Yolanda Quijano

Recomendaciones GESITRA-SEIMC y RESITRA sobre prevención y tratamiento de la infección por citomegalovirus en pacientes trasplantados

La infeccion por citomegalovirus (CMV) es una complicacion importante del trasplante. La ultima decada se ha caracterizado por los avances en su tratamiento, reduciendo su morbilidad y la mortalidad. Estos avances han sido decisivos en el diagnostico y prevencion. Se han desarrollado tecnicas de diagnostico rapidas y sensibles. Entre las estrategias de prevencion destaca el uso correcto de los productos sanguineos, las inmunoglobulinas y los farmacos antivirales, empleados en profilaxis o en terapia anticipada. El reciente desarrollo de farmacos eficaces por via oral como el valganciclovir permitira el tratamiento ambulatorio de los pacientes infectados. Es necesario trasladar este conocimiento a la practica clinica diaria. Con este objetivo el Grupo de Estudio de la Infeccion en el Trasplante (GESITRA) de la Sociedad Espanola de Microbiologia Clinica y Enfermedades Infecciosas (SEIMC) ha desarrollado este documento de consenso que incluye las ultimas recomendaciones en el tratamiento de la infeccion por CMV postrasplante.

Liver Transplantation in HIV-infected recipients

Liver transplantation is being evaluated as a therapeutic option for human immunodeficiency virus (HIV)‐infected patients with end‐stage liver disease, but experience is still scarce. We describe the outcome of 4 HIV‐infected patients who underwent liver transplantation in our hospital between July 2002 and April 2003. HIV‐infected liver transplant recipients meet the same standard criteria for transplantation as do HIV‐negative candidates. In addition, HIV infected persons are required to have a CD4 T‐cell count greater than 100/mL (CD4 T‐cells are targets for HIV infection). Immunosuppressive regimens, perioperative surgical prophylaxis, and prophylaxis for opportunistic infections are standard in the Liver Transplantation Unit in our hospital. Four patients, including 3 former intravenous drug users, received a liver transplant (2 from deceased donors and 2 from living donors), with a median follow‐up of 510 days. Three patients (75%) are alive, with 1 death occurring 17 months posttransplantation in a patient who developed fibrosing cholestatic hepatitis. Rejection occurred in 1 patient, and was managed with no complications. Hepatitis C virus (HCV) recurrence occurred in 3 patients. HIV‐infection has remained under control with antiretroviral treatment. A combination of 3 nucleoside analogs was used in 3 patients, with no need for drug adjustments. No opportunistic infections or other significant infectious complications developed. In conclusion, orthotopic liver transplantation seems a safe therapeutic option in the short term for HIV‐infected persons with end stage liver disease, including patients with a history of drug abuse. If indicated, an antiretroviral regimen consisting of 3 nucleosides could be used to avoid interactions with immunosuppressive drugs. (Liver Transpl 2005;11:76–81.)

Does robotic distal pancreatectomy surgery offer similar results as laparoscopic and open approach? A comparative study from a single medical center.

In the field of pancreatic surgery, robotic surgery has yet to be evaluated against open and laparoscopic approaches. The outcomes of robotic surgery for distal pancreatectomy were analysed and the results compared with those of laparoscopic and open procedures.

