrine tumor (P-NET; Grade 3, Ki67: 25%) with multiple liver and lymph node metastases and started chemotherapy with streptozosin (500 mg/m2/day) in combination with lanreotide acetate (120 mg). After six courses of (daily) streptozosin, the patient had progressive disease, as assessed by computed tomography (CT), and peptide receptor radionuclide therapy (PRRT) was started as second-line treatment. As PRRT was remarkably successful and the tumor shrank, surgery was performed to resect the primary pancreatic tumor, liver metastases, and lymph node metastases. CT evaluation performed six months after the surgery showed a complete response.

Totally laparoscopic ALPPS procedure for multiple bilobar colorectal liver metastases: is there any limit to the number of resectable nodules?

Totally laparoscopic ALPPS procedure for multiple bilobar colorectal liver metastases: is there any limit to the number of resectable nodules?

Bioengineering scalable and drug-responsive in vitro human multicellular non-alcoholic fatty liver disease microtissues encapsulated in the liver extracellular matrix-derived hydrogel.

Non-alcoholic fatty liver disease (NAFLD) is a high-prevalence and progressive disorder. Due to lack of reliable in vitro models to recapitulate the consecutive phases, the exact pathogenesis mechanism of this disease and approved therapeutic medications have not been revealed yet. It has been proven that the interplay between multiple hepatic cell types and liver extracellular matrix (ECM) are critical in NAFLD initiation and progression. Herein, a liver microtissue (LMT) consisting of Huh-7, THP-1, and LX-2 cell lines and human umbilical vein endothelial cells (HUVEC), which could be substituted for the main hepatic cells (hepatocyte, Kupffer, stellate, and sinusoidal endothelium, respectively), encapsulated in liver derived ECM-Alginate composite, was bioengineered. When the microtissues were treated with free fatty acids (FFAs) including Oleic acid (6.6×10-4M) and Palmitic acid (3.3×10-4M), they displayed the key features of NAFLD, including similar pattern of transcripts for genes involved in lipid metabolism, inflammation, insulin-resistance, and fibrosis, as well as pro-inflammatory and pro-fibrotic cytokines' secretions and intracellular lipid accumulation. Continuing FFAs supplementation, we demonstrated that the NAFLD phenomenon was established on day 3 and progressed to the initial fibrosis stage by day 8. Furthermore, this model was stable until day 12 post FFAs withdrawal on day 3. Moreover, administration of an anti-steatotic drug candidate, Liraglutide (15 μM), on the NAFLD microtissues significantly ameliorated the NAFLD phenomenon. Overall, we bioengineered a drug-responsive, cost-benefit liver microtissues which can simulate the initiation and progression of NAFLD. It is expected that this platform could potentially be used for studying molecular pathogenesis of NAFLD and high-throughput drug screening. See also the graphical abstract(Fig. 1).

Primary Leiomyosarcoma of Suprahepatic Inferior Vena Cava with Metastases.

A 67-year-old female presented with shortness of breath, weight loss, abdomen, and back pain for 2 months. Ultrasound of the abdomen revealed multiple focal liver lesions. 18F-Fluorodeoxyglucose whole-body positron emission tomography/computed tomography revealed a hypermetabolic lesion in the suprahepatic inferior vena cava extending into the right atrium. Multiple hypermetabolic lesions were seen in liver, bones, and abdominal lymph nodes, suggestive of metastases. Histopathology and immunohistochemistry of the lesions revealed it to be metastatic leiomyosarcoma.

Pancreatic cancer with multiple liver metastasis complicating multi organ infarcts from Marantic endocarditis and Trousseau’s syndrome

Background: Marantic endocarditis and Trousseau’s syndrome are historically linked with pancreatic cancer. The patient had catastrophic embolic events which caused multi organ infarct due to underlying advanced pancreatic cancer. Doctors should be aware of early signs and symptoms of pancreatic cancer and conduct necessary clinical assessments and investigations that can prevent any severe complications. Case Presentation: A middle-aged healthy gentleman who presented with left-sided weakness, slurred speech, left-sided sensory neglect, mild headache, and fever. CT head showed acute right-sided temporal ischemic changes with subsequent magnetic resonance imaging (MRI) head showed multiple infarcts in the brain. A transesophageal echocardiogram reported possible MV vegetation. MRI of the liver was done due to deranged LFTs which showed multiple liver metastasis with a primary mass in the tail of the pancreas. Left leg ultrasound Doppler showed a large left leg deep vein thrombosis involving the femoral vein as he complained of left leg pain for 2 months and went to GP with right leg pain 3 months ago which was treated as a right ankle sprain. The clinical events explained that most likely he developed Trousseau’s syndrome 3 months ago and the embolic phenomena were due to rare Marantic endocarditis (Non-bacterial thrombotic endocarditis) secondary to pancreatic cancer. Ultrasound-guided biopsy of liver metastasis was planned, but sadly the patient passed away the next day. Conclusion: The diagnosis of early pancreatic cancer with imaging poses a challenge sometimes, therefore the pancreatic protocol of CT or MRI is the first line of investigation. Moreover, the cause of unprovoked thrombo-embolism should be investigated to rule out any underlying malignancy.

