Unresectable locally advanced pancreatic cancer: a multimodal treatment using neoadjuvant chemoradiotherapy (gemcitabine plus stereotactic radiosurgery) and subsequent surgical exploration.

BACKGROUND: Pancreatic cancer accounts for approximately 3% of cancer deaths in Europe. Locally advanced pancreatic cancer (LAPC) involves vascular structures, and resectability is low, with a median survival time of 6 to 11 months. We conducted a prospective, nonrandomized study of patients with LAPC to assess the effect of stereotactic body radiotherapy (SBRT) on local response, pain control, and quality of life (QOL). METHODS: Twenty-three patients with histologically confirmed LAPC underwent SBRT. Radiotherapy (30 Gy) was delivered in three fractions, and treatment toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE v. 3.0). All patients received also gemcitabine chemotherapy and were followed up until death. Local control was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, pain control was assessed with a visual analog scale, and QOL was assessed with the SF-36 instrument (Italian v. 1.6). RESULTS: No grade 2 or higher acute or late toxicity was observed. The overall local response ratio was 82.6% (14 partial response, 2 complete response, 3 stable disease). SBRT showed a good short-term efficacy in controlling both pain and QOL. Median survival was 10.6 months, with a median follow-up of 9 months. The LAPC became resectable in 8% of the patients. Median time to progression of disease was 7.3 months. Six patients developed early metastatic disease. CONCLUSIONS: The SBRT method is a promising treatment for LAPC. Local control rates, even compared to historical data from conventional radiotherapy, can be achieved with minimal toxicity. Resectability can also be achieved.

New therapeutic approaches to liver fibrosis: a practicable route?

The progress of research on the molecular pathogenesis of liver fibrosis and the consequent discoveries are likely to open new possibilities for therapeutic approaches to the management of this disease in the future. A key step towards this goal is a deeper comprehension of both the complex molecular and cellular mechanisms and the signaling involved in the development of hepatic fibrosis. It is not yet clear, in fact, what role apoptosis, cytokines, oxidants and other molecules play and what relationships exist between them in favouring or delaying the onset of these adverse mechanisms. At present, a unique mechanism is recognized to be the main reason for the cause and development of liver fibrosis: sustained hepatic stellate cell activation and transformation. Therefore, in this review, after considering the cause, development of fibrosis and interrelation between molecular and cellular profibrotic mechanisms, the part played in counteracting both of these actions by some anti-oxidants and anti-fibrotic molecules such as cytokines, prostacyclin and others will be taken into consideration. The gene therapy and the possible therapeutic use of liver stem cells and tissue engineering will also be dealt with briefly. At the moment, however, the efficacy of these novel strategies still needs to be further validated in animal studies and confirmed in clinical trials. Some data that are already available from in vitro and animal studies demonstrating the effectiveness of novel approaches to inhibiting or treating liver fibrosis can only offer moderate hope.

Postmeal portal flow variations in HCV-related chronic hepatitis and liver cirrhosis with and without hyperdynamic syndrome.

BACKGROUND: Doppler ultrasonography (US) of portal blood flow and portal flow volume (PFV) are useful to define changes in portal hemodynamics of patients with chronic liver diseases. The meal test with postmeal PFV measurements is generally accepted as a reproducible noninvasive test to evaluate the severity of portal hypertension. The aim of this study was to evaluate whether monitoring PFV changes after ingestion of a standard meal would be useful to characterize patients with chronic hepatitis or liver cirrhosis in the presence or absence of hyperdynamic syndrome (HS) characterized by elevated PFV, splenomegaly, systemic hypotension and/or increased cardiac output. PATIENTS AND METHODS: Thirty-seven patients (22 men and 15 women, median age 53 years) with hepatitis C virus infection and 20 healthy age- and sex-matched volunteers (Controls) were enrolled in the study. There were 19 (51.4%) patients with chronic hepatitis (Group A) and 18 (48.6%) with ultrasonographic evidence of liver cirrhosis (Child-Pugh class B), 9 of whom had an HS (Group B) while the remainder (Group C) did not. Each patient underwent liver color Doppler US and the test was repeated 30, 60 and 90 minutes after administration of a standard meal (300 kcal fluid meal containing 12 g of proteins, 11.6 g of lipids and 36.8 g of carbohydrates). RESULTS: The baseline PFV did not differ (p=NS) between Controls and both Groups A and C, while the PFV of Group B patients was significantly (p<0.01) higher. After 30 minutes, the PFV increased (p<0.01) both in Controls and Group A patients, while the differences were not significant in cirrhotic patients (Groups B and C). Our study confirmed that the postmeal PFV increases in both healthy individuals and in patients with chronic hepatitis, while in cirrhotic patients no significant changes occur. In conclusion, monitoring the portal blood flow in cirrhotic patients before and after administration of a standard meal might be a suitable test to evaluate potential disturbances of the flow itself. Moreover, the test could be useful to determine optimal pharmacological or surgical interventions aimed at restoring a better flow to the liver by reducing or favouring the occurrence of spontaneous mesenteric-systemic venous shunts.