The role of multimodality therapy for resectable esophageal cancer

BACKGROUND There is an increasing interest in the role of combined therapy to achieve long-term survival for patients with resectable esophageal neoplasms. Surgery provides excellent palliation with relatively low morbidity and mortality rates, but cure remains elusive. MATERIAL AND METHODS From January 1988 to January 1998, a total of 137 patients met eligibility criteria for a combined multimodal therapy, prospective, nonrandomized protocol of induction chemoradiation therapy followed by surgical resection, based on radiological and endoscopic assessment of the extension (all patients were initially considered to be at clinical stages I to III, locoregional). Consequently, patients with high grade Barretts dysplasia or any squamous carcinoma in situ (stage 0) and those with distant metastatic disease (stage IV) were excluded. Among this group, 48 operable patients with biopsy-proven esophageal cancer finally entered and completed the protocol and are the sample of the present study. Multivariate logistic regression models were used to identify risk factors for death or recurrence. Actuarial survival was calculated since the beginning of the induction protocol by the Kaplan-Meier method, and comparisons between groups were made by the log-rank test. RESULTS Mean age was 61.6 (range 45 to 71), and 72.9% were male. The majority of the tumors (70.8%) were located at the lower third/cardia and as many as 18.8% were adenocarcinoma. After a mean of 7.5 weeks (range 5 to 12) after the completion of the induction phase, 68.7% underwent a transthoracic esophagectomy and 31.3% a transhiatal esophagectomy. The in-hospital mortality rate was 10.4% (5 patients). A complete response (no evidence of tumor within the specimen: pT0) was achieved in 25% (12 patients). After a mean follow-up of 20.2 months, mean survival for the entire group was 18.2 months (95% confidence interval 14 to 22). At the end of the study, 25% (12) remained alive. Actuarial survival rates at 12, 23, and 37 months were 56.2%, 36.9%, and 21.9%, respectively. CONCLUSIONS Esophageal resection after induction therapy seems to be related to a slightly higher mortality rate compared with historical series, and for this reason, neoadjuvant therapy must be considered still experimental. However, no statistical significant difference in survival is showed in those cases with complete pathological response (pT0). Factors influencing survival are recurrence and age. Surgery alone remains the standard therapy for esophageal cancer.

Management of biliary duct confluence injuries produced by hepatic hydatidosis.

Abstract. From 1978 to 1999 a total of 850 patients underwent surgical treatment for hydatid disease of the liver at our surgical department. Biliary duct confluence injuries produced by hepatic hydatidosis (HH) were founded in six patients (0.7%). Surgical intervention was undertaken to relieve the obstructive jaundice and clinical manifestations of cholangitis and to treat the hydatid cyst. A partially open cystopericystectomy technique was used in three patients with a double bilioenteric Roux-en-Y reconstruction. The remaining three patients (two with prehepatic portal hypertension and one with triple hepatic duct confluence) were subjected to a cystojejunostomy. There were no hospital deaths. Two cases of anastomotic leakage following a high bilioenteric anastomosis occurred but did not require surgical treatment. During the follow-up (5–19 years) one patient suffered local recurrence of the hydatid disease 7 years after cystojejunostomy. The site of intrahepatic biliary and vascular involvement, the presence of biliary duct anomalies, and the presence of portal hypertension are decisive factors when choosing the “ideal” procedure for reconstruction. Conservative surgical approaches (partial cystectomy and cystojejunostomy) are the treatments of choice. Radical surgery is often a serious matter.

Robotic versus laparoscopic rectal resection: is there any real difference? A comparative single center study.

Robotic surgery has gained worldwide acceptance in the past decade, and several studies have shown that this technique is safe and feasible. The aim of this study is to compare main outcomes of laparoscopic and robotic rectal resection.

A prospective pilot study of target-guided personalized chemotherapy with intensity-modulated radiotherapy in patients with early rectal cancer.

