A 30-year analysis of colorectal adenocarcinoma in transplant recipients and proposal for altered screening.

PURPOSE: The risk of malignancy after solid-organ transplantation is well documented. However, the incidence and specific risk for colorectal adenocarcinoma, although previously proposed, has been difficult to calculate. We reviewed the University of Wisconsin transplant database for all cases of colorectal adenocarcinoma to assess the risk of this malignancy, as well as the need for improved screening in this population. METHODS: The transplant database was queried using diagnosis codes for colorectal adenocarcinoma to configure a list of eligible patients. Exclusion criteria included: age less than 18 years at the time of transplant, diagnosis of colorectal cancer or patient death less than 12 months posttransplant, and pretransplant history of colorectal cancer or proctocolectomy. Statistical analysis determined overall incidence, age-specific incidence, and survival for this population. RESULTS: A total of 5,603 kidney, liver, or combination transplants were eligible for analysis from 1966 through 2004. The mean follow-up was 9.3 years. We identified 40 cases of colorectal adenocarcinoma. Twenty-five of these cases (62%) occurred in kidney transplant recipients, 13 after liver transplant, and two after kidney-pancreas combination. Twenty-seven patients (68%) diagnosed with cancer have died, 12 of metastatic disease. The median survival postcancer diagnosis was 2.3 years. These results were compared to the National Cancer Institute Survival, Epidemiology, and End Results (SEER) database for colon and rectal cancer. The current age-adjusted annual incidence based on year 2000 census data is 0.053% (52.9/100,000), and the extrapolated 10-year incidence is 0.27%. The 10-year incidence in the transplanted cohort is 0.71% (incidence ratio = 2.6). The 5-year survival postcancer diagnosis is 63.5% in the general population (SEER), vs. 30.7% in the transplant cohort. The SEER median age at diagnosis of colorectal adenocarcinoma is 72.0 years. Of the transplant recipients who developed cancer, the median age at diagnosis was 58.7 years (32.4 to 78.2), and 11 patients (27%) were diagnosed at or before age 50. In the U.S. population, the annual incidence of colorectal adenocarcinoma below the age of 50 is 0.0055% (5.52/100,000) and the 10-year extrapolated incidence is 0.11%. The 10-year incidence in the under-50 transplant cohort is 0.33% (incidence ratio = 3.0). In this under-50 cohort, median time from transplant to cancer diagnosis was 7.8 years. CONCLUSION: The incidence of and 5-year survival after diagnosis of colorectal adenocarcinoma in transplant recipients is markedly different than the general population. Patients are often diagnosed at a younger age. With current screening guidelines, over 25% of at-risk patients would not be screened. We propose modifying these guidelines to allow earlier detection of colorectal cancer in this population.

Identifying nitrogen sources to thermal tide pools in Kapoho, Hawai'i, U.S.A, using a multi-stable isotope approach.

Nitrogen (N) enrichment often results in coastal eutrophication, even in remote areas like Hawai'i. Therefore, determining N sources to coastal waters is important for their management. This study identified N sources to tide pools in Kapoho, Hawai'i, and determined their relative importance using three stable isotopes (δ(15)N, δ(18)O, δ(11)B). Surface waters and macroalgal tissues were collected along 100-m onshore-offshore transects in areas of high groundwater input for three months at low tide. Water samples from possible N sources were also collected. Mixing model output, along with macroalgal δ(15)N values, indicated that agriculture soil (34%) was the largest anthropogenic N source followed by sewage (27%). These findings suggest that more effective fertilizer application techniques and upgrading sewage treatment systems can minimize N leaching into groundwater. Overall, our multi-stable isotope approach for identifying N sources was successful and may be useful in other coastal waters.

Enhanced T-cell-independent antitumor effect of cyclophosphamide combined with anti-CD40 mAb and CpG in mice.