An unusual post-traumatic case of extrahepatic bile duct compression.

Jaundice and cholestatic disease by external bile duct compression may be caused by several conditions, including pancreatic masses, portal cavernoma, Ormond's disease, metastases from gallbladder cancer, neurinomas, and hydronephrotic kidney. We report a case of bile duct compression in a 56-year-old man with a known small (28 mm) right renal cyst and crossed, fused renal ectopia. The patient had a history of recent abdominal trauma due to a motorcycle accident and recurrent septic-type fever and jaundice. He also reported a weight loss of 5 kg in the last two months. Abdominal ultrasonography showed intra- and extra-hepatic bile duct dilatation, and computed tomography scan showed hydronephrosis, dilatation of intra- and extra-hepatic biliary tract, and a right renal complex cyst of more than 9 cm. One can hypothesize a relationship between the abdominal trauma and the increase in size of the renal cyst, which, moreover, had changed its original shape. The patient underwent cefuroxime and metronidazole therapy, with complete recovery from the cholangitis within one week. The treatment of choice would have been surgical excision or, alternatively, an image-guided percutaneous aspiration of the cyst, in order to avoid further episodes of cholangitis. Unfortunately, the patient refused either surgical or more conservative treatment and was lost to follow-up.

Iloprost enhances portal flow velocity and volume in patients with systemic sclerosis.

BACKGROUND: Iloprost, a prostacyclin analog, reduces hepatic microcirculatory damage after ischemia-reperfusion injury in animal liver models. The objective of this study was to evaluate whether the portal flow velocity changes after Iloprost infusion in patients with systemic sclerosis and Raynaud's phenomenon, who usually have increased risk of microvascular thrombosis and transient liver disturbances. PATIENTS AND METHODS: Fifteen patients (3 males and 12 females, median age 58 years, range 47-66 years), with systemic sclerosis and Raynaud's phenomenon, were exclusively treated with an infusion of Iloprost (2 ng/kg/min, 6 h/day) for 5 days. In each subject, the portal flow velocity (PV, cm/sec) and portal flow volume (PFV, mL/min) were obtained by using portal color Doppler ultrasonography equipment. RESULTS: Iloprost administration significantly (p<0.001) increased both the PV (23.6+/-3.4 cmlsec vs. 29.1+/-3.9 cm/sec) and PFV (1748.8+/-310. 7 mL/min vs. 2254.9+/-404.1 mL/min) values. CONCLUSION: Hepatic perfusion significantly improved after Iloprost administration, suggesting that such treatment might be useful in preventing vascular complications in patients with systemic sclerosis. Iloprost improves the portal hemodynamics, favoring local microvascular patency, and its effectiveness may be safely monitored by using portal color Doppler ultrasonography.

Isolated hepatocytes versus hepatocyte spheroids: in vitro culture of rat hepatocytes.

The use of hepatocytes that express liver-specific functions to develop an artificial liver is promising. Unfortunately, the loss of specialized liver functions (dedifferentiation) is still a major problem. Different techniques, such as collagen entrapment, spherical multicellular aggregates (spheroids), and coculture of hepatocytes with extracellular matrix, have been used to improve the performance of hepatocytes in culture. The aim of this study was to compare two different models of hepatocyte isolation in culture: isolated hepatocytes (G1) and hepatocyte spheroids (60% hepatocytes, 40% nonparenchymal cells, and extracellular matrix) (G2). To test functional activity of hepatocytes, both synthetic and metabolic, production of albumin and benzodiazepine transformation into metabolites was tested. G2 showed a high albumin secretion, while a decrease after 15 days of culture in G1 was noted. Diazepam metabolites were higher in G2 than in G1 in all samples, but had statistical significance at days 14 and 21 (p < 0.01). The glycogen content, after 30 days of culture, was very low in G1 (14.2 +/- 4.4%), while in G2 it was 72.1 +/- 2.6% (p < 0.01). Our study confirms the effectiveness of a culture technique with extracellular matrix and nonparenchymal cells. Maintenance of a prolonged functional activity has been related to restoration of cell polarity and close cell-to-cell contact. We showed that isolated hepatocytes maintain their functional activity for a period significantly reduced, when compared to the hepatocyte spheroids. We confirmed the role of extracellular matrix as a crucial component to promote hepatocyte homeostasis, and the close link between cellular architecture and tissue-specific functions.