Ectopic Adrenocorticotropic Hormone Syndrome due to Pancreatic Neuroendocrine Carcinoma: A Case Report.

A 55-year-old woman presented to her primary care physician with facial and lower leg edema. After being referred to our hospital because of hypothyroidism and hypokalemia on blood tests, she also had elevated adrenocorticotropic hormone (ACTH) and cortisol levels, but a dexamethasone suppression test showed no cortisol suppression. Ectopic ACTH syndrome due to pancreatic neuroendocrine carcinoma (PNEC) was suspected. endoscopic ultrasound-guided fine-needle aspiration was performed, and a histopathological examination of the obtained specimen revealed multiple liver metastases of the PNEC. Imaging after etoposide and cisplatin therapy showed cystic changes in the primary lesions and shrinkage of the liver metastases, and the ACTH levels were within the normal range.

Dosimetric Effect of Target Position Accuracy on Single-Isocenter Multiple Liver Metastases SBRT.

Purpose: To evaluate the dosimetric effects of intrafraction baseline shifts combined with rotational errors on Four-dimensional computed tomography-guided stereotactic body radiotherapy for multiple liver metastases (MLMs). Methods: A total of 10 patients with MLM (2 or 3 lesions) were selected for this retrospective study. Baseline shift errors of 0.5, 1.0, and 2.0 mm; and rotational errors of 0.5°, 1°, and 1.5°, were simulated about all axes. All of the baseline shifts and rotation errors were simulated around the planned isocenter using a matrix transformation of 6° of freedom. The coverage degradation of baseline shifts and rotational errors were analyzed according to the dose to 95% of the planning target volume (D95) and the volume covered by 95% of the prescribed dose (V95), and related changes in gross tumor volume were also analyzed. Results: At the rotation error of 0.5° and the baseline offset of less than 0.5 mm, the D95 and V95 values of all targets were >95%. For rotational errors of 1.0° (combined with all baseline shift errors), 36.3% of targets had D95 and V95 values of <95%. Coverage worsened substantially when the baseline shift errors were increased to 1.0 mm. D95 and V95 values were >95% for about 77.3% of the targets. Only 11.4% of the D95 and V95 values were >95% when the baseline shift errors were increased to 2.0 mm. When the rotational error was increased to 1.5° and baseline shift errors increased to 1.0 mm, the D95 and V95 values were >95% in only 3 cases. Conclusions: The multivariate regression model analysis in this study showed that the coverage of the target decreased further with reduced target volume, increasing the baseline drift, the rotation error, and the distance to the target.

Management of Spinal Hemangioblastoma in Von Hippel-Lindau Disease: A Case Report

Vertebral body location of hemangioblastomas (HB) is extremely rare. The authors report a case of spinal mass involving lower thoracic region with cord compression, approved to be spinal HB. A 57-year-old man presented to our center with eight months history of progressive intractable back pain and paraparesis. Admission computed tomography and magnetic resonance imaging (MRI) of the thoracolumbar spine demonstrated a lytic and expansile spinal mass with pedicle expansion and vivid contrast enhancement involving T11 and T12 vertebral bodies on the right side. He was a known case of von Hippel-Lindau (VHL) and he had history of 4th ventricular asymptomatic hemangioblastoma near Obex, multiple pancreatic cystic adenomas, multiple liver cysts, and right non-chromaffin adrenal mass. The patient underwent a T11-T12 partial transpedicular corpectomy with T5 to L3 posterior spinal fixation to bridge the invaded segment. The pathological and immunohistochemical findings were consistent with vertebral HB. Spinal HB although extremely rare, may be managed with subtotal tumor resection and fixation of normal adjacent vertebrae by cemented screws.

A case of primary duodenal NET that recurred 17 years later as multiple liver metastases and obstructive jaundice

A case of primary duodenal NET that recurred 17 years later as multiple liver metastases and obstructive jaundice

A Case of Treatment-resistant Extensive-disease Small-cell Lung Cancer with Multiple Liver Metastases Shrunk by Whole Liver Radiotherapy

A Case of Treatment-resistant Extensive-disease Small-cell Lung Cancer with Multiple Liver Metastases Shrunk by Whole Liver Radiotherapy

Endothelial progenitor cells systemic administration alleviates multi-organ senescence by down-regulating USP7/p300 pathway in chronic obstructive pulmonary disease

