Acquired erythropoietic uroporphyria secondary to myelodysplastic syndrome with chromosome 3 alterations: a case report.

Congenital erythropoietic porphyria is a rare autosomal recessive disease caused by a deficiency of uroporphyrinogen III synthase, owing to mutations in UROS in chromosome 10. Occasionally, patients show a mild, late-onset disease, without germline UROS mutations, associated with haematological malignancies. We report a 65-year-old patient with photosensitivity, overexcretion of porphyrins and thrombocytopenia. Bone marrow analysis gave a diagnosis of myelodysplastic syndrome (MDS) with the presence of a derivative chromosome 3, possibly due to an inversion including 3q21 and 3q26 break points. After allogeneic stem-cell transplantation, complete remission of MDS and uroporphyria was achieved. To our knowledge, this is the first reported case of acquired erythropoietic uroporphyria associated with MDS, with chromosome 3 alterations.

Oncological strategies for locally advanced rectal cancer with synchronous liver metastases, interval strategy versus rectum first strategy: a comparison of short-term outcomes.

BACKGROUND: The goal of treatment for patients with synchronous liver metastases (SLM) from rectal cancer is to achieve a complete resection of both tumor locations. For patients with symptomatic locally advanced rectal cancer with resectable SLM at diagnosis, our usual strategy has been the rectum first approach (RF). However, since 2014, we advocate for the interval approach (IS) that involves the administration of chemo-radiotherapy followed by the resection of the SLM in the interval of time between rectal cancer radiation and rectal surgery. METHODS: From 2010 to 2016, 16 patients were treated according to this new strategy and 19 were treated according RF strategy. Data were collected prospectively and analyzed with an intention-to-treat perspective. Complete resection rate, duration of the treatment and morbi-mortality were the main outcomes. RESULTS: The complete resection rate in the IS was higher (100%, n = 16) compared to the RF (74%, n = 14, p = 0.049) and the duration of the strategy was shorter (6 vs. 9 months, respectively, p = 0.006). The incidence of severe complications after liver surgery was 14% (n = 2) in the RF and 0% in the IS (p = 1.000), and after rectal surgery was 24% (n = 4) and 12% (n = 2), respectively (p = 1.000). CONCLUSION: The IS is a feasible and safe strategy that procures higher level of complete resection rate in a shorter period of time compared to RF strategy.

Treatment strategies for rectal cancer with synchronous liver metastases: surgical and oncological outcomes with propensity-score analysis.

BACKGROUND: The optimal sequence of surgery for rectal cancer (RC) with synchronous liver metastases (SLM) is controversial. OBJECTIVES: The primary objective was to explore differences between the rectum first (RF) and the liver first strategy (LF) to achieve the complete resection (CR) of both tumors. METHODS: Patients diagnosed of RC with resectable or potentially resectable SLM were included. Data collected prospectively were analyzed with an intention-to-treat perspective, adjusting for between-sample differences (propensity score). The complete resection rate (CRR) was the main outcome variable. RESULTS: During a 5-year period, 23 patients underwent the LF strategy and 24 patients the RF strategy. Median overall survival (OS) was 32 months in the LF group and 41 months in the RF group (p = 0.499), and was 51 and 17 months, respectively, for patients achieving or not achieving CR of both tumors (p < 0.001). CRR's were 65% in liver first group and 63% in rectum first group, (p = 0.846). No between-strategy differences in morbidity or duration of treatment were observed. CONCLUSIONS: This study supports the notion that the achievement of CR of RC and SLM should be the goal of oncological treatment. Both RF and LF strategies are feasible and safe, but no between-strategy differences have been found in the CRR.

Long-term outcomes of patients with 10 or more colorectal liver metastases.

