Capecitabine, Oxaliplatin, Irinotecan, and Bevacizumab Combination Followed by Pazopanib Plus Capecitabine Maintenance for High-Grade Gastrointestinal Neuroendocrine Carcinomas.

OBJECTIVES: Gastrointestinal neuroendocrine carcinoma (NEC) is a lethal, uncommon, and understudied neoplasm. We present the efficacy and safety of first-line capecitabine (CP), oxaliplatin, irinotecan, and bevacizumab (CAPOXIRI-BEV) combination followed by pazopanib plus CP maintenance therapy in patients with advanced high-grade poorly differentiated gastrointestinal NEC. METHODS: This was a two-stage phase II study conducted at multiple institutions. Patients were consecutively enrolled and had advanced NEC of the colon or small bowel. Patients received irinotecan 125 mg/m, oxaliplatin 80 mg/m on day 1, CP 1000 mg/m twice daily on days 1 to 14, plus bevacizumab 8 mg/kg on day 1 for six 21-day cycles. Maintenance therapy was given to those who responded (complete response/partial response) or had stable disease after 6 cycles with CAPOXIRI-BEV with pazopanib 800 mg daily plus CP 1600 mg/m daily on days 1 to 14 every 3 weeks until disease progression or unacceptable toxicity. Patients who progressed on CAPOXIRI-BEV received standard etoposide-carboplatin. The primary endpoint was overall response rate. RESULTS: Twenty-two patients were enrolled of whom 19 were evaluable. The median age was 60 years. The overall response rate (3 complete response/6 partial response) was 47.4% (95% confidence interval: 29.5-76.1), the overall disease control rate was 78.9% (95% confidence interval: 62.6-99.6), and, at median 30 (11 to 41 mo) months' follow-up, 5 patients (26.3%) were still alive. Median progression-free survival was 13 months, and the 1-year progression-free survival rate was 52.6%. The median overall survival was 29 months. The median overall survival of the 9 patients who responded versus those with stable disease/progressive disease was 30.5 versus 14 months, respectively. The median duration of response was 16 months. Predictable toxicity was observed. CONCLUSIONS: First-line CAPOXIRI-BEV followed by pazopanib plus CP maintenance therapy for advanced NEC demonstrates promising efficacy and predictable toxicity. Further investigation is warranted.

Adult pancreatoblastoma: A case report and review of the literature.

The present study describes the case of a 24-year-old patient who presented with obstructive jaundice and weight loss, and was diagnosed with pancreatoblastoma (PB). Abdominal imaging studies revealed a heterogenous lesion of the pancreatic head with dilatation of the common bile duct. The patient underwent pancreaticoduodenectomy, however, three months after surgery multiple liver and bone metastases were identified on follow-up computed tomography scans. Despite treatment with four cycles of systemic chemotherapy and five courses of radiofrequency ablation, the patient succumbed due to tumour dissemination 13 months after initial diagnosis. PB is a malignant tumour of the pancreas that typically occurs in the pediatric population. The aim of the present study was to highlight the aggressive behavior of this rare clinical entity, focusing on the pitfalls of pre-operative diagnosis and the lack of management strategy guidelines in adults. Preoperative diagnosis of PB based on radiographic features may be difficult, as the imaging characteristics are non-specific. Furthermore, cytology may also be misleading, as the neoplasm consists of multiple cell lines (acinar, ductal and neuroendocrine cells) and diagnosis depends largely on the identification of the distinctive histological characteristic of squamoid corpuscles, which present as nests of flattened cells with a squamous appearance. Despite the use of surgical resection and adjuvant chemoradiotherapy for the treatment of this malignancy, its aggressive nature means that PB is associated with a poor prognosis in adult patients.

Current trends in the management of infected necrotizing pancreatitis.

