Multiethnic Trends in Early Onset Colorectal Cancer.

Current characteristics of early onset colorectal cancer (EOCRC) in the United States have been mainly studied in Whites, African Americans, and Hispanics, but little is known in regard to EOCRC in Asians and Native Hawaiians in the US. EOCRC was examined in Hawaii's multiethnic population. Data from the Hawaii Tumor Registry was used to analyze colorectal cancer (CRC) cases diagnosed in Hawaii from 2000-2019 by subsite, age, gender, ethnicity, and stage. Ethnicity analyses were limited to 3524 CRC cases, diagnosed between 2015-2019. Average annual 5-year age-adjusted incidence and mortality rates, average annual percent change over time, and 5-year survival were evaluated. Group comparisons utilized Chi-square and binomial proportion tests. Overall CRC incidence and mortality declined and were more pronounced for colon than rectal/rectosigmoid junction cancers. Colon cancer incidence rates significantly increased 1.46-fold for cases diagnosed under 45 years of age and rectal/rectosigmoid cancers significantly increased 1.54-fold for cases 45-54 years of age. CRC incidence increased sharply for females aged 45-54 years from 2000-2009 to 2010-2019, and increases in colon and rectal/rectosigmoid cancer among individuals aged 45-54 were higher for females. Among both sexes, the increase in rectal/rectosigmoid cancer incidence for individuals under 55 years was highest for stage I cancers. Overall, the mean (SD) age of CRC diagnosis was 5-10 years earlier for Native Hawaiians (60.6 [13.3] years) compared with Japanese, Chinese, Filipinos, Whites, and Other Asians (p < 0.001). Native Hawaiians constituted a greater proportion of CRC diagnosed under age 55 years and, conversely, a smaller proportion of cases 55 years and older compared with Japanese, Chinese, Filipinos, Whites, and Other Asians. Native Hawaiians had a significantly higher CRC-related mortality rate (14.5 per 100,000 [95% CI: 12.4, 16.8]) compared with Japanese (10.7 per 100,000 [95% CI: 9.3, 12.3]) and a significantly lower CRC survival rate (62.2% [95% CI: 59.1, 65.2]) compared with Japanese (71.9% [95% CI: 69.9, 73.8]), Filipinos (71.9% [95% CI: 69.2, 74.4]), Chinese (70.2% [95% CI: 65.5, 74.4]), Whites (69.3% [95% CI: 67.1, 71.4]), and Other Asians (71.7% [95% CI: 66.2, 76.5]). In our diverse US population, Native Hawaiians contribute disproportionately to EOCRC and present 5-10 years earlier than Whites, Japanese, Chinese, and Filipinos. EOCRCs are increasing faster in females than males in Hawaii, which differs from trends in the general US population. Emerging ethnic disparities in EOCRC in the US speak to the need for studies on targeted interventions and ethnic-specific risk factors for EOCRC.

Use of an over-the-scope clip in managing adult anastomotic ulcer bleeding.

Bleeding from anastomotic ulcers following surgical procedures such as ileocolonic resection in patients without Crohn's disease is a rare occurrence and difficult to manage. Although a number of treatment options have been explored, they have all had varying success. This case characterizes the first reported successful treatment of recurrent gastrointestinal bleeding in an adult due to an anastomotic ulcer with an over-the-scope clip.

Serum micro-RNA Identifies Early Stage Colorectal Cancer in a Multi-Ethnic Population.