Purpose:To investigate the feasibility of personalizing chemotherapy in patients with rectal cancer. Methods:Patients with cT3 or cN1 and cM0 rectal cancer were eligible. A set of 6 molecular markers including KRAS, BRAF, and PI3K mutations and expression of topoisomerase-1 (Topo-1), ERCC-1, and thymidylate synthase (TS) using immunohistochemistry were performed in a tumor biopsy. All patients were treated with capecitabine 625 to 825 mg/m2/12 h M-F in combination with either irinotecan or oxaliplatin based on Topo-1 and ERCC-1 expression plus either bevacizumab or cetuximab based on the mutation status. All patients received intensity-modulated radiation therapy. A surgery was performed 6 to 8 weeks after the treatment. Results:Fifteen patients (94%) had T3 tumor and 10 (62%) N+ disease of 16 patients enrolled. In all patients, the full set of markers was analyzed within 10 days. Seven patients had K-ras mutation, and 4, 5, and 10 expressed Topo-1, ERRC-1 and TS, respectively. All patients had wild-type BRAF and PI3K tumors. The median time from obtaining informed consent to the treatment period was 18 days and all patients completed the chemoradiation treatment. Fifty percent achieved a complete pathologic response to treatment. Four patients (25%) developed grade 3 proctitis or diarrhea. There were no relevant surgical complications. Sixty-nine percent of the patients received adjuvant XELOX. Conclusions:The individualization of neoadjuvant chemotherapy in patients with rectal cancer is feasible and leads to a high rate of pathologic response.

Alternative Arterial Reconstruction After Extended Pancreatectomy. Case Report and Some Considerations of Locally Advanced Pancreatic Cancer

CONTEXT The clinical benefits of distal pancreatectomy with en bloc celiac axis resection for locally advanced pancreatic body cancer remains controversial and, therefore, declared unresectable in most cases. Appleby first described extended distal pancreatectomy with celiac axis resection for locally advanced gastric cancer. CASE REPORT We report a case of a 65-year-old female who presented a locally advanced pancreatic carcinoma with infiltration of celiac axis. After radio-chemo neoadjuvant treatment, the patient underwent exploratory laparoscopy and subsequent distal pancreatectomy with en bloc resection of celiac axis. Arterial reconstruction was necessary as hepatic flow was not adequate, determined by intraoperative Doppler ultrasonography. It consisted of end to end anastomosis with prosthetic graft between hepatic artery directly to the aorta, as an atheromatous plaque was at the origin of the celiac axis. The postoperative course was uneventful with a perfect relief of pain. She presents a long term survival of 36 months, very exceptional for this type of disease. CONCLUSION The particularity of this case is not only the surgical treatment, rarely offered to these patients, but also and especially the subsequent vascular reconstruction. To our knowledge, this is the first report of this type of arterial reconstruction. Besides, we briefly discuss the recent advances in results of extended distal pancreatectomy with arterial resection for locally advanced pancreatic carcinoma.

Pharmacokinetics of Oral Valganciclovir and Intravenous Ganciclovir Administered to Prevent Cytomegalovirus Disease in an Adult Patient Receiving Small-Intestine Transplantation