BACKGROUND: Although the number of colorectal liver metastases (CLM) is decreasingly considered as a contraindication to surgery, patients with 10 CLM or more are often denied liver surgery. This study aimed to evaluate the outcome after liver surgery and to identify prognostic factors of survival in such patients. METHODS: The study population consisted of a multicentre cohort of patients with CLM (N=12 406) operated on, with intention to resect, from January 2005-June 2013 and whose data were prospectively collected in the LiverMetSurvey registry. RESULTS: Overall, the group ⩾10 CLM (N=529, 4.3%) experienced a 5-year overall survival (OS) of 30%. A macroscopically complete (R0/R1) resection (72.8% of patients) was associated with a 3- and 5-year OS of 61% and 39% vs 29% and 5% for R2/no resection patients (P<0.0001). At multivariate analysis, R0/R1 resection emerged as the strongest favourable factor of OS (HR 0.35 (0.26-0.48)). Other independent favourable factors were as follows: maximal tumour size <40 mm (HR 0.67 (0.49-0.92)); age <60 years (HR 0.66 (0.50-0.88)); preoperative MRI (HR 0.65 (0.47-0.89)); and adjuvant chemotherapy (HR 0.73 (0.55-0.98)). The model showed that 5-year OS rates of 30% was possible provided R0/R1 resection associated with at least an additional favourable factor. CONCLUSIONS: Liver resection might provide long-term survival in patients with ⩾10 CLM staged with preoperative MRI, provided R0/R1 resection followed by adjuvant therapy. A validation of these results in another cohort is needed.

PARAGON II - A single arm multicentre phase II study of neoadjuvant therapy using irinotecan bead in patients with resectable liver metastases from colorectal cancer.

PURPOSE: Perioperative chemotherapy confers a 3-year progression free survival advantage following resection of colorectal liver metastases (CRLM), but is associated with significant toxicity. Chemoembolisation using drug eluting PVA microspheres loaded with irinotecan (DEBIRI) allows sustained delivery of drug directly to tumour, maximising response whilst minimising systemic exposure. This phase II single arm study examined the safety and feasibility of DEBIRI before resection of CRLM. METHODS: Patients with resectable CRLM received lobar DEBIRI 1 month prior to surgery, with a radiological endpoint of near stasis. The trial had a primary end-point of tumour resectability (R0 resection). Secondary end-points included safety, pathologic tumour response and overall survival. RESULTS: 40 patients received DEBIRI, with a median dose of 103 mg irinotecan (range 64-175 mg). Morbidity was low (2.5%, CTCAE grade 2) with no evidence of systemic chemotoxicity. All patients proceeded to surgery, with 38 undergoing resection (95%, R0 resection rate 74%). 30-day post-operative mortality was 5% (n = 2), with neither death TACE related. 66 lesions were resected, with histologic major or complete pathologic response seen in 77.3% of targeted lesions. At median follow up of 40.6 months, 12 patients (34.3%) had died of recurrent disease with a median overall survival of 50.9 months. Nominal 1, 3 and 5-year OS was 93, 78 & 49% respectively. CONCLUSIONS: Resection after neoadjuvant DEBIRI for CRLM is feasible and safe. Single treatment with DEBIRI resulted in tumour pathologic response and median overall survival comparable to that seen after systemic neoadjuvant chemotherapy. Registered at clinicaltrials.gov (NCT00844233).

Expert opinion on advanced techniques for hemostasis in liver surgery.

BACKGROUND: Reduction of perioperative blood loss and intraoperative transfusion are two major factors associated with improving outcomes in liver surgery. There is currently no consensus as to the best technique to achieve this. METHODS: An international Panel of Experts (EP), made up of hepatobiliary surgeons from well-known high-volume centres was assembled to share their experience with regard to the management of blood loss during liver resection surgery. The process included: a review of the current literature by the panel, a face-to-face meeting and an on-line survey completed by the EP prior to and following the face-to-face meeting, based on predetermined case scenarios. During the meeting the most frequently researched surgical techniques were appraised by the EP in terms of intraoperative blood loss. RESULTS: All EP members agreed that high quality research on the subject was lacking. Following an agreed risk stratification algorithm, the EP concurred with the existing research that a haemostatic device should always be used along with any user preferred surgical instrumentation in both open and laparoscopic liver resection procedures, independently from stratification of bleeding risk. The combined use of Ultrasonic Dissector (UD) and saline-coupled bipolar sealing device (Aquamantys(®)) was the EP preferred technique for both open and laparoscopic surgery. CONCLUSIONS: This EP propose the use of a bipolar sealer and UD for the best resection technique and essential equipment to minimise blood loss during liver surgery, stratified according to transfusion risk, in both open and laparoscopic liver resection.

Late-onset cutaneous porphyria in a patient heterozygous for a uroporphyrinogen III synthase gene mutation.

