Conversion to Complete Resection and/or Ablation Using Hepatic Artery Infusional Chemotherapy in Patients with Unresectable Liver Metastases from Colorectal Cancer: A Decade of Experience at a Single Institution

Background

When feasible, surgical treatment of colorectal liver metastases (CRLM) is the treatment of choice. Regional hepatic artery infusional (HAI) chemotherapy effectively treats CRLM. The combination of HAI and systemic chemotherapy may downsize tumors and allow for complete resection and/or ablation (R/A). This study analyzes the combination of HAI and systemic chemotherapy for treating unresectable CRLM, focusing on conversion to complete R/A.

Methods

All patients with unresectable CRLM treated with HAI and systemic chemotherapy from 2000 to 2009 were included. Patients who responded sufficiently to undergo complete R/A were compared to those who did not convert. Survival was compared using a landmark analysis to account for bias.

Results

A total of 373 patients were included; 93 patients (25 %) subsequently underwent complete R/A. The percentage of patients submitted to complete R/A increased from 16 % during 2000–2003 to 30 % during 2004–2009. Factors associated with conversion on multivariate analysis were more recent treatment (2004–2009), no prior chemotherapy, clinical risk score <3, treatment on clinical protocol, and younger age. Median and predicted 5-year survival from the time of HAI pump placement was 59 months and 47 %, respectively, in the patients who converted to complete R/A, compared with 16 months and 6 %, respectively in those who did not (p < 0.001).

Conclusions

Despite extensive disease, 25 % of patients with unresectable CRLM responded sufficiently to undergo complete R/A following HAI plus systemic chemotherapy. Combination HAI and systemic chemotherapy is an effective strategy to convert patients to complete resection with an associated excellent long-term survival.     

Characterization of N-acetyltransferase 1 and 2 polymorphisms and haplotype analysis for inflammatory bowel disease and sporadic colorectal carcinoma

Background  

N-acetyltransferase 1 (NAT1) and 2 (NAT2) are polymorphic isoenzymes responsible for the metabolism of numerous drugs and carcinogens. Acetylation catalyzed by NAT1 and NAT2 are important in metabolic activation of arylamines to electrophilic intermediates that initiate carcinogenesis. Inflammatory bowel diseases (IBD) consist of Crohn's disease (CD) and ulcerative colitis (UC), both are associated with increased colorectal cancer (CRC) risk. We hypothesized that NAT1 and/or NAT2 polymorphisms contribute to the increased cancer evident in IBD.     

Natural killer (NK) cells in chronic progressive multiple sclerosis patients treated with lymphoblastoid interferon

Natural killer (NK) cell functional activity, as defined by the lysis of 51Cr-labelled K-562 cells, and number, defined phenotypically by anti-Leu-11, are significantly decreased in chronic progressive multiple sclerosis (MS) when compared to normal controls. When age- and sex-matched populations are compared, NK cell functional activity is again significantly reduced in MS compared to controls but not when compared to a control group of other medical disease (OMD). The MS group could be differentiated from the OMD group, however, when results of NK cell functional activity are combined with NK cell phenotype. With the administration of lymphoblastoid interferon daily for 6 months, NK cell activity increased significantly at 48 h and at 1 week. By 1 month, activity decreased to a level slightly above placebo treatment values. The results likely reflect interferon's enhancement of mature NK cell activity combined with a variable effect on recruitment of pre-NK cells.     