OBJECTIVE: Certain microRNAs (miR) have been previously described to be dysregulated in cancers and can be detected in blood samples. Studies examining the utility of miRs for colon cancer screening have primarily been performed in ethnically homogeneous groups of patients, thus the performance of miRs in multiethnic populations is unknown. METHODS: Four miRs were selected that were shown to be aberrantly expressed in the blood or stool of patients with colorectal cancer (CRC) of various ethnicities. In this study, the ability of these miRs to discern early stage CRC was determined in a previously untested multiethnic population of 73 CRC cases and 18 controls. RESULTS: The ratios of non-vesicular to extracellular vesicular levels of miR's -21, -29a, and -92a were statistically and quantitatively related to CRC stage compared to controls. CONCLUSION: Serum levels of miR-21, miR-29a and miR-92a were able to significantly detect early stage CRC in a multiethnic and previously untested population.
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Nonalcoholic Fatty Liver Disease: An Important Consideration for Primary Care Providers in Hawai'i.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD is a broad term for both non-alcoholic fatty liver (NAFL), which describes simple fatty liver without inflammation, and non-alcoholic steatohepatitis (NASH), the more severe phenotype with hepatocellular inflammation. The population of Hawai'i is particularly vulnerable to the NAFLD and obesity epidemics due to its large proportions of high-risk ethnic minorities exposed to varying degrees of westernization. Unfortunately, primary care providers (PCPs) often face a lack of awareness on the diagnosis and disease spectrum of NAFLD. Early initiation of treatment for NAFLD is crucial to slow its progression and prevent liver-related morbidity and mortality. This review aims to raise awareness for NAFLD among PCPs in Hawai'i by summarizing the disease's epidemiology, diagnosis, and treatment. The diagnostic workup of NAFLD in the primary care setting involves exclusion of other liver disease etiologies and staging assessment of fibrosis and steatosis through non-invasive means such as serum biomarkers or elastography. Patients with overt signs and symptoms of cirrhosis or a high likelihood of advanced hepatic fibrosis should be referred to liver disease specialists. The role of PCPs in NAFLD management involves facilitating weight loss through therapeutic lifestyle modifications and treatment of comorbid cardiovascular conditions. Evidence-based pharmacologic therapies for NAFLD are available, such as vitamin E and pioglitazone, with more currently in development.

Association of Sulindac and Erlotinib vs Placebo With Colorectal Neoplasia in Familial Adenomatous Polyposis: Secondary Analysis of a Randomized Clinical Trial.

Importance: Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for colorectal polyps and cancer. A combination of sulindac and erlotinib led to a 71% reduction in duodenal polyp burden in a phase 2 trial. Objective: To evaluate effect of sulindac and erlotinib on colorectal adenoma regression in patients with FAP. Design, Setting, and Participants: Prespecified secondary analysis for colorectal adenoma regression was carried out using data from a double-blind, randomized, placebo-controlled trial, enrolling 92 patients with FAP, conducted from July 2010 to June 2014 in Salt Lake City, Utah. Interventions: Patients were randomized to sulindac, 150 mg twice daily, and erlotinib, 75 mg daily (n = 46), vs placebo (n = 46) for 6 months. Main Outcomes and Measurements: The total number of polyps in the intact colorectum, ileal pouch anal anastomosis, or ileo-rectum were recorded at baseline and 6 months. The primary outcomes were change in total colorectal polyp count and percentage change in colorectal polyps, following 6 months of treatment. Results: Eighty-two randomized patients (mean [SD] age, 40 [13] years; 49 [60%] women) had colorectal polyp count data available for this secondary analysis: 22 with intact colon, 44 with ileal pouch anal anastomosis and 16 with ileo-rectal anastomosis; 41 patients received sulindac/erlotinib and 41 placebo. The total colorectal polyp count was significantly different between the placebo and sulindac-erlotinib group at 6 months in patients with net percentage change of 69.4% in those with an intact colorectum compared with placebo (95% CI, 28.8%-109.2%; P = .009). Conclusion and Relevance: In this double-blind, placebo-controlled, randomized trial we showed that combination treatment with sulindac and erlotinib compared with placebo resulted in significantly lower colorectal polyp burden after 6 months of treatment. There was a reduction in polyp burden in both those with an entire colorectum and those with only a rectal pouch or rectum. Trial Registration: clinicaltrials.gov Identifier: NCT01187901.

Effect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis: A Randomized Clinical Trial.