Deficiency of uroporphyrinogen III synthase (UROS) causes congenital erythropoietic porphyria (CEP). The disease, originating from the inheritance of mutations within the UROS gene, presents a recessive form of transmission. In a few patients, a late-onset CEP-like phenotype without UROS mutations appears to be associated with a myelodysplastic syndrome. We report a 60-year-old man with late-onset signs of cutaneous porphyria and accumulation in urine, plasma and faeces of type I porphyrin isomers characteristic of CEP. Analysis of DNA from peripheral leucocytes, skin and bone marrow aspirate showed that he was a heterozygous carrier of a Cys73Arg (c.217 T>C) mutation within UROS. Sequencing of cDNA from peripheral blood confirmed heterozygosity and expression of the normal allele. Measurement of UROS enzymatic activity in erythrocytes showed values ~70% of normal, indirectly indicating expression of the normal allele. Differently from other cases of late-onset uroporphyria, the patient did not present thrombocytopenia or any evidence of a myelodysplastic syndrome. Five years of clinical follow-up showed persistence of skin signs and increased excretion of porphyrins, independently of lifestyle factors or changes in medication regimes. We hypothesize acquired mosaicism (in the bone marrow) affecting the UROS gene. Thus, unstable cellular clones initiated overproduction of isomer I porphyrins leading to a CEP phenotype. This could be explained either by a clonal expansion of the porphyric (Cys73Arg) allele or by loss of function of the normal allele. Cellular turnover would facilitate release of uroporphyrins into circulation and subsequent skin lesions. This is the first case of a CEP heterozygous carrier presenting clinical manifestations.

Extreme liver surgery as treatment of liver tumors involving the hepatocaval confluence.

OBJECTIVE: Analyze the characteristics, surgical technique, morbidity and survival of patients treated with extreme liver surgery. MATERIALS AND METHODS: We present a series of consecutive patients with malignant liver tumors in hepatocaval confluence treated in a single center with extreme liver surgery (April 2008-March 2015). Data were collected prospectively and analyzed with SPSS 21.0. RESULTS: 12 patients were included. 50 % were male and 50 % were female with a mean age of 59 ± 10 years old. The median of comorbidities was 7 according to the Charlson Age Comorbidity Index. The 75 % of the tumors were metastases, most of them from colorectal cancer. Most of the patients received neoadjuvant chemotherapy and in 58 % preoperative portal embolization was performed. Major hepatectomies were performed (66.7 % extended right hepatectomy, 33.3 % left extended hepatectomy). The 83.3 % of the patients needed vascular reconstruction. Postoperative morbidity was more than grade II in 50 % of the patients according to Dindo-Clavien classification. There was no intraoperative mortality. The postoperative mortality rate at 90 days was 33 % due to hepatic failure and biliary fistula. In December 2015, 33 % of the patients are still alive with a mean survival of 19 months (13-23) with an ECOG Performance Status of 0. CONCLUSION: Extreme liver surgery carries a high rate of morbidity and mortality that seem to increase with age and with higher tumor volumes, according to the literature. It is a therapeutic option to consider in patients with low comorbidity suffering from malignant neoplasms that involve the hepatocaval confluence, when no other treatment with curative intention can be performed.

Is radical surgery feasible in liver hydatid cysts in contact with the inferior vena cava?

BACKGROUND: Cysts in contact with the inferior vena cava (IVC) represent a challenge for hepato-pancreatico-biliary surgeons. Although the literature on the topic is scarce, the most widely accepted approach is conservative surgery. Partial cyst resection is recommended, because radical resection is considered a high-risk procedure. STUDY DESIGN: This was a retrospective study over the period January 2007-December 2012. We operated on 103 patients with liver hydatidosis. A total of 32 patients (31 %) had a liver cyst in contact with the IVC. We proposed a cyst classification based on location of the cyst and length of contact and degrees of involvement of the IVC. RESULTS: Median size of the contacting cyst measured by computed tomography (CT) was 12 cm. On CT, median length of contact with the IVC was 37 mm. The median degree of involvement was 90°. Radical surgery was performed in 20 patients (62.5 %). No IVC resection was done. Morbidity rate was 28 %, and mortality was 3 %. In follow-up (median 27 months), no relapses or problems related to IVC flow were detected. Postoperative stay and transfusion rate were higher in the conservative surgery group, but these patients presented fewer complications. There was no relationship between circumferential grades and length of contact with the IVC and the type of surgery performed. CONCLUSIONS: Liver hydatid cysts in contact with the IVC are large cysts usually located in the right liver. They do not normally cause clinical symptoms related to IVC contact. Radical surgery is feasible, and was performed in 60 % of our series, but it is technically demanding. We propose a classification of cysts in contact with the IVC.