Severe acute pancreatitis is a potentially life-threatening disease. Pancreatic necrosis is associated with an aggravated prognosis, while superimposed infection is almost always lethal without surgery. Bacterial translocation mainly from the gut is the most widely accepted mechanism in the pathogenesis of infected pancreatic necrosis. Infected pancreatic necrosis should be suspected in the presence of the usual markers of systemic inflammation (i.e., fever and leukocytosis), organ failure, or a protracted severe clinical course. The diagnostic method of choice to confirm the diagnosis of pancreatic necrosis is contrast-enhanced computed tomography, where necrotic areas are evidenced as regions without enhancement. The presence of pancreatic necrotic infection should be based on a combination of clinical manifestations, results of laboratory investigation (mainly increased levels of CRP and / or procalcitonin), and can be confirmed by image-guided fine-needle aspiration and gram stain /culture of the aspirates. Surgery remains the treatment of choice for the management of infected pancreatic necrosis and involves open necrosectomy (debridement) and wide drainage of the peripancreatic areas, often in association with continuous irrigation. Planned reoperations may be required to achieve complete removal of the necrotic / infected material. The timing of surgery is of paramount importance; ideally, surgery should be performed after 2 or 3 weeks from the onset of pancreatitis. Recently, various minimally invasive approaches have been described, but they have not been compared in prospective trials with the classical open surgery. Antibiotic therapy is routinely used in patients with infected necrotizing pancreatitis, in conjunction with surgical debridement; its role, however, in the management of patients with sterile necrosis is recently questioned. Nutritional support should be taken into consideration in these patients; enteral nutrition should be preferred over total parenteral nutrition to improve the anatomical and functional integrity of the gut mucosa, thereby preventing bacterial translocation.

Hepatic resection for hepatocellular carcinoma exceeding Milan criteria.

BACKGROUND: Many hepatocellular carcinomas (HCCs) are discovered at an advanced stage. The efficacy of transplantation for such tumors is doubtable. The aim of this retrospective study was to determine liver resection efficacy in patients with large HCC regarding long term and disease- free survival. METHODS: Between 2002 and 2008, sixty six patients with large HCC (>5cm) underwent hepatectomy. Fifty nine patients had background cirrhosis due to hepatitis B, C or other reason and preserved liver function (Child A). Liver function was assessed by both Child's-Pugh grading and MELD score. Conventional approach of liver resection was performed in most cases. RESULTS: The 5-year overall survival was 32% with a median follow up of 33 months. The three year disease-free survival was 33% in our cohort. On multivariate analysis, only tumor size and grade remained independent predictors of adverse long term outcome. Multivariate analysis identified size of the primary tumour and degree of differentiation as risk factors for recurrence. Median blood loss was 540ml and median transfusion requirements were two units of pack red blood cells. Morbidity included pleural effusion (n=18), biliary fistula (n=4), peri-hepatic abscess (n=4), hyperbilirubinemia (n=3), pneumonia (n=5) and wound infection (n=6). No peri-operative mortality was reported in our study. CONCLUSION: Partial hepatectomy is safe in selective patients with large HCC. Surgical resection if feasible is suggested in patients with large HCC because it prolongs both overall and disease-free survival with low morbidity.

Pleurobiliary fistula, a rare complication of hepatocellular carcinoma after locoregional chemotherapy: a case report.

A rare complication of the compilation of high intrahepatic biliary pressure and the formation of a subdiaphragmatic abscess is that of pleurobiliary fistula. We present a case of 67-year-old male who presented with pleurobiliary fistula following transarterial chemoembolization in a patient with a large hepatocellular carcinoma, as well as the course of the diagnostic procedures and the therapeutics interventions which took place.

Model for end-stage liver disease (MELD) score, as a prognostic factor for post-operative morbidity and mortality in cirrhotic patients, undergoing hepatectomy for hepatocellular carcinoma.

