Mazen Hassanain

Clostridium difficile colitis: Increasing incidence, risk factors, and outcomes in solid organ transplant recipients

Background Clostridium difficile-associated diarrhea (CDAD) is an increasingly important diagnosis in solid organ transplant recipients, with rising incidence and mortality. We describe the incidence, risk factors, and outcomes of colectomy for CDAD after solid organ transplantation. Methods Patients with CDAD were identified from a prospective transplant database. Complicated Clostridium difficile colitis (CCDC) was defined as CDAD associated with graft loss, total colectomy, or death. Results From 1999 to 2010, we performed solid organ transplants for 1331 recipients at our institution. The incidence of CDAD was 12.4% (165 patients); it increased from 4.5% (1999) to 21.1% (2005) and finally 9.5% (2010). The peak frequency of CDAD was between 6 and 10 days posttransplantation. Age more than 55 years (hazard ratio [HR]: 1.47, 95% confidence interval [CI]=1.16–1.81), induction with antithymocyte globulin (HR: 1.43, 95% CI=1.075–1.94), and transplant other than kidney alone (liver, heart, pancreas, or combined kidney organ) (HR: 1.41, 95% CI=1.05–1.92) were significant independent risk factors for CDAD. CCDC occurred in 15.8% of CDAD cases. Independent predictors of CCDC were white blood cell count more than 25,000/&mgr;L (HR: 1.08, 95% CI=1.025–1.15) and evidence of pancolitis on computed tomography scan (HR: 2.52, 95% CI=1.195–5.35). Six patients with CCDC underwent colectomy with 83% patient survival and 20% graft loss. Of the medically treated patients with CCDC (n=20), the patient survival was 35% with 100% graft loss. Conclusions We have identified significant risk factors for CDAD and predictors of progression to CCDC. Furthermore, we found that colectomy can be performed with excellent survival in selected patients.

Portal vein embolization stimulates tumour growth in patients with colorectal cancer liver metastases

OBJECTIVES Portal vein embolization (PVE) can facilitate the resection of previously unresectable colorectal cancer (CRC) liver metastases. Bevacizumab is being used increasingly in the treatment of metastatic CRC, although data regarding its effect on post-embolization liver regeneration and tumour growth are conflicting. The objective of this observational study was to assess the impact of pre-embolization bevacizumab on liver hypertrophy and tumour growth. METHODS Computed tomography scans before and 4 weeks after PVE were evaluated in patients who received perioperative chemotherapy with or without bevacizumab. Scans were compared with scans obtained in a control group in which no PVE was administered. Future liver remnant (FLR), total liver volume (TLV) and total tumour volume (TTV) were measured. Bevacizumab was discontinued ≥ 4 weeks before PVE. RESULTS A total of 109 patients and 11 control patients were included. Portal vein embolization induced a significant increase in TTV: the right lobe increased by 33.4% in PVE subjects but decreased by 34.8% in control subjects (P < 0.001), and the left lobe increased by 49.9% in PVE subjects and decreased by 33.2% in controls (P= 0.022). A total of 52.8% of the study group received bevacizumab and 47.2% did not. There was no statistical difference between the two chemotherapy groups in terms of tumour growth. Median FLR after PVE was similar in both groups (28.8% vs. 28.7%; P= 0.825). CONCLUSIONS Adequate liver regeneration was achieved in patients who underwent PVE. However, significant tumour progression was also observed post-embolization.

Pretransplantation α-fetoprotein slope and milan criteria: strong predictors of hepatocellular carcinoma recurrence after transplantation.