Retrospective analysis of pathological response in colorectal cancer liver metastases following treatment with bevacizumab.

AIMS: Pathological response has been shown to be a predictor for survival after preoperative chemotherapy and surgical resection of colorectal cancer liver metastases. This retrospective analysis evaluated the effect on pathological response of adding bevacizumab to standard neoadjuvant chemotherapy in patients with metastatic colorectal cancer (mCRC) and liver metastases. METHODS: Patient records from two Spanish centres were retrospectively examined for this analysis. Patients were included if they had stage IV mCRC with liver metastases, were unresectable or marginally resectable tumour before chemotherapy, and had oxaliplatin- or irinotecan-based chemotherapy, with or without bevacizumab, before resection. Tumour response was evaluated using response evaluation criteria in solid tumours (RECIST). Pathological response was assessed by pathologists blinded to treatment. RESULTS: Ninety-five patients were included. Good pathological responses (PR0/PR1) were observed in 37 patients (39 %). The RECIST response rate was 51 %. Only 42 % of patients with a good pathological response had a complete or partial response according to RECIST, while 57 % of those with a poor pathological response had a complete or partial response according to RECIST. RECIST response rates were similar with and without bevacizumab, although 49 % of bevacizumab-treated patients had a good pathological response versus 27 % of those receiving chemotherapy alone (χ (2) P = 0.0302). CONCLUSION: Pathological response may be a better indicator of treatment efficacy than RECIST for patients with mCRC receiving bevacizumab in the neoadjuvant setting. Adding bevacizumab to chemotherapy has the potential to increase pathological response rates. Well-designed prospective clinical studies are required to establish the efficacy and tolerability of this approach.

Randomized clinical trial of pancreaticogastrostomy versus pancreaticojejunostomy on the rate and severity of pancreatic fistula after pancreaticoduodenectomy.

BACKGROUND: Anastomotic leakage of pancreaticojejunostomy (PJ) remains the single most important source of morbidity after pancreaticoduodenectomy (PD). The primary aim of this randomized clinical trial comparing PG with PJ after PD was to test the hypothesis that invaginated PG would result in a lower rate and severity of pancreatic fistula. METHODS: Patients undergoing PD were randomized to receive either a duct-to-duct PJ or a double-layer invaginated PG. The primary endpoint was the rate of pancreatic fistula, using the definition of the International Study Group on Pancreatic Fistula. Secondary endpoints were the evaluation of severe abdominal complications (Clavien-Dindo grade IIIa or above), endocrine and exocrine function. RESULTS: Of 123 patients randomized, 58 underwent PJ and 65 had PG. The incidence of pancreatic fistula was significantly higher following PJ than for PG (20 of 58 versus 10 of 65 respectively; P = 0.014), as was the severity of pancreatic fistula (grade A: 2 versus 5 per cent; grade B-C: 33 versus 11 per cent; P = 0.006). The hospital readmission rate for complications was significantly lower after PG (6 versus 24 per cent; P = 0.005), weight loss was lower (P = 0.025) and exocrine function better (P = 0.022). CONCLUSION: The rate and severity of pancreatic fistula was significantly lower with this PG technique compared with that following PJ. REGISTRATION NUMBER: ISRCTN58328599 (http://www.controlled-trials.com).

[Outcome at two years corrected age of a cohort of very low birth weight infants from hospitals within the neonatal SEN1500 network]. / Evolución a los 2 años de edad corregida de una cohorte de recién nacidos con peso inferior o igual a 1.500g de los hospitales pertenecientes a la red neonatal SEN1500.