BACKGROUND/AIMS: To evaluate the ability of the model for end-stage liver disease (MELD) in predicting the post-hepatectomy outcome for hepatocellular carcinoma (HCC). METHODS: Between 2001 and 2004, 69 cirrhotic patients with HCC underwent hepatectomy and the results were retrospectively analysed. MELD score was associated with post-operative mortality and morbidity, hospital stay and 3-year survival. RESULTS: Seventeen major and 52 minor resections were performed. Thirty-day mortality rate was 7.2%. MELD < or = 9 was associated with no peri-operative mortality vs. 19% when MELD > 9 (P < 0.02). Overall morbidity rate was 36.23%; 48% when MELD > 9 vs. 25% when MELD < or = 9 (P < 0.02). Median hospital stay was 12 days [8.8 days, when MELD < or = 9 and 15.6 days when MELD > 9 (P = 0.037)]. Three-year survival reached 49% (66% when MELD < or = 9; 32% when MELD > 9 (P < 0.01). In multivariate analysis, MELD > 9 (P < 0.01), clinical tumour symptoms (P < 0.05) and American Society of Anesthesiologists (ASA) score (P < 0.05) were independent predictors of peri-operative mortality; MELD > 9 (P < 0.01), tumour size >5 cm (P < 0.01), high tumour grade (P = 0.01) and absence of tumour capsule (P < 0.01) were independent predictors of decreased long-term survival. CONCLUSION: MELD score seems to predict outcome of cirrhotic patients with HCC, after hepatectomy.

Perioperative risk assessment for hepatocellular carcinoma by using the MELD score.

BACKGROUND/AIMS: The aim of this study was to evaluate the ability of Model for End-Stage Liver Disease (MELD) in predicting post hepatectomy outcome for hepatocellular carcinoma (HCC). METHODS: Between 2001 and 2005, 94 cirrhotic patients with HCC underwent hepatectomy and were analyzed retrospectively. MELD score associated with postoperative mortality and morbidity, hospital stay, and 3-year survival. RESULTS: Twenty-eight major and 66 minor resections were performed. Thirty-day mortality rate was 6.4%. MELD 9 (p = 0.01). Overall morbidity rate was 32%; 21% when MELD 9 (p = 0.01). Median hospital stay was 11 days (7 days, when MELD 9; p = 0.03). Three-year survival reached 48% (63% when MELD 9; p < 0.01). In multivariate analysis, MELD > 9 (p = 0.01), clinical tumor symptoms (p = 0.04), and American Society of Anesthesiologists score (p = 0.04) were independent predictors of perioperative mortality; MELD > 9 (p = 0.01), tumor size >5 cm (p = 0.01), presence of tumor symptoms (p = 0.02), high tumor grade (p = 0.01), and absence of tumor capsule (p = 0.01) were independent predictors of decreased long-term survival. CONCLUSION: MELD score seems to predict outcome of cirrhotic patients with HCC after hepatectomy.

Hepatic parenchyma resection using stapling devices: peri-operative and long-term outcome.

BACKGROUND: Stapler-assisted hepatectomy has not been well established, as a routine procedure, although few reports exist in the literature. This analysis assesses the safety and outcome of the method based on peri-operative data. MATERIALS AND METHODS: From February 2005 to December 2006, endo GIA vascular staplers were used for parenchymal liver transection in 62 consecutive cases in our department. There were 18 (29%) patients with hepatocellular carcinoma (HCC), 31 (50%) with metastatic lesions and 13 (21%) with benign lesions [adenoma, focal nodular hyperplasia (FNH), simple cysts]. Twenty-one patients underwent major resections (33.9%) (i.e. removal of three segments or more) and 41 (66.1%) minor hepatic resections. RESULTS: Median blood loss was 260 ml. The median total operative time was 150 min and median transection time was 35 min. No patient required more than 2 days of intensive care unit (ICU) treatment. The median hospital stay was 8 days. Surgical complications included two (3%) cases of bile leak, two (3%) cases of pneumonia, two (3%) cases with wound infection and two (3%) cases with pleural effusion. The peri-operative mortality was zero. In a 30-month median follow-up, all patients with benign lesions were alive and free of disease. The 3-year disease-free survival for patients with HCC was 61% (57% for patients with colorectal metastases) and the 3-year survival 72% (68% for patients with colorectal metastases). CONCLUSION: Stapler-assisted liver resection is feasible with a low incidence of surgical complications. It can be used as an alternative for parenchyma transection especially in demanding hepatectomies for elimination of the operating time and control of bleeding.

Liver transplantation for severe hepatic trauma: experience from a single center.