IMPORTANCE: Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for duodenal polyps and cancer. Surgical and endoscopic management of duodenal neoplasia is difficult and chemoprevention has not been successful. OBJECTIVE: To evaluate the effect of a combination of sulindac and erlotinib on duodenal adenoma regression in patients with FAP. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled trial, enrolling 92 participants with FAP, conducted from July 2010 through June 2014 at Huntsman Cancer Institute in Salt Lake City, Utah. INTERVENTIONS: Participants with FAP were randomized to sulindac (150 mg) twice daily and erlotinib (75 mg) daily (n = 46) vs placebo (n = 46) for 6 months. MAIN OUTCOMES AND MEASURES: The total number and diameter of polyps in the proximal duodenum were mapped at baseline and 6 months. The primary outcome was change in total polyp burden at 6 months. Polyp burden was calculated as the sum of the diameters of polyps. The secondary outcomes were change in total duodenal polyp count, change in duodenal polyp burden or count stratified by genotype and initial polyp burden, and percentage of change from baseline in duodenal polyp burden. RESULTS: Ninety-two participants (mean age, 41 years [range, 24-55]; women, 56 [61%]) were randomized when the trial was stopped by the external data and safety monitoring board because the second preplanned interim analysis met the prespecified stopping rule for superiority. Grade 1 and 2 adverse events were more common in the sulindac-erlotinib group, with an acne-like rash observed in 87% of participants receiving treatment and 20% of participants receiving placebo (P < .001). Only 2 participants experienced grade 3 adverse events. [table: see text]. CONCLUSIONS AND RELEVANCE: Among participants with FAP, the use of sulindac and erlotinib compared with placebo resulted in a lower duodenal polyp burden after 6 months. Adverse events may limit the use of these medications at the doses used in this study. Further research is necessary to evaluate these preliminary findings in a larger study population with longer follow-up to determine whether the observed effects will result in improved clinical outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT 01187901.

Colonoscopy Screening among Native Hawaiians at Queen's Medical Center between August 2011 and January 2013.

A retrospective chart review in the Endoscopy Department at Queen's Medical Center identified 358 Native Hawaiian patients who had completed a colonoscopy screening procedure between August 2011 and January 2013, through either the Direct Referral Colonoscopy program or its Traditional Referral program. The differences in the characteristics of Native Hawaiian patients were summarized and compared between the two referral programs to identify potential barriers for future interventions and increase colorectal cancer screening. The combined colonoscopy screening rate among Native Hawaiians was 13%. Younger patients and those with private insurance were found to be undergoing colonoscopy screening through the Direct Referral program. The findings of this study underscore the need to reduce disparities in colonoscopy screening among Native Hawaiians.

Design, synthesis, and biological evaluation of sulfonyl acrylonitriles as novel inhibitors of cancer metastasis and spread.

The spread of intra-abdominal cancers is a vexing clinical problem for which there is no widely effective treatment. We discovered previously that (2E)-3-[(4-tert-butylphenyl)sulfonyl]acrylonitrile (1) induced cancer cell apoptosis during adhesion to normal mesothelial cells which line the peritoneum. We recently demonstrated that the sulfonylacrylonitrile portion of 1 and hydrophobic aryl substitution were essential for pro-apoptotic activity in cancer cells. Here we synthesized a diverse series of analogues of 1 in order to improve the efficacy and pharmaceutical properties. Analogues and 1 were compared in their ability to cause cancer cell death during adhesion to normal mesothelial cell monolayers. Potent analogues identified in the in vitro assay were validated and found to exhibit improved inhibition of intra-abdominal cancer in two clinically relevant murine models of ovarian and pancreatic cancer spread and metastasis, highlighting their potential clinical use as an adjunct to surgical resection of cancers.

Regulation of sonic hedgehog expression by integrin ß1 and epidermal growth factor receptor in intestinal epithelium.

We previously found that conditional deletion of integrin ß1 in intestinal epithelium of mice caused early postnatal lethality and intestinal phenotypic changes including excessive proliferation and defective differentiation of intestinal epithelium due to loss of Hedgehog expression. Here, we link these defects to the Hedgehog (Hh) signaling pathway and show that loss of integrin ß1 leads to excessive phosphorylation of MEK-1 and increased expression of ErbB receptors, including the epidermal growth factor receptor (EGFR). We show that increased EGFR signaling attenuates Hh abundance and that an EGFR inhibitor rescues conditional ß1 integrin null pups from postnatal lethality. These studies link the loss of Hh expression in the intestinal epithelium of integrin ß1-deficient mice to excessive EGFR/MAPK signaling, and identify a unique mechanism for crosstalk between stromal and epithelial signaling pathways that is critical for intestinal epithelial differentiation and function.