Cytomegalovirus (CMV) is the most common viral pathogen following intestine transplantation, with an overall incidence of 30 to 40% (2). Current prophylactic strategies are center specific and usually include intravenous (i.v.) ganciclovir (GCV) for 6 months. Administration of i.v. GCV is problematic because of the risk of infection associated with the use of a long term-catheter. Oral GCV capsules have a low bioavailability (6%) and limit the drug concentration in serum, which is especially important in these patients. Valganciclovir (VGCV) is a prodrug of GCV. Following oral intake, the great majority of VGCV is rapidly converted to GCV by intestinal and hepatic esterases; no other metabolites have been detected. The absolute bioavailability of GCV from VGCV tablets following oral administration is approximately 60% (3). No data about safety and bioavailability have been reported for the use of VGCV in small-intestine transplant recipients for CMV infection prophylaxis. We report the pharmacokinetic profile of VGCV in an adult patient with a small-intestine transplantat performed because of an intestinal desmoid tumor. The patient was a 23-year-old female. She weighted 50 kg. She was seropositive for CMV and had received an organ from a donor seropositive for CMV. She had a long history on total parenteral nutrition (TPN) requirements. After transplantation, she had an episode of acute cellular rejection resolved by an increase in the doses of the immunosuppressors and a bolus of corticosteroids. She started to eat on day 12 after transplantation, although she received concomitant support by parenteral nutrition until week 8. The immunosuppression regimen was azatioprine, tacrolimus, corticosteroids, and basiliximab. Tacrolimus was changed from the i.v. to the oral route on day 17. The patient received i.v. GCV as CMV prophylaxis while waiting for the approval of VGCV for compassionate use. On month 2 after transplantation, CMV prophylaxis was changed from i.v. GCV to oral VGCV. At the time, she was receiving a diet of 2,600 cal/day, containing 15 to 20% protein, 30 to 35% fat, and 50 to 60% carbohydrate. We obtained scheduled serum samples to measure GCV levels on the last day she received i.v. GCV (5 mg/kg once a day [q.d.]) and also during the first day she received oral VGCV (900 mg q.d.). Before obtaining the samples for GCV levels of i.v. GCV and also for oral VGCV, the patient had a 3-day washout period. The GCV levels were determined by high-performance liquid chromatography as described previously (4). Bioavailability was calculated as follows: [AUC of oral VGCV × i.v. GCV dose (milligrams)]/[AUC of i.v. GCV × oral VGCV dose (milligrams)]. The results are shown in Fig. ​Fig.1.1. The area under the concentration-time curve over 24 h (AUC0-24 h) for i.v. GCV was 35.27 μg · h/ml, and that for oral VGCV was 85.67 μg · h/ml. The maximal drug concentration achieved with i.v. GCV was 14.36 μg/ml, and that obtained with oral VGCV was 9.82 μg/ml. The time to the maximum observed drug concentration was 1 h with i.v. GCV and 6 h with oral VGCV. The absolute bioavailability of GCV derived from 900 mg of oral VGCV administered once daily was 64.7%. FIG. 1. Concentrations of GCV over the 24-h dosing interval after administration of a single dose of i.v. GCV (5 mg/kg) and oral VGCV (900 mg q.d.) determined in serum samples by high-performance liquid chromatography. The patient continued receiving oral VGCV, adjusted to renal function, until month 6 after transplantation. She was monitored monthly by pp65 antigenemia and by scheduled viral culture of small-intestine biopsies, and she did not develop a CMV infection during the first year after transplantation. Oral VGCV has been studied in different populations as prophylaxis and treatment of CMV infection. The bioavailability of oral VGCV is 60%. In liver transplant recipients, the mean AUC of GCV following a single dose of 900 mg of VGCV was greater (41.7 μg · h/ml) (3) than that observed in human immunodeficiency virus-infected patients (24.8 μg · h/ml) (1). Greater AUCs in transplant recipients are probable due to the longer terminal elimination resulting from the use of nephrotoxic immunosuppressive drugs (e.g., tacrolimus). Too large a GCV AUC could lead to an increase in the frequency of hematological and renal toxicity. Preliminary studies have shown that oral VGCV is effective for the prevention of CMV disease, including donor-positive, recipient-negative solid-organ transplant recipients (C. Paya, 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. LB-4, 2002). In a study analyzing the pharmacokinetic profile of GCV in a population of solid-organ transplant patients after 100 days of oral administration of VGCV, the average daily systemic exposure (AUC0-24 h) was 40.2 μg · h/ml ± 41. Viremia was totally suppressed during prophylaxis when the GCV AUC0-24 h was >50 μg · h/ml. The development of CMV disease 1 month after prophylaxis ended was reduced with a greater AUC. The development of CMV disease within 1 year of transplantation was 17.6% and was independent of exposure to GCV during prophylaxis. The greater systemic exposure to GCV delivered by VGCV was associated with delayed development of viremia (H. Wiltshire, S. Hirankarn, C. Farrell, and K. Zuideveld, 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. A-1794, 2003). However, there are concerns about the absorption of oral VGCV in recipients of small-intestine transplants. Patients with functional grafts are able to be completely weaned from TPN within 4 to 6 weeks postoperatively, although patients may require partial TPN during episodes of rejection and infection. Most patients are started on enteral feeding via a jejunostomy tube within 2 weeks posttransplantation. Adequate absorption is a good indicator of satisfactory function of the transplanted intestine and is determined by serial monitoring of carbohydrate and fat absorption. The ability to maintain a stable and satisfactory tacrolimus (FK-506) level can also be an indicator of adequate absorption. An appropriate tacrolimus level is usually achieved within 1 month posttransplantation (5). Oral VGCV was an effective approach for CMV infection prophylaxis in this patient with an intestinal transplant. This situation represents a challenge for oral therapy because of the difficult absorption and the risk of CMV infection. The levels of GCV while the patients was receiving oral VGC were in the GCV AUC range for efficient suppression of viremia, providing effective prophylaxis of CMV infection. Adjusting the dosing of oral VGCV to creatinine clearance is the best way to avoid renal and hematological toxicity. VGCV may be preferable to GCV for long-term prophylaxis given the ease of administration and the good drug levels in plasma achieved after its administration. The optimal duration of the prophylaxis remains unknown.