Liver transplantation has been reported in the literature as an extreme intervention in cases of severe and complicated hepatic trauma. The main indications for liver transplant in such cases were uncontrollable bleeding and postoperative hepatic insufficiency. We here describe four cases of orthotopic liver transplantation after penetrating or blunt liver trauma. The indications were liver failure, extended liver necrosis, liver gangrene and multiple episodes of gastrointestinal bleeding related to portal hypertension, respectively. One patient died due to postoperative cerebral edema. The other three patients recovered well and remain on immunosuppression. Liver transplantation should be considered as a saving procedure in severe hepatic trauma, when all other treatment modalities fail.

Solitary necrotic nodule of the liver mimicking hepatocellular carcinoma: a case report.

INTRODUCTION: Solitary necrotic nodule of the liver is a rare lesion, with similar radiologic findings to those of hepatic metastases or other liver masses. CASE PRESENTATION: We here report a case of a 30-year-old male with hepatic solitary necrotic nodule discovered after an episode of acute abdominal pain and high grade fever. Routine laboratory data revealed leukocytosis and abnormal liver function. The imaging features of the lesion suggested malignancy or liver adenoma. The patient underwent surgical resection of segments V and VI. Histology was compatible with solitary necrotic nodule and localized vein thrombosis at the periphery. CONCLUSION: Solitary necrotic nodule of the liver is a benign lesion which can mimic liver malignancies. Abdominal imaging and liver biopsy are often equivocal. In such circumstances liver resection is mandatory to exclude HCC or other malignant liver lesions.

Hepatic resection for large hepatocellular carcinoma in the era of UCSF criteria.

BACKGROUND: Treating patients with hepatocellular carcinoma (HCC) remains a challenge, especially when the disease presents at an advanced stage. The aim of this retrospective study was to determine the efficacy of liver resection in patients who fulfil or exceed University of California San Francisco (UCSF) criteria by assessing longterm outcome. METHODS: Between 2002 and 2008, 59 patients with large HCC (>5 cm) underwent hepatectomy. Thirty-two of these patients fulfilled UCSF criteria for transplantation (group A) and 27 did not (group B). Disease-free survival and overall survival rates were compared between the two groups after resection and were critically evaluated with regard to patient eligibility for transplant. RESULTS: In all patients major or extended hepatectomies were performed. There was no perioperative mortality. Morbidity consisted of biliary fistula, abscess, pleural effusion and pneumonia and was significantly higher in patient group B. Disease-free survival rates at 1, 3 and 5 years were 66%, 37% and 34% in group A and 56%, 29% and 26% in group B, respectively (P < 0.01). Survival rates at 1, 3 and 5 years were 73%, 39% and 35% in group A and 64%, 35% and 29% in group B, respectively (P= 0.04). The recurrence rate was higher in group B (P= 0.002). CONCLUSIONS: Surgical resection, if feasible, is suggested in patients with large HCC and can be performed with acceptable overall and disease-free survival and morbidity rates. In patients eligible for transplantation, resection may also have a place in the management strategy when waiting list time is prolonged for reasons of organ shortage or when the candidate has low priority as a result of a low MELD (model for end-stage liver disease) score.

Primary hepatic carcinoid; a diagnostic dilemma: a case report.

INTRODUCTION: Primary hepatic carcinoid tumours (PHCTs) are extremely rare neuroendocrine neoplasms. Only 58 cases have been reported in the literature and less than 10 cases were functional. CASE PRESENTATION: We present a case of a 65 years old, Caucasian female with a large unresectable primary hepatic carcinoid tumor secreting 5-hydroxyindoleacetic acid (5-HIAA), presented with flushing and diarrhoea and treated with trans-catheter arterial embolization (TACE) and subsequent administration of lanreotide (long acting somatostatin analogue). CONCLUSION: The diagnosis of PHCTs is difficult due to their common radiologic characteristics with other liver lesions. Their diagnosis is based on the exclusion of other sites of disease and the histologic confirmation. Although the mainstay of treatment when is technically feasible is surgical resection with optimal 5-year survival and low recurrence rate, in cases of unresectable disease palliation with combination of TACE and administration of somatostatin analogues have good results in controlling the disease and the patients symptoms.