BackgroundChronic obstructive pulmonary disease (COPD) has impacted approximately 390 million people worldwide and the morbidity is increasing every year. However, due to the poor treatment efficacy of COPD, exploring novel treatment has become the hotpot of study on COPD. Endothelial progenitor cells (EPCs) aging is a possible molecular way for COPD development. We aimed to explore the effector whether intravenous administration of EPCs has therapeutic effects in COPD mice.MethodsCOPD mice model was induced by cigarette smoke exposure and EPCs were injected intravenously to investigate their effects on COPD mice. At day 127, heart, liver, spleen, lung and kidney tissues of mice were harvested. The histological effects of EPCs intervention on multiple organs of COPD mice were detected by morphology assay. Quantitative real-time PCR and Western blotting were used to detect the effect of EPCs intervention on the expression of multi-organ senescence-related indicators. And we explored the effect of EPCs systematically intervening on senescence-related USP7/p300 pathway.ResultsCompared with COPD group, senescence-associated β-galactosidase activity was decreased, protein and mRNA expression of p16 was down-regulated, while protein and mRNA expression of cyclin D1 and TERT were up-regulated of multiple organs, including lung, heart, liver, spleen and kidney in COPD mice after EPCs system intervention. But the morphological alterations of the tissues described above in COPD mice failed to be reversed. Mechanistically, EPCs systemic administration inhibited the expression of mRNA and protein of USP7 and p300 in multiple organs of COPD mice, exerting therapeutic effects.ConclusionsEPCs administration significantly inhibited the senescence of multiple organs in COPD mice via down-regulating USP7/p300 pathway, which presents a possibility of EPCs therapy for COPD.

Painful burning lesions on the chest wall of a patient with advanced breast cancer

A 90-year-old woman presented at our emergency department complaining of dyspnea (sO2 88% on room air, respiratory rate 24/min) and severe (NRS 8/10) burning chest pain. Ten years earlier, she had undergone a bilateral radical mastectomy and radio-chemotherapy for breast cancer. In September 2023, she developed some nodules on her chest skin treated with electrochemotherapy, multiple liver lesions, and a bilateral paraneoplastic pleural effusion.

Infiltrative Optic Neuropathy in a Patient with Gastric Carcinoma: Case Report and State of the Art

Introduction: Metastatic tumors to the optic disc are a rare event. Infiltration of the optic nerve head is usually a unilateral process with characteristic funduscopic features. Loss of vision is its main symptom. Neuroimaging should be performed in every patient suspected of infiltrative optic neuropathy. The patient should be referred for appropriated chemotherapy for the systemic cancer plus external ocular irradiation. Case Presentation: The case of a 75-year-old man with progressive vision loss in his left eye is presented. Among his medical background a gastric adenocarcinoma (GAC) with multiple liver metastases is highlighted. The exploration showed an optic nerve head invaded by chalky whitish infiltrates, associated to flameshaped hemorrhages along the vascular arcades; the magnetic resonance imaging (MRI) demonstrated signal enhancement of the posterior region of the left ocular globe, affecting the optic nerve head. Orbital radiotherapy was ruled out due to patient’s systemic situation. Discussion: Metastases and optic nerve infiltration should be suspected in every oncologic patient who develops optic neuropathy. Though a rare condition with poor systemic prognosis, patients should be studied and offered orbital radiotherapy in order to stabilize the ocular progression.

Oncological role of surgical resection in patients with pancreatic ductal adenocarcinoma with liver-only synchronous metastases in a single-center retrospective study.

Surgical resection for liver-only synchronous metastases of pancreatic ductal adenocarcinoma remains controversial. We investigated the role of conversion surgery in patients with a favorable response to systemic chemotherapy. Patients (n=49) were diagnosed liver-only synchronous metastases using staging laparoscopy or open laparotomy between 2007 and 2022. Clinical outcomes were retrospectively compared among patients who underwent conversion surgery (n=10), upfront surgery with or without short-term neoadjuvant chemotherapy (UpS/short NAC) for oligometastases and occult metastases limited to the liver (n=8), and chemotherapy only for resectable or borderline resectable disease with occult liver-only metastases (n=31). The surgical indication of conversion surgery was fixed as the ABC criteria, namely, Anatomical objective response of disappearance of liver metastases on imaging studies, Biological response of CA19-9 level decrease to ≤150 U/mL, and Conditional response of surgical fitness. In addition to the above ABC criteria, tumor disappearance at the liver was repeatedly confirmed using staging laparoscopy (laparoscopic response; L), and metabolic complete responses were confirmed using positron emission tomography-computed tomography (CT) (metabolic response; M). Median survival time from initial treatment was 9.9 months [95% confidence interval (CI): 8.3-10.9] in the chemotherapy group, 10.4 months (95% CI: 6.6-17.8) in the UpS/short NAC group, and 36.7 months (95% CI: 19.0-84.8) in the conversion surgery group (conversion surgery vs. UpS/short NAC, P=0.002; conversion surgery vs. chemotherapy, P<0.001; UpS/short NAC vs. chemotherapy, P=0.554). One patient in the UpS/short NAC group and three in the conversion surgery group achieved 5-year survival. Among them, two patients with initially multiple liver metastases (≥10) in the conversion surgery group survived beyond 5 years. Only conversion surgery was a significant independent prognostic factor in a total cohort (hazard ratio; 0.173, P=0.002). Conversion surgery, but not UpS/short NAC, may enhance survival in patients with synchronous liver metastases and favorably anatomical, biological and conditional responses to systemic chemotherapy.