Background Hepatocellular carcinoma (HCC) is a major cause of orthotropic liver transplantations (OLT). However, tumor recurrence remains a concern. Our group has shown that a rising natural &agr;-fetoprotein (AFP) slope (NAS) correlates with tumor characteristics. We want to assess if a rising NAS predicts tumor recurrence. Methods We reviewed first OLT for HCC (n=144) at our center from 1992 to 2010. Patients with less than two AFP values before treatment were excluded (n=52). A rising NAS (>0.1 &mgr;g/L/day) was found in 28 patients whereas 64 presented a stable or dropping NAS. Demographics, pre-OLT therapy, and tumor characteristics were collected. Statistical analysis was performed using ANOVA, chi-square or Fisher’s test, and logistic regression for recurrence after OLT. Results Demographics were similar among the recurrence (n=12) and nonrecurrence (n=80) groups. Patients who recurred received more treatment (P=0.017), had a higher number of lesions (P=0.025), a greater total tumor size (P=0.001), and a higher incidence of microvascular invasion (P=0.013). More patients exceeded the Milan criteria (75.0% vs. 31.3%, odds ratio [OR] 6.60, 95% confidence interval [CI] 1.45–4.05, P=0.008) and had a rising NAS (58.3% vs. 26.3%, OR 3.20, 95% CI 1.11–9.22, P=0.024) among the recurrence group. NAS was also a strong predictor of microvascular invasion (P=0.040). After correcting for age and sex, both a rising NAS (OR 3.98, 95% CI 1.01–15.81, P=0.039) and nonadherence to Milan criteria (OR 5.69, 95% CI 1.14–28.38, P=0.034) were strong predictors of recurrence after OLT. Conclusion The NAS is a predictor of microvascular invasion, a finding exclusive to pathology and in itself a predictor of HCC recurrence after OLT. The NAS and Milan criteria are good predictors of recurrence. These results encourage a frequent monitoring of AFP variations before OLT.

Predictors of response to radio‐embolization (TheraSphere®) treatment of neuroendocrine liver metastasis

BACKGROUND Neuroendocrine tumours (NET) frequently metastasize to the liver. NET liver metastasis has been shown to respond to Yttrium-90 microspheres therapy. The aims of the present study were to define factors that predict the response to radio-embolization in patients with NET liver metastases. METHODS From January 2006 until March 2009, all patients with NET liver metastasis that received radio-embolization using TheraSphere® (glass microspheres) were reviewed. The response was determined by a change in the percentage of necrosis (ΔN%) after the first radio-embolization based on the modified RECIST criteria (mRECIST) criteria. The following confounding variables were measured: age, gender, size of the lesions, liver involvement, World Health Organization (WHO) classification, the presence of extra-hepatic metastasis, octereotide treatment and previous operative [surgery and (RFA)] and non-operative treatments (chemo-embolization and bland-embolization). RESULTS In all, 25 patients were identified, with a median follow-up of 21.7 months. The median age was 64.6 years, 28% had extra-hepatic metastasis and 56% were WHO stage 2. Post-treatment, the mean ΔN% was 48.4%. Previous surgical therapy was a significant predictor of the response with a response rate of 66.7 ΔN% vs. 31.5 ΔN% (P= 0.02). Bilateral liver disease, a high percentage of liver involvement and large metastatic lesions were inversely related to the degree of tumour response although did not reach statistical significance. CONCLUSION Radio-embolization increased the necrosis of NET liver metastasis mainly in patients with less bulky disease. This may imply that surgical therapy before radio-embolization would increase the response rates.

Perioperative glucose and insulin administration while maintaining normoglycemia (GIN therapy) in patients undergoing major liver resection.