Isolated hepatocyte transplantation for Crigler-Najjar syndrome type 1.

Crigler-Najjar syndrome type 1 (CN1) is an inherited disorder characterized by the absence of hepatic uridine diphosphoglucuronate glucuronosyltransferase (UDPGT), the enzyme responsible for the conjugation and excretion of bilirubin. We performed allogenic hepatocyte transplantation (AHT) in a child with CN1, aiming to improve bilirubin glucuronidation in this condition. A 9-year-old boy with CN1 was prepared with plasmapheresis and immunosuppression with prednisolone and tacrolimus. When a graft was made available, 7.5 x 10(9) hepatocytes were isolated and infused into the portal vein percutaneously. After 2 weeks phenobarbitone was added to promote the enzymatic activity of UDPGT of the transplanted hepatocytes. Nocturnal phototherapy was continued throughout the studied period. Total bilirubin was considered a reliable marker of allogenic cell function. There was no significant variation of vital signs nor complications during the infusion. Mean +/- SD bilirubin level was 530 +/- 38 micromol/L before and 359 +/- 46 micromol/L after AHT (t-test, p < 0.001). However, the introduction of phenobarbitone was followed by a drop of tacrolimus level with increase of alanine aminotransferase (ALT) and increase of bilirubin. After standard treatment of cellular rejection bilirubin fell again but from then on it was maintained at a greater level. After discharge the patient experienced a further increase of bilirubin that returned to predischarge levels after readmission to the hospital. This was interpreted as poor compliance with phototherapy. Only partial correction of clinical jaundice and the poor tolerability to nocturnal phototherapy led the parents to refuse further hepatocyte infusions and request an orthotopic liver transplant. After 24 months the child is well, with good liver function on tacrolimus and prednisolone-based immunosuppression. Isolated AHT, though effective and safe, is not sufficient to correct CN1. Maintenance of adequate immunosuppression and family compliance are the main factors hampering the success of this procedure.

Iloprost: an adjunctive approach to chronic viral hepatitis treatment.

Chronic viral liver disease may evolve to cirrhosis. The medical treatment to slow down this passage is based on anti-viral and anti-fibrotic properties of interferon. Recently, we evidenced significant increase of portal vein flow velocity and volume after a prostacyclin analog (iloprost) infusion in subjects without and with chronic viral hepatitis. On the basis of these results and considering both the pathophysiology of viral liver disease and the mechanism of action of iloprost in portal microcirculation, we hypothesize that it may be of some efficacy in chronic liver disease ameliorating the portal hemodynamics and producing an anti-oxidant liver effect.

[Traumatic rupture of the pancreatic isthmus complicated by concomitant rupture of the duodenum and right kidney]. / Rottura traumatica dell'istmo pancreatico complicata da rotture concomitanti del duodeno e del rene destro.

The Authors describe a case of complete traumatic transection of the pancreatic isthmus associated with complete transection of the first portion of the duodenum and the isthmus of a horseshoe kidney. The treatment of the pancreatic lesion was intestinal drainage of the distal portion of the pancreas and closure of the proximal one. The authors stress the advantages and good outcome of the conservative operation, performed at an early stage, with the clinical indications and adequate surgical techniques.

Improved hepatic perfusion after iloprost infusion in patients with HCV chronic infection: a pilot study with possible therapeutic implications.