Consequences of needle tract seeding of hepatocellular cancer after liver transplant.

Although liver biopsy is a relatively safe procedure, needle tract seeding (NTS) of hepatocellular carcinoma (HCC) is described in up to 5% of patients after liver biopsy. The rate of NTS in patients with HCC who had liver transplantation is unknown. We performed a retrospective analysis of 759 HCC cases from August 1992 to August 2011. Demographics, ethnicities, risk factors, tumor characteristics, treatments, recurrence, and survival were collected. Patients who underwent percutaneous liver biopsy, resection, and transplant were identified. In all, 359 underwent biopsy to diagnose HCC and 42 patients underwent liver transplant. None of 171 patients who underwent radiofrequency ablation alone had seeding. None of the 11 patients who had biopsy and radiofrequency ablation performed in a single session developed NTS; however, two of 12 patients who had biopsy and radiofrequency ablation performed at separate sessions had NTS. Two patients underwent liver transplantation and subsequently developed needle tract seeding eventually died from HCC. Although the incidence of needle tract seeding was low in liver transplant patients, it can potentially change a curative therapy into a non-curative one. Single-session liver biopsy and radiofrequency ablation may reduce the risk of needle tract seeding of HCC.

The atypical histone macroH2A1.2 interacts with HER-2 protein in cancer cells.

Because HER-2 has been demonstrated in the nuclei of cancer cells, we hypothesized that it might interact with transcription factors that activate ERBB2 transcription. Macrohistone 2A1 (H2AFY; mH2A1) was found to interact with HER-2 in cancer cells that overexpress HER-2. Of the two human mH2A1 isoforms, mH2A1.2, but not mH2A1.1, interacted with HER-2 in human cancer cell lines. Overexpression of mH2A1.2, but not mH2A1.1, in cancer cells significantly increased HER-2 expression and tumorigenicity. Inhibition of HER-2 kinase activity diminished mH2A1 expression and mH2A1.2-induced ERBB2 transcription in cancer cells. Chromatin immunoprecipitation of mH2A1.2 in cancer cells stably transfected with mH2A1.2 showed enrichment of mH2A1.2 at the HER-2 promoter, suggesting a role for mH2A1.2 in driving HER-2 overexpression. The evolutionarily conserved macro domain of mH2A1.2 was sufficient for the interaction between HER-2 and mH2A1.2 and for mH2A1.2-induced ERBB2 transcription. Within the macro domain of mH2A1.2, a trinucleotide insertion (-EIS-) sequence not found in mH2A1.1 was essential for the interaction between HER-2 and mH2A1.2 as well as mH2A1.2-induced HER-2 expression and cell proliferation.

Synthesis and biological evaluation of sulfonyl acrylonitriles as novel inhibitors to peritoneal carcinomatosis.

The vast majority of cancer patients die from metastasis, the process by which cancer cells spread to secondary tissues through body fluids. Peritoneal carcinomatosis is a type of metastasis in which cancer cells gain access to the intra-abdominal cavity and then implant in the peritoneum, the thin tissue that lines the abdominal wall and internal organs. Unfortunately, peritoneal carcinomatosis can occur following surgical resection of intra-abdominal malignancies. We previously reported proapoptotic activity of (2E)-3-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2-propenenitrile (BAY 11-7085, 1) on colon and pancreatic cancer cells during adhesion and demonstrated that this compound could significantly inhibit peritoneal carcinomatosis in mice.(1,2) In order to determine the chemical basis of the anti-metastatic properties of BAY 11-7085, a series of analogs were synthesized and evaluated for their ability to induce apoptosis in pancreatic and ovarian cancer cells during adhesion to mesothelial cells, which line the surface of the peritoneum. The co-culture assay results were validated using a murine peritoneal carcinomatosis model. These analogs may greatly benefit patients undergoing surgical resections of colorectal, pancreatic, and ovarian cancers depending on their tolerability.