BACKGROUND: Although hyperglycemia is a well-recognized risk factor in the context of cardiac surgery, the relevance of perioperative glycemic control for patients undergoing major noncardiac operations has received little attention. We designed this study to assess the hyperglycemic response to liver resection, and to test the hypothesis that perioperative glucose and insulin administration while maintaining normoglycemia (GIN therapy) provides glycemic control superior to that achieved by the conventional use of insulin. METHODS: Patients were randomly assigned to GIN therapy or standard therapy (control group). In the GIN therapy group, insulin was administered at 2 mU · kg−1 · min−1 during surgery. At the end of surgery, the insulin infusion was decreased to 1 mU · kg−1 · min−1 and continued for 24 hours. Dextrose 20% was infused at a rate adjusted to maintain blood glucose within the target range of 3.5 to 6.1 mmol · L−1 (63–110 mg · dL−1). Patients in the standard therapy group received a conventional insulin sliding scale during and after surgery. The mean and SD of blood glucose as well as the percentage of blood glucose values within the target range were calculated. To evaluate intrasubject variability, the coefficient of variability (CV) of blood glucose was calculated for each patient. Episodes of severe hypoglycemia, i.e., blood glucose <2.2 mmol · L−1 (40 mg · dL−1), were recorded. The primary outcome was the proportion of normoglycemic measurements. RESULTS: We studied 52 patients. The mean blood glucose value in patients receiving GIN therapy always remained within the target range. The blood glucose levels were lower in the GIN therapy group than in the standard therapy group (during surgery, P < 0.01; after surgery, P < 0.001). In nondiabetic patients receiving GIN therapy (n = 19), target glycemia was achieved in 90.1% of the blood glucose measurements during surgery and in 77.8% of the measurements after surgery. In diabetic patients receiving GIN therapy (n = 7), target glycemia was achieved in 81.2% of the blood glucose measurements during surgery and in 70.5% of the measurements after surgery. In nondiabetic patients receiving standard therapy (n = 19), target glycemia was achieved in 37.4% of the blood glucose measurements during surgery and in 18.3% of the measurements after surgery. In diabetic patients receiving standard therapy (n = 7), target glycemia was achieved in 4.3% of the blood glucose measurements during surgery and in 2.9% of the measurements after surgery. The SD and CV of blood glucose were smaller in the GIN therapy group than in the standard therapy group, especially in nondiabetic patients after surgery (SD, P < 0.001; CV, P = 0.027). No patients receiving GIN therapy experienced severe hypoglycemia during surgery. One patient receiving GIN therapy experienced hypoglycemia in the intensive care unit after surgery without neurological sequelae. CONCLUSIONS: GIN therapy effectively provides normoglycemia in patients undergoing liver resection (clinicaltrials.gov, NCT00774098).

Successful salvage of kidney allografts threatened by ureteral stricture using pyelovesical bypass.

Ureteral stricture is the most common urologic complication after renal transplantation. When endourologic management fails, open ureteral reconstruction remains the standard treatment. The complexity of some of these procedures makes it necessary to explore other means of repair. This study evaluated the intermediate‐term outcome of subcutaneous pyelovesical bypass graft (SPBG) on renal transplant recipients. We reviewed 8 patients (6 male and 2 female; mean age 52 years) with refractory ureteral strictures postrenal transplantation, who received SPBG as salvage therapy. All patients failed endourologic management and half failed open management of their strictures. After a mean follow‐up of 19.4 months, 7 out of 8 renal grafts have good function with mean GFR of 58.5 mL/min/1.73 m2, without evidence of obstruction or infection. One patient lost his graft due to persistent infection of the SPBG and one patient developed a recurrent urinary tract infection managed with long‐term antibiotics. SPBG offers a last resort in the treatment of ureteral stricture after renal transplantation refractory to conventional therapy.

Perioperative chemotherapy with bevacizumab and liver resection for colorectal cancer liver metastasis

BACKGROUND Surgery remains the only curative option for patients with colorectal cancer liver metastases (CRLM). Perioperative chemotherapeutic strategies have become increasingly popular in the treatment of CRLM. Although the role of bevacizumab (Bev) in this setting remains unclear, its widespread use has raised concerns about the use of Bev as part of perioperative chemotherapy. METHODS We retrospectively reviewed all patients who received Bev and underwent liver resection between July 2004 and July 2008 at the McGill University Health Center. Chemotherapy-related toxicity, response to chemotherapy, surgical morbidity and mortality, liver function and survival data were assessed. RESULTS A total of 35 patients were identified. Of these, 26 (74.3%) patients received oxaliplatin-based cytotoxic chemotherapy, six (17.1%) received irinotecan-based therapy and the remainder received both agents. A total of 17 patients (48.6%) underwent portal vein embolization prior to resection and 12 (34.3%) underwent staged resection for extensive bilobar disease. A median of six cycles of preoperative Bev were administered. Nine patients (25.7%) experienced grade 3 or higher chemotherapy-related toxicities. Four events were deemed to be related to Bev. The overall response rate was 65.7% (complete and partial response). One patient progressed on therapy, but this did not prevent R0 resection. The incidence of postoperative morbidity was 42.3%. A total of 21.7% of complications were Clavien grade 3 or higher. There were no perioperative mortalities. There were no cases of severe sinusoidal injury or steatohepatitis. The Kaplan-Meier estimate of 4-year survival was 52.5%. CONCLUSIONS These data confirm the safety of chemotherapy regimens which include Bev in the perioperative setting and demonstrate that such perioperative chemotherapy in patients with CRLM does not adversely affect patient outcome. There was no increase in perioperative morbidity compared with published rates. The addition of Bev to standard chemotherapy may improve response rates, which may, in turn, impact favourably on patient survival.