We performed a pilot study to evaluate whether portal flow volume (PFV) changed in subjects with chronic hepatitis C virus (HCV) infection with respect to control patients after infusion of iloprost, a prostacyclin analog. Six subjects with chronic HCV infection and arteriopathy of the lower limbs (CHCVIA) and 4 control patients affected only by HCV infection (CHCV) were studied with color Doppler sonography. CHCVIA patients were examined before and after 3 days of iloprost infusion, and CHCV patients were examined before and after 3 days with no treatment. In each patient, PFV was obtained after calculating portal flow velocity (PV), portal diameter, and portal vein cross-sectional area. The mean difference between basal and final values of the PFV of CHCVIA patients was significant (p = 0.03), as was the difference in the PFV (final values expressed as percent of basal values) in CHCVIA patients compared with those obtained in the CHCV patients (p = 0.01). We have observed significant improvement in hepatic perfusion in CHCVIA patients compared with CHCV patients after iloprost infusion. In light of these results, we suggest some possible therapeutic implications in patients with HCV infection. Further studies are necessary to confirm this hypothesis.

Hepatocyte transplantation in the treatment of acute liver failure: microencapsulated hepatocytes versus hepatocytes attached to an autologous biomatrix.

A liver transplant is considered today to be the only effective therapeutic solution for many otherwise intractable hepatic disorders. However, liver transplantation is beset by shortage of donors. Over the years, many liver support systems have been developed to supply the liver functions, mostly as a bridge to transplantation. Transplantation of isolated hepatocytes (HcTx) instead of whole liver has constituted one of the most appealing possibilities to treat several diseases. We compared two different models of HcTx in a surgical model of acute liver failure in pigs, using microencapsulated hepatocytes (MHcTx) and hepatocytes attached to a porcine biomatrix (PBMHcTx), both transplanted into peritoneum. The collected data were survival, laboratory findings, hemodynamic parameters, light microscopy, histology, MTT, and glycogen content. The group with PBMHcTx has a better outcome than the group with MHcTx (p < 0.05). Histology showed normal morphology of the hepatocytes, high glycogen content, 75% viability, positive MTT, and 95% adhesion of the hepatocytes to the biomatrix. Our biomatrix (PBM) provides cell-to-cell contact and interaction with extracellular matrix, which have been shown to play major roles in hepatocyte survival and physiologic regulation of gene expression, and guarantee a prompt engraftment and an adequate neovascularization. PBMHcTx is a useful method to treat acute liver failure and it indicates a possible liver-direct gene therapy in the treatment of inherited and acquired disorders.

Hemodynamic effects of a prostacyclin analog (iloprost) on portal flow velocity and volume and visceral artery circulation in patients with lower limb arteriopathy.

Previous studies demonstrated that iloprost improves the peripheral circulation. In this study, we examined, by Doppler sonography, portal flow velocity (cm/s) and volume (mL/min), and resistance index (RI) of visceral arteries in 23 patients before and after 7 days of iloprost infusion. Statistically significant hemodynamic changes were only seen in portal vein (pre-iloprost vs. post-iloprost treatment mean portal flow velocity and volume values: 23.9 cm/s vs. 29.0 cm/s, p < 0.001 and 1824.6 mL/min vs. 2294.4 mL/min, p < 0.001, respectively). On the other hand, the interlobar renal artery RI, reduced after iloprost treatment in most patients, was not statistically significant; conflicting results were obtained on the hepatic and mesenteric arteries. Our results indicate that iloprost significantly increases portal flow velocity and volume. The understanding of the mechanism through which iloprost plays a role in portal microcirculation could be useful for its new medical indications in liver hemodynamic disorders.

Development of a new bioartificial liver using a porcine autologous biomatrix as hepatocyte support.

Long-term maintenance of hepatocyte viability and differentiated function expression is crucial for bioartificial liver support. The maintenance of hepatocyte function in a bioreactor is still a problem. A major advance was the recognition that hepatocytes in attachment cultures can maintain their differentiation longer. To restore hepatocyte polarity and prolong their function, we developed a new bioreactor with a cross-flow geometry configuration and an original hepatocyte extracellular autologous biomatrix (Porcine Bio-Matrix) support. To test this new bioreactor, we compared it with a standard bioartificial liver cartridge in a suitable surgical model of acute liver failure in pigs. In our model, we performed a total hepatectomy, followed by partial liver transplantation after an 18 hour anhepatic phase. The results showed that the bioreactor containing the biomatrix was able to bridge the animal to transplantation and to sustain the transplanted liver until all function recovered (80% of animals survived, p = 0.0027). No animal survived more than 24 hours after liver transplantation in the group treated with the traditional bioartificial liver, whereas hepatocyte viability on the Porcine Bio-Matrix was 65% after 12 hours of treatment. The results suggest that our biomatrix is a suitable cell support and guarantees long-term maintenance of metabolic activity of hepatocytes. Further studies are needed, but the results obtained with this new three-dimensional bioreactor are promising, and its potential is attractive.