Composite sequential arterial reconstruction for limb salvage

OBJECTIVE: Autogenous vein is the conduit of choice in patients presenting for infrainguinal arterial reconstruction. Venous conduit may be limited because of inadequacy or prior utilization. Our group and others use prosthetics to maximize limb salvage with moderate results. However, in cases where patients present with an isolated popliteal segment that may extend below the knee, we have performed prosthetic bypasses to this above-knee segment and then used a venous reconstruction from the native arterial circulation to a more distal outflow tract. In this report, we will analyze our results using this type of reconstruction in patients who present for limb salvage with no all-autogenous option. METHOD: From 1992 to 2000, 27 patients presented for limb salvage with an isolated popliteal artery and inadequate vein for continuous bypass. There were 106 patients in this period without an isolated popliteal segment or adequate vein who underwent prosthetic bypass with distal vein cuff or arteriovenous fistula. The vascular registry and patient charts were reviewed for indication, demographics, and type of composite reconstruction. Outcomes were calculated with use of life table methods and compared by log rank analysis. RESULTS: Demographics revealed 16 (59%) men, 16 (59%) patients with diabetes, and 4 (15%) smokers with a mean age of 71 years (range, 51-87 years). The venous reconstructions had the inflow taken from the distal native popliteal artery in 26 (above knee in 8 and below knee in 18) and the peroneal artery in one. The outflow involved the below-knee popliteal in one (4%), a tibial in 23 (85%), and the dorsalis pedis artery in 3 (11%). Morbidity included bleeding (4%), wound infection (4%), and limb loss (4%). Mortality occurred in one patient (4%), and no revisions were required in follow-up. Six late failures were identified, one of which resulted in amputation. Primary patency and limb salvage were 80% and 88% at 1 year, respectively. For comparison, our results using prosthetic with vein cuff had a 1-year primary patency of 52% and limb salvage of 92% (P = NS), whereas prosthetic with an arteriovenous fistula was 73% and 84%, respectively (P = NS). CONCLUSIONS: Composite sequential reconstruction using an isolated popliteal segment as inflow for the distal reconstruction is an acceptable option in patients presenting for limb salvage reconstruction with limited venous conduit. This type of reconstruction, when available, may be a better option than pure prosthetic with or without a vein cuff or arteriovenous fistula.     

Risks and side effects of islet transplantation

Islet transplantation can deliver stable glycemic control, relief from recurrent severe hypoglycemia, and insulin independence. Accessing the portal vein via the percutaneous hepatic approach carries the risk of bleeding, and the infusion of islets a risk of portal vein thrombosis. In the long term, common minor problems with immunosuppression are mouth ulcers, diarrhea, and acne. Longer-term risks include malignancy and serious infection, both rare to date in clinical islet transplantation. Sensitization to donor antigens may also occur. The long-term diabetes complications may stabilize, but of this aspect little is known to date. In the short term, there may be some elevation of serum cholesterol and blood pressure, in some patients there has been a decline in renal function, and in a few, acute retinal bleeds. For most, improvement in glucose control with resolution of glycemic lability and hypoglycemia has been a net benefit.     

Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63

Waanders E, Venselaar H, te Morsche RHM, de Koning DB, Kamath PS, Torres VE, Somlo S, Drenth JPH. Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63. Polycystic liver disease (PCLD) is characterized by intralobular bile duct cysts in the liver. It is caused by mutations in PRKCSH, encoding hepatocystin, and SEC63, encoding Sec63p. The main goals of this study were to screen for novel mutations and to analyze mutations for effects on protein structure and function. We screened 464 subjects including 76 probands by direct sequencing or conformation‐sensitive capillary electrophoresis. We analyzed the effects of all known and novel mutations using a combination of splice site recognition, evolutionary conservation, secondary and tertiary structure predictions, Poly Phen , and p Mut and sift . We identified a total of 26 novel mutations in PRKCSH (n = 14) and SEC63 (n = 12), including four splice site mutations, eight insertions/ deletions, six non‐sense mutations, and eight missense mutations. Out of 48 PCLD mutations, 13 were predicted to affect splicing. Most mutations were located in highly conserved regions and homology modeling for two domains of Sec63p showed severe effects of the residue substitutions. In conclusion, we identified 26 novel mutations associated with PCLD and we provide in silico analysis in order to delineate the role of these mutations.     

Decreased inducibility of TNF expression in lipid-loaded macrophages

Background  

Inflammation and immune responses are considered to be very important in the pathogenesis of atherosclerosis. Lipid accumulation in macrophages of the arterial intima is a characteristic feature of atherosclerosis which can influence the inflammatory potential of macrophages. We studied the effects of lipid loading on the regulation of TNF expression in human monocyte-derived macrophages.