Surgical management of large adrenal tumours: the University of Miami experience using liver transplantation techniques.

OBJECTIVE: To report our experience in the surgical management of patients with large adrenal masses and describe the key steps in performing radical resections, which are especially demanding where thrombi extend into the inferior vena cava (IVC). PATIENTS AND METHODS: From 2003 to 2007, 14 patients presented with large adrenal mass, and underwent surgical extirpation. In five patients thrombi extended into the IVC, causing Budd-Chiari syndrome in one. RESULTS: The median (range) patient age was 48 (40-58) years. The excision was radical with negative tumour margins in all cases. Cardiopulmonary bypass (CPB) was required in one case with adherent intra-atrial thrombus. The mean blood loss was 500 (250-1500) mL except in the patient who required CPB. Morbidity included pleural effusion (three patients) and postoperative pneumonia (two), which responded to conservative management. All patients were alive and free of disease at a median follow-up of 12 (5-42) months. CONCLUSIONS: Surgical extirpation of large adrenal masses requires technical experience to optimize outcome. Total tumour excision is the only therapeutic option in such cases and provides acceptable results in survival and quality of life.

Selection criteria for liver resection in patients with hepatocellular carcinoma and chronic liver disease.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with an annual occurrence of one million new cases. An etiologic association between HBV infection and the development of HCC has been established with a relative risk 200-fold greater than in non-infected individuals. Hepatitis C virus is also proving an important predisposing factor for this malignancy with an incidence rate of 7% at 5 years and 14% at 10 years. The prognosis depends on tumor stage and degree of liver function, which affect the tolerance to invasive treatments. Although surgical resection is generally accepted as the treatment of choice for HCC, new treatment strategies, such as local ablative therapies, transarterial embolization and liver transplantation, have been developed nowadays. With increasing detection of small HCCs from screening programs for cirrhotic patients, it is foreseen that locoregional therapy will play an important role in the near future.

Transthoracic approach (TTA) for subdiaphragmatic liver metastasectomy.

BACKGROUND: Hepatic and pulmonary recurrences are major determinants of survival for patients who have undergone curative resection of colorectal carcinoma. In a selected group of patients, resection of metachronous, liver and lung metastases prolongs survival despite the aggressive nature of these lesions. The experience from an exclusive transthoracic, transdiaphragmatic approach (TTA) is limited. We present our experience with metastasectomy in patients with metachronous liver and right lung metastases, in whom an exclusive transthoracic approach was performed. METHODS: Between 2002 and 2007, seven patients with metachronous colorectal liver and right-lung metastases, underwent an exclusive transthoracic approach. There were five men and two women, with a median age of 69 years (range 55 to 78 years). Liver resections performed included segmentectomy of segments VII, VIII, or both. Previous operations, including colon resection, adhesiolysis, ventral hernia repair, or transabdominal segment V resection, were performed in all patients. RESULTS: No peri-operative mortality was documented. Morbidity included pleural effusion (n=3) and post-operative pneumonia (n=1), which responded to conservative management. Median hospital stay was 8 days (range 5-12 days). With a median follow-up of 31 months, one patient died of generalized disease. CONCLUSION: The factors that led to the increase of performances in colonoscopy in our department were the use of proper sedation and analgesia, the permanent internal audit of the maneuver, as well as the motivation of the endoscopist to obtain good results.

Intrahepatic biliary cystadenoma: a need for radical resection.