Enhanced portal flow velocity and volume following Iloprost treatment.

OBJECTIVE: We studied, with color Doppler sonography, portal flow velocity (PV) and volume (PFV) before and after Iloprost infusion. BACKGROUND: Iloprost is a prostacyclin analogue with arterial vasodilator and platelet aggregation inhibitor properties. Recently, hemodynamic effects after treatment with Iloprost have been demonstrated in subjects with arteriopathy of lower limbs. METHODS: We treated 10 subjects (2 males and 8 females; mean age 64 +/- 8.2 years) affected by arteriopathy of lower limbs with intravenous infusion of Iloprost, at a dosage of 2 ng/Kg/min (16 hours/day) for 3 days. In all patients portal vein flow velocity (PV) (cm/s) and volume (PFV) (ml/min) were assessed. PV was directly determined by the Doppler system, whereas PFV was calculated using the formula "CSA x PV", after measuring the portal vein cross sectional area (CSA) (mm2). RESULTS: The patients showed markedly increased PV and PFV after Iloprost infusion (pre-Iloprost vs post-Iloprost treatment mean portal flow velocity and volume values: 23.12 +/- 3.89 cm/s vs 28.49 +/- 3.90 cm/s, p < 0.01 and 1743.9 +/- 241.7 ml/min vs 2271.7 +/- 333.5 ml/min, p < 0.001, respectively). CONCLUSIONS: This study confirms our previous results about increased PV and PFV values after Iloprost treatment. In the light of these results we suggest some possible therapeutic implications in patients undergoing liver transplantation. However, further studies are necessary to confirm this hypothesis.

Morphological and functional modifications of the aneurysm-endograft complex following endoluminal exclusion in 30 consecutive cases.

Data from 30 consecutive excluded abdominal aortic aneurysms (AAA) have been analysed, to verify whether important morphological changes take place after exclusion, and whether these can be considered as risk factors for functional (leaks, flow alterations) and clinical complications (rupture, obstruction). All AAAs have been initially successfully excluded and patients have been followed up by clinical examinations and ct scan controls post-operatively, at the third and sixth month, then yearly. At a mean follow-up of 17 months, dimension of the proximal neck increased significantly (> 2 mm in diameter) in five pts and graft was distally dislodged in two. Maximum aneurysm diameter reduced significantly (at east 10% than originally) in half of the case and more than 25% in 10% of cases. Four AAAs presented an initial increase, that reduced only in two. Calculation of length of the AAA was unreliable due to tortuosity. Two secondary type II leaks and one secondary type III leak were observed associated to stable or slightly increased AAA diameter (the latter patient suddenly died probably for miocardial infarction, but a rupture could not be formally excluded). Marked tortuosity of the graft was seen in five patients, all associated with frank shrinkage of the aneurysmal sac. Parietal thrombosis without explanation was observed in five, and in one progressed to obstruction of an iliac branch. Two pts needed anticoagulation. These data indicate that endoluminal aneurysm exclusion can not be considered as a definitive solution, for long-term outcome is unforeseeable in a number of patients.

Cytokines and liver failure: modification of TNF- and IL-6 in patients with acute on chronic liver decompensation treated with Molecular Adsorbent Recycling System (MARS).

Liver transplantation, considered today as the most effective treatment for end-stage liver diseases, can not always be performed on every patient affected with a liver disease. Patients with end-stage liver diseases, usually have high bilirubin, encephalopathy and renal failure. In these situations cytokines play an important role in different processes, from apoptosis to regeneration. The aim of this clinical study has been to analyse the action of new artificial liver system, called Molecular Adsorbent Recycling System (MARS) on cytokines metabolism in patients affected with acute on chronic liver failure. The results are intriguing because an increase of IL-6 and a decrease of TNF-alpha observed during MARS treatment. The study confirms the efficacy of MARS therapy in terms of homeostasis of the cytokines network and suggests an usefulness of monitoring their level during liver failure.

[Gastrin-secreting neuroendocrine carcinoma: two cases identified and treated surgically with a radio-guided technique]. / Carcinoma neuroendocrino a secrezione gastrinica: due casi identificati e trattati chirurgicamente con tecnica radioguidata.