Early changes in kidney function predict long-term chronic kidney disease and mortality in patients after liver transplantation.

Background. Chronic kidney disease (CKD) is a well-known complication after liver transplantation (LT) and is associated with increased mortality. The purpose of this study was to determine risk factors of advanced CKD and mortality after LT. Methods. Four hundred forty-five adult patients underwent LT between June 1990 and September 2007 and survived more than 1 month. Multivariate Cox regression analyses were performed for time to CKD stage 4 (glomerular filtration rate [GFR] ≤30 mL/min), time to chronic dialysis, and all-cause mortality. Several patient and disease characteristics were used as independent pre- and posttransplant variables. We specifically analyzed a drop more than or equal to 30% in the estimated GFR (eGFR) during the first year posttransplant. Results. Diabetes mellitus pretransplant and a drop more than or equal to 30% in the eGFR between 3 and 12 months predicted CKD stage 4 (odds ratio [OR] 4.1, 95% confidence interval [CI] 1.9–5.4, P<0.001 and OR 16.1, 95% CI 5.9–44.5, P<0.0001, respectively), the need for chronic dialysis (OR 3.8, 95% CI 1.1–13.2, P=0.03 and OR 14.6, 95% CI 3.0–71.4, P<0.001, respectively), and all-cause mortality (OR 1.9, 95% CI 1.2–2.9, P=0.004 and OR 2.6, 95% CI 1.6–4.4, P<0.001, respectively), more than 1 year after LT. Conclusions. Diabetes mellitus pretransplant and a drop more than or equal to 30% in the eGFR within the first year are strong predictors of advanced CKD, chronic dialysis, and death more than 1 year after LT. These easily determined clinical variables define a population at risk for CKD who should be targeted for renal protection strategies.

Portal vein embolization and its effect on tumour progression for colorectal cancer liver metastases

The aim of this study was to evaluate the long‐term outcomes of patients with colorectal cancer liver metastasis (CRCLM) exhibiting disease progression after portal vein embolization (PVE).

Impact of early graft function on 10-year graft survival in recipients of kidneys from standard- or expanded-criteria donors

Background The use of kidneys from expanded-criteria donors (ECD) is regarded with caution. Methods We compared 279 kidney transplant recipients (KTxR) from standard-criteria donors (SCD) and 237 from ECD, transplanted between January 1990 and December 2006. We evaluated the impact of immediate graft function (IGF), slow graft function (SGF), and delayed graft function (DGF) and the drop in estimated glomerular filtration rate (&Dgr;eGFR) ⩽30% or >30% during the first year after transplantation on long-term patient and death-censored graft survival (DCGS). Results Ten-year patient survival was similar in SCD- or ECD-KTxR (P=0.38). DCGS was better in SCD-KTxR versus ECD-KTxR (77.3% vs. 67.3%; P=0.01). DCGS did not differ in either group experiencing IGF (P=0.17) or DGF (P=0.12). However, DCGS was worse in ECD-KTxR experiencing SGF (84.9% vs. 73.7%; P=0.04). Predictors of DCGS were 1-year serum creatinine (hazard ratio, 1.03; P<0.0001) and &Dgr;eGFR >30% between 1 and 12 months (&Dgr;1-12eGFR) after transplantation (hazard ratio, 2.2; P=0.02). In ECD-KTxR with IGF and more than 1-year follow-up, 10-year DCGS was better in those with &Dgr;1-12eGFR ⩽30% versus those with &Dgr;1-12eGFR >30% (83.8% vs. 53.6%; P=0.01). Conclusion Recipients of SCD or ECD kidneys with IGF or DGF had similar 10-year patient survival and DCGS. SGF had a worse impact on DCGS in ECD-KTxR. In addition to 1-year serum creatinine, &Dgr;1-12eGFR >30% is a negative predictor of DCGS. Larger studies should confirm if increasing the use of ECD, avoiding factors that contribute to SGF or DGF, and/or a decline in eGFR during the first year after transplantation may expand the donor pool and result in acceptable long-term outcomes.