Pearls and pitfalls on ALPPS procedure: new complications in a new technique

The Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) procedure is a new innovative surgical strategy aiming to potentially overcome the liver failure secondary to major liver resection. It represents a modification of the two-stage hepatectomy in which a complete parenchymal transection is associated along with the tumor clearance of one lobe along with the ligation of the contralateral portal vein, too. It allows increase in the future liver remnant (FLR) hypertrophy in a shorter time. Since the first report of this technique by Baumgart [1] a number of case reports have been published, gaining a wide interest and reactions from all over the world [2]. ALPPS benefits are mostly clear; however, its indications and postoperative morbidity/mortality are still under investigations. It is difficult to draw conclusions about it as only case reports and case series with heterogeneous groups have been reported. The aim of this letter is to describe the experience acquired with ALPPS procedure in our center in order to point out the ‘‘pearls’’ and ‘‘pitfalls’’ of this technique. Between January 2011 and May 2013, five ALPPS procedures were performed in our center. Four for colorectal liver metastases (3 metachronous, 1 synchronous) and received preoperative chemotherapy, one for intrahepatic cholangiocarcinoma (Table 1). One patient underwent concomitant right colectomy for colonic cancer. In the first stage we have cleared the FLR from malignancies, associating the liver partition and ligation of opposite portal vein. Planned CT scan volumetry was performed post-first ALPPS stage at 7 days, in order to calculate the FLR hypertrophy. Second stage is performed when an adequate FLR is reached, repeating CT scan every week. Parenchymal resection is performed with electrocautery and CUSA device. Post-hepatectomy liver failure was determined according to the International Study Group of Liver Surgery classification [3]. Complications are classified according to the Clavien-Dindo classification [4]. Along the first step of ALPPS procedure, in case 1 we noted a macroscopic liver turgidity and change in color of the FLR, maybe due to an hyper perfusion, confirmed by Doppler ultrasound (100 cm/s). A spleno-renal venous shunt was performed to reduce the portal inflow allowing normalization of previous macroscopic and ultrasound characteristics (20 cm/s). The patient had a severe liver insufficiency, later recovered with MARS therapy. In case 3 a longitudinal left supra-hepatic vein resection was necessary to complete the liver transection (Table 1). Severe postoperative morbidity (CIIIB) occurred in three patients (60 %); mortality was in one patient (20 %) (Table 1). Reviewing the recent literature [2], there are not yet clearly reliable data concerning the actual complications of this technique. However, it seems that severe complications are higher than in the standard ‘‘two-stage’’ hepatectomy [5] when compared with the ALPPS procedure. In the last E-AHPBA meeting at Belgrade, the ALPPS mean morbidity reported ranged 43.8–50 % with a mean mortality of 14.9 % [5]. Main conclusions were that ALPPS is better than conventional ‘‘two-stage’’ procedures to achieve complete resection but at the price of a higher morbidity and mortality. B. Ielpo (&) Y. Quijano E. Vicente Sanchinarro University Hospital, Calle Oña 10, 28050 Madrid, Spain e-mail: ielpo.b@gmail.com