OBJECTIVE: To describe growth and neurodevelopmental status of 4,944 children who completed a follow-up at two years of corrected age out of the 10,456 newborns with weight ≤1500g born between the years 2002-2007 and discharged from hospitals within the network SEN1500. A total of 522 newborns were excluded as they had some type of malformation. The total number of children assessed represents the 49.76% of children discharged alive and without malformations. METHODS: A retrospective review was conducted using prospectively collected data in the SEN1500 database. We compared growth data at two years of corrected age according to birth weight and sex. Motor impairment, incidence of cerebral palsy, visual and hearing disabilities, and abnormal neurodevelopment for gestational age were analysed between groups. We studied the associations between cerebral palsy (CP) and perinatal factors. RESULTS: At 2 years of age 44.2% of children had a weight <2 SD for corrected age. Children with birth weight ≤1000g showed worse outcomes in growth. Some type of motor impairment was observed in 6.96% of the infants, and 4.56% of them were diagnosed with CP. The incidence was higher among males with birth weight ≤1000g. There was an incidence of 5.21% of visual disability, with 0.5% of children being blind in one or both eyes. Cerebral palsy was associated with retinopathy of prematurity, severe intraventricular haemorrhage, and periventricular leukomalacia, in particular cystic periventricular leukomalacia.

Preoperative treatment with bevacizumab in combination with chemotherapy in patients with unresectable metastatic colorectal carcinoma.

PURPOSE: This prospective observational study assessed the efficacy of bevacizumab in combination with chemotherapy as preoperative treatment to downsize tumours for radical resection in patients with unresectable metastatic colorectal cancer (mCRC). PATIENTS/METHODS: Patients with mCRC initially unresectable according to predefined criteria were included. Preoperative treatment consisted of bevacizumab (5 mg/kg) combined with oxaliplatin- or irinotecan-based chemotherapy, which was followed by surgery in patients showing clinical benefit. Resection rate was the primary endpoint. Response rate (RR) and clinical benefit of preoperative chemotherapy, and overall survival (OS) were secondary endpoints. RESULTS: A total of 120 eligible patients were included and received preoperative treatment. Chemotherapy was irinotecan-based in 73 (61 %) patients, oxaliplatin-based in 25 (21 %) and 22 (18 %) patients received more than one line. A RR of 30 % and a clinical benefit rate of 73 % were observed with preoperative chemotherapy. Metastatic resection was possible in 61 (51 %) patients. Median OS was 33 months (95 % CI 31-NA months) for patients undergoing surgery, and 15 months (95 % CI 11-25 months) in non-operated patients. Thirty-five patients experienced 59 postoperative complications (morbidity rate 57 %). CONCLUSION: Preoperative bevacizumab-based chemotherapy offers a high surgical rescue rate in patients with initially unresectable mCRC.

Cysto-biliary communication in liver hydatidosis.

BACKGROUND: Liver hydatidosis is a severe health problem in endemic areas. Due to migration from these countries to other zones, now it is a worldwide problem. Liver hydatidosis can provoke many complications (abscess, fistula to adjacent organs, migration, etc.), but the most frequent and one of the most severe complication is the communication between the cyst and the biliary tree. AIM: The aim of this study is to perform a review on the epidemiology, clinical features, diagnostic methods, and therapeutic options to treat the communication between the cyst and the biliary tree. RESULTS: Due to the lack of randomized clinical trial or meta-analysis on this topic, we performed a classical review and included our personal algorithm. CONCLUSIONS: The communication between the cyst and the biliary tree varies from a small communication to a frank intrabiliary rupture. The percentage of patients with the communication between the cyst and the biliary tree is not well known because there is no accepted definition. The therapeutic options are multiple and related to the size of the communication, the location of the cyst, and the experience of the hepatobiliary surgeon. ERCP is now an important tool for the treatment of the communication between the cyst and the biliary tree.

Multidisciplinary approach of colorectal liver metastases.