We have earlier demonstrated T-cell-independent antitumor effects of a combination of anti-CD40 monoclonal antibody (mAb) and CpG oligodeoxynucleotides (CpG) which involved macrophages. As some immunotherapeutic treatments can be potentiated by chemotherapy, we tested if cyclophosphamide (CY) would enhance the antitumor effect of anti-CD40 mAb+CpG. Treatment of B16 melanoma-bearing mice with CY and anti-CD40 mAb+CpG resulted in a significant reduction in tumor growth in immunocompetent mice compared with either CY alone or anti-CD40 mAb with CpG. This enhanced antitumor effect was maintained in severe combined immunodeficiency mice, as measured by both tumor growth and overall survival. Natural killer cells were not required for this antitumor effect as it was also observed in severe combined immunodeficiency/beige mice. Moreover, although CY treatment of immunocompetent mice suppressed natural killer cell activity, it did not negatively affect the antitumor activity of their macrophages when assayed in vitro. Depletion of macrophages in vivo reduced the antitumor effect of CY and anti-CD40 mAb+CpG. These results suggest that therapeutic strategies to activate macrophages may have potential for clinical application in cancer patients receiving chemotherapy.

Radiofrequency ablation combined with KS-IL2 immunocytokine (EMD 273066) results in an enhanced antitumor effect against murine colon adenocarcinoma.

PURPOSE: Radiofrequency ablation (RFA) is a common treatment modality for surgically unresectable tumors. However, there is a high rate of both local and systemic recurrence. EXPERIMENTAL DESIGN: In this preclinical study, we sought to enhance the antitumor effect of RFA by combining it with huKS-IL2 immunocytokine [tumor-specific monoclonal antibody fused to interleukin-2 (IL2)] in mice bearing CT26-KS colon adenocarcinoma. Mice were treated with RFA, huKS-IL2 via intratumoral injection, or combination therapy. RESULTS: Treatment of mice bearing s.c. tumors with RFA and huKS-IL2 resulted in significantly greater tumor growth suppression and enhanced survival compared with mice treated with RFA or huKS-IL2 alone. When subtherapeutic regimens of RFA or huKS-IL2 were used, tumors progressed in all treated mice. In contrast, the combination of RFA and immunocytokine resulted in complete tumor resolution in 50% of mice. Treatment of a tumor with RFA and intratumoral huKS-IL2 also showed antitumor effects against a distant untreated tumor. Tumor-free mice after treatment with RFA and huKS-IL2 showed immunologic memory based on their ability to reject subsequent challenges of CT26-KS and the more aggressive parental CT26 tumors. Flow cytometry analysis of tumor-reactive T cells from mice with complete tumor resolution showed that treatment with RFA and huKS-IL2 resulted in a greater proportion of cytokine-producing CD4 T cells and CD8 T cells compared with mice treated with RFA or huKS-IL2 alone. CONCLUSIONS: These results show that the addition of huKS-IL2 to RFA significantly enhances the antitumor response in this murine model, resulting in complete tumor resolution and induction of immunologic memory.

Intratumoral immunocytokine treatment results in enhanced antitumor effects.

Immunocytokines (IC), consisting of tumor-specific monoclonal antibodies fused to the immunostimulatory cytokine interleukin 2 (IL2), exert significant antitumor effects in several murine tumor models. We investigated whether intratumoral (IT) administration of IC provided enhanced antitumor effects against subcutaneous tumors. Three unique ICs (huKS-IL2, hu14.18-IL2, and GcT84.66-IL2) were administered systemically or IT to evaluate their antitumor effects against tumors expressing the appropriate IC-targeted tumor antigens. The effect of IT injection of the primary tumor on a distant tumor was also evaluated. Here, we show that IT injection of IC resulted in enhanced antitumor effects against B16-KSA melanoma, NXS2 neuroblastoma, and human M21 melanoma xenografts when compared to intravenous (IV) IC injection. Resolution of both primary and distant subcutaneous tumors and a tumor-specific memory response were demonstrated following IT treatment in immunocompetent mice bearing NXS2 tumors. The IT effect of huKS-IL2 IC was antigen-specific, enhanced compared to IL2 alone, and dose-dependent. Hu14.18-IL2 also showed greater IT effects than IL2 alone. The antitumor effect of IT IC did not always require T cells since IT IC induced antitumor effects against tumors in both SCID and nude mice. Localization studies using radiolabeled (111)In-GcT84.66-IL2 IC confirmed that IT injection resulted in a higher concentration of IC at the tumor site than IV administration. In conclusion, we suggest that IT IC is more effective than IV administration against palpable tumors. Further testing is required to determine how to potentially incorporate IT administration of IC into an antitumor regimen that optimizes local and systemic anticancer therapy.