The authors present two cases of gastrin-producing carcinoma demonstrated by scintigraphy with In-111 pentetreotide. The possible malignant evolution of such tumours and the good results that can be achieved with surgical therapy suggest the usefulness of a radio-guided intraoperative strategy to locate the lesions and minimise invasive procedures. This approach enabled us to detect a lymph-node metastasis concealed in the adipose tissue in the first case and to exclude any other gastrin-producing tumour localisations in the second. We recommend that the radio-guided strategy should be included among the guidelines for the treatment of gastrinomas and believe that the procedure can also be used in other functioning endocrine tumours.

Neoadjuvant strategies for pancreatic cancer.

Pancreatic cancer (PC) is the fourth cause of cancer death in Western countries, the only chance for long term survival is an R0 surgical resection that is feasible in about 10%-20% of all cases. Five years cumulative survival is less than 5% and rises to 25% for radically resected patients. About 40% has locally advanced in PC either borderline resectable (BRPC) or unresectable locally advanced (LAPC). Since LAPC and BRPC have been recognized as a particular form of PC neoadjuvant therapy (NT) has increasingly became a valid treatment option. The aim of NT is to reach local control of disease but, also, it is recognized to convert about 40% of LAPC patients to R0 resectability, thus providing a significant improvement of prognosis for responding patients. Once R0 resection is achieved, survival is comparable to that of early stage PCs treated by upfront surgery. Thus it is crucial to look for a proper patient selection. Neoadjuvant strategies are multiples and include neoadjuvant chemotherapy (nCT), and the association of nCT with radiotherapy (nCRT) given as either a combination of a radio sensitizing drug as gemcitabine or capecitabine or and concomitant irradiation or as upfront nCT followed by nRT associated to a radio sensitizing drug. This latter seem to be most promising as it may select patients who do not go on disease progression during initial treatment and seem to have a better prognosis. The clinical relevance of nCRT may be enhanced by the application of higher active protocols as FOLFIRINOX.

Hepatic colorectal metastases involving infra-hepatic inferior vena cava in high risk patients for extended resection: an alternative method for achieving radical resection in patient with borderline liver remnant.

Resection is the only chance of cure for isolated liver metastases from colorectal cancer. In the case of extended parenchymal resections, one crucial point is the ischemic damage to the remnant liver. We report an alternative technique for extremely extended liver resections without total hilar clamping for borderline liver remnants. Two patients presented with invasion of the infrahepatic vena cava, both with an estimated live remnant ≤20 %. The crucial point of the technique is the absence of a portal triad clamping in under beating heart-extracorporeal circulation. In both patients resection margins were free of disease. No signs of liver insufficiency were noted. Survival was more than 2 years in both cases. We believe that aggressive treatment of liver colorectal metastases should be given to all suitable patients. This operation may be added to the techniques that can be offered to these patients.

Chemoradiation treatment with gemcitabine plus stereotactic body radiotherapy for unresectable, non-metastatic, locally advanced hilar cholangiocarcinoma. Results of a five year experience.

BACKGROUND: Hilar cholangiocarcinoma (Klatskin tumor-KT) accounts for about 0.5-1.5% of all gastrointestinal cancers and for 40-60% of all biliary malignancies. Tumor resection is attainable in about 30-50% of patients. When resection is not possible other treatment options have little or no impact on survival. We present the results of hypofractionated Stereotactic Body Radiotherapy (SBRT) on a small series of non resectable locally advanced KT patients. MATERIALS AND METHODS: Ten patients with histologically proven KT underwent SBRT plus gemcitabine. Radiotherapy (30Gy) was delivered in three fractions. Treatment toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE v. 3.0). Alive patients with less than 1 year of follow up were excluded from the present study. Local control was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS: Two grade 1 and Two grade 2 acute toxicities were observed, moreover one grade 2 late toxicity was recorded. The overall local response ratio was 80% (4 PR+2 SD). SBRT showed a good efficacy in achieving local control. Median time to progression was 30 months. Two-year survival was 80% and four-year survival 30%. Six patients developed metastatic disease. Response to treatment and nodal metastases were the only independent indicators of prolonged survival. CONCLUSIONS: The chemoradiation given by SBRT plus gemcitabine is a promising treatment for non-metastatic unresectable KT. High local control rates, even compared to historical data from conventional radiotherapy, can be achieved with minimal toxicity.