Colorectal cancer (CRC) is the second most common cause of cancer death in Spain. Fifty percent of patients will develop colorectal liver metastases (CLM) during the course of the disease. Less than 20% of patients with CLM are initially resectable and for them 5-year disease-free survival (DFS) is about 20-25%, with a high recurrence rate. CLM is a heterogeneous disease. From a clinical point of view, four main groups can be differentiated: initially resectable, not optimally resectable, unresectable that could be resectable and unresectable that never will be likely to be resected. Treatment of CLM must be established, always, in a multidisciplinary team discussion with an analysis of prognostic factors and resectability. For patients with resectable CLM, the EORTC trial 364 demonstrated that chemotherapy plus surgery is better than surgery alone. Consequently most patients should be treated with perioperative chemotherapy based on oxaliplatin, and if resection has been done without chemotherapy, they should receive adjuvant chemotherapy after R0 resection. Based on oncological factors, the 5-year survival rate after resection of CLM ranges from 60% to only 14% with a poor score. If a patient has more than one of the poor prognostic factors he should probably be referred for preoperative (induction) chemotherapy. Only a minority of patients with CLM are amenable to surgery; therefore, efforts have been made to increase the percentage of patients who could be candidates for resection. Studies, mostly retrospective, have confirmed the ability of neoadjuvant chemotherapy (conversion chemotherapy) to render some metastases resectable. The regimens we must use depend on the KRAS mutational status and the toxicity profiles of drugs in the context of each patient. In k-ras mutated tumours we can use bevacizumab combined with standard chemotherapy or concomitant administration of the three active agents (FOLFOXIRI) in suitable patients. In k-ras wild-type patients, the combination of cetuximab and FOLFIRI-FOLFOX improved response rates and resection rate in phase III-II trials. With a lower level of evidence, panitumumab is an alternative combined with FOLFOX. Bevacizumab is also an alternative as it does not depend on KRAS status. Radiotherapy is becoming an alternative in selected patients, where surgery is not an alternative. For the majority of patients, who will never be resectable, the continuum of care with chemotherapy will be the paradigm for their management.

Complex liver resection for hepatic tumours involving the inferior vena cava.

BACKGROUND: Resection of liver tumours with involvement of inferior vena cava (IVC) is considered to have a high surgical risk. AIM: We retrospectively reviewed 23 patients who underwent hepatectomy with IVC resection in two West-European liver surgery Units. METHODS: The tumours included liver metastases (n = 13), hepatocellular carcinoma (n = 4), intrahepatic cholangiocarcinoma (n = 3), liver haemangioma (n = 1), primary hepatic lymphoma (n = 1) and recurrent right adrenal gland carcinoma (n = 1). RESULTS: IVC resection was associated with right hepatectomy in 8 cases, extended right hepatectomy in 9 cases, extended left hepatectomy in 3 cases, minor liver resection in 2 cases, and right hepatectomy with nephrectomy in one case. In 16 patients the IVC wall involvement was <30% of its circumference, and a tangential vena cava resection was performed. In 7 patients (30%) with >50% involvement, a caval segment was resected and replaced with a 20 mm ringed polytetrafluoroethylene graft. R0-resection was achieved in all patients. Median intraoperative blood loss was 1.100 ml (range 490-15,000). Fourteen patients were transfused with a median of 3 PRC units per patient (range 1-25). Major complications occurred in 9 patients. Postoperative stay in ICU was 2.3 ± 3.4 days (range 1-14) and hospital stay was 17.3 ± 2.6 days (range 5-62). In 14 patients, final pathology demonstrated microscopic IVC infiltration. CONCLUSIONS: In selected patients with malignant involvement of the liver and IVC, surgical resection en bloc with IVC is the only possibility to achieve R0 resection, with acceptable mortality and morbidity, in units specialized in liver surgery.

Surgical treatment for hepatocellular carcinoma in cirrhotic patients. Guide to the selection and decision-making process in a context of multimodal strategy.

Hepatocellular carcinoma (HCC) is the fifth most frequent malignant tumour and the third leading cause of death due to cancer worldwide [1]. Surgical treatment is the only long-term curative therapy. But the resection rate remains low in cirrhotic patients due to contraindications imposed mainly by hepatic insufficiency and excessively advanced tumoral stages. In recent years, however, due to the extended use of screening programmes in high-risk patients, tumours are smaller at presentation, making treatments easier. In the current context of shortage of organs for transplantation, surgical resection remains the best available treatment option for most patients with HCC in cirrhotic livers. Despite the encouraging results reported by several groups in terms of overall survival, the high recurrence rate is still an unsolved problem. Recently, a large, randomised, placebo-controlled trial has shown that a multikinase inhibitor targeting Ras-kinase and VEGFR-2, sorafenib, improves survival of patients with advanced HCC. Sorafenib was approved by regulatory agencies during 2007 and is likely to become the new standard therapy for HCC patients with advanced disease.