BACKGROUND: Intrahepatic biliary cystadenoma (IBC) is a rare liver tumour, which has strong tendency to recur and malignant potential as it can progress to cystadenocarcinoma (IBCa). METHODS: From June 2003 to December 2006, four patients diagnosed with hepatic cystadenoma were operated on our Liver Surgical Unit. All patients were females with median age of 51 years (range 45-63 years). Liver resections included three left and one right hepatectomies. In two patients, IBC was diagnosed by abdominal imaging and serum tumour markers but the rest of the patients were initially misdiagnosed as simple cysts, treated by laparoscopic fenestration and referred to our unit after cyst recurrence. RESULTS: In all cases, the pathology report was consistent with liver cystadenomas. The postoperative course was uneventful and the median hospital stay was 8 days (range 5-12 days). In a median 18-month follow-up (range 2-40 months), all patients are alive and free of recurrence. CONCLUSION: Liver cystadenomas can be easily misdiagnosed with other hepatic cystic lesions. An aggressive surgical approach is recommended, due to their malignant potential and high recurrence rate after fenestration.

Obstructive jaundice in polycystic liver disease related to coexisting cholangiocarcinoma.

Although jaundice rarely complicates polycystic liver disease (PLD), secondary benign or malignant causes cannot be excluded. In a 72-year-old female who presented with increased abdominal girth, dyspnea, weight loss and jaundice, ultrasound and computed tomography confirmed the diagnosis of PLD by demonstrating large liver cysts causing extrahepatic bile duct compression. Percutaneous cyst aspiration failed to relief jaundice due to distal bile duct cholangiocarcinoma, suspected by magnetic resonance cholangiopancreatography (MRCP) and confirmed by endoscopic retrograde cholangiopancreatography (ERCP). Coexistence of PLD with distal common bile duct cholangiocarcinoma has not been reported so far.

Radiofrequency-assisted liver resection.

BACKGROUND: Surgical resection remains the treatment of choice for primary, secondary liver cancer and a number of benign liver lesions. Complications are mainly related to blood loss. Radiofrequency-assisted liver resection (RF-LR) has been proposed in order to achieve minimal blood loss during parenchymal transection. PATIENTS AND METHODS: Between May 2005 and April 2007, 46 consecutive patients with various hepatic lesions underwent RF-LR using Radionics, Cool-Tip System. There were 28 men and 18 women with median age 65 years (range 54-76 years). Twelve major and 34 minor hepatectomies were performed for various diseases: hepatocellular carcinoma (n=19), metastatic carcinoma (n=23), focal nodal hyperplasia (n=2) and intrahepatic cholangiocarcinoma (ICC) (n=2). Hepatic inflow occlusion was not used. RESULTS: No perioperative death was documented. Median blood loss was 100ml (range 30-300cm(3)). Blood transfusion was required postoperatively in one patient. Median transection time was 35min (15-60min). Three patients developed biliary fistulas, four patients pleural effusions, one patient hyperbilirubinemia, two pneumonia and four wound infection. The median postoperative hospital stay was 6 days (range 4-10 days). In a median 12 month follow-up (range 3-24 months), four patients with colorectal metastases (CRM) and one patient with ICC developed recurrence. CONCLUSIONS: Cool-Tip RF device provides a unique, simple and safe method of bloodless liver resections and is indicated in cirrhotic patients with challenging hepatectomies (segment VIII, central resections).

Combined liver and inferior vena cava resection for hepatic malignancy.

OBJECTIVE: The experience from a single center, in combined liver and inferior vena cava (IVC) resection for liver tumors, is presented. METHODS: Twelve patients underwent a combined liver resection with IVC replacement. The median age was 45 years (range 35-67 years). Resections were carried out for hepatocellular carcinoma (n = 4), colorectal metastases (n = 6), and cholangiocarcinoma (n = 2). Liver resections included eight right lobectomies and four left trisegmentectomies. The IVC was reconstructed with ringed Gore-Tex tube graft. RESULTS: No perioperative deaths were reported. The median operative blood transfusion requirement was 2 units (range 0-12 units) and the median operative time was 5 hr. Median hospital stay was 10 days (range 8-25 days). Three patients had evidence of postoperative liver failure, resolved with supportive management. Two patients developed bile leaks, resolved conservatively. With a median follow up of 24 months, all vascular reconstructions were patent and no evidence of graft infection was documented. CONCLUSIONS: Aggressive surgical management of liver tumors, offer the only hope for cure or palliation. We suggest that liver resection with vena cava replacement may be performed safely, with acceptable morbidity, by specialized surgical teams.