Pharmacologic downregulation of c-FLIP(L) restores juxtacrine death receptor-mediated apoptosis in cancer cells in a peritoneal carcinomatosis model.

Metastasis occurs when circulating cancer cells implant in normal secondary tissues. Paradoxically, many cancer cells express death receptors while many normal tissues express the cognate death receptor ligands, suggesting that cancer cells possess mechanisms to inhibit death receptor signaling. Pharmacological restoration of juxtacrine-mediated death receptor signaling could prevent cancer cells from implanting in normal tissues such as the peritoneum. The results showed that BAY 11-7085 significantly inhibited peritoneal carcinomatosis in mice following the introduction of colon and pancreatic cancer cell lines into the intra-abdominal cavity. Treatment with BAY 11-7085 restored juxtacrine death receptor signaling during the adhesion of the cancer cells to mesothelial cells, which line the peritoneum. BAY 11-7085 rapidly inhibited c-FLIP(L) expression in colon and pancreatic cancer cell lines during adhesion to mesothelial cells. Pancreatic cancer cells sorted for high c-FLIP(L) expression formed peritoneal implants much more readily than cells with low c-FLIP(L) expression, and RNAi inhibition of c-FLIP(L) in colon cancer cells dramatically reduced peritoneal implantation. This is a novel demonstration that the restoration of death receptor-mediated apoptotic signaling in cancer cells through the pharmacological inhibition of c-FLIP(L) can inhibit tumor implantation in a clinically relevant model of peritoneal carcinomatosis, a fatal disease. Pharmacological inhibitors of FLIP hold promise as a way to curtail cancer cell colonization of secondary tissues.

A rationale for mTOR inhibitors as chemoprevention agents in Peutz-Jeghers syndrome.

Peutz-Jeghers patients frequently develop clinically significant complications, namely hemorrhage and bowel obstruction, from small intestinal hamartomatous polyps that frequently require surgery. In addition, many PJS patients develop epithelial malignancies in a variety of organs. The vast majority of PJS is due to germline alterations in the STK11 gene that encodes a protein that modulates PI3-kinase signaling, a key regulator of cell survival and growth. One of the major downstream mediators of PI3-kinase signaling is mTOR, the mammalian target of rapamycin. Several drugs that inhibit the PI3-kinase signal transduction pathway are in development and one, RAD001 (everolimus), an mTOR inhibitor, was recently approved for the treatment of renal cell carcinoma. Effective chemoprevention of intestinal polyps would be a first step in simplifying and improving the management of PJS patients. We present here, the rationale for the first human PJS chemoprevention trial using an mTOR inhibitor.

Colorectal adenomas and cancer link to chromosome 13q22.1-13q31.3 in a large family with excess colorectal cancer.

BACKGROUND: Colorectal cancer is the fourth most common type of cancer and the second most common cause of cancer death. Fewer than 5% of colon cancers arise in the presence of a clear hereditary cancer condition; however, current estimates suggest that an additional 15-25% of colorectal cancers arise on the basis of unknown inherited factors. AIM: To identify additional genetic factors responsible for colon cancer. METHODS: A large kindred with excess colorectal cancer was identified through the Utah Population Database and evaluated clinically and genetically for inherited susceptibility. RESULTS: A major genetic locus segregating with colonic polyps and cancer in this kindred was identified on chromosome 13q with a non-parametric linkage score of 24 (LOD score of 2.99 and p=0.001). The genetic region spans 21 Mbp and contains 27 RefSeq genes. Sequencing of all candidate genes in this region failed to identify a clearly deleterious mutation; however, polymorphisms segregating with the phenotype were identified. Chromosome 13q is commonly gained and overexpressed in colon cancers and correlates with metastasis, suggesting the presence of an important cancer progression gene. Evaluation of tumours from the kindred revealed a gain of 13q as well. CONCLUSIONS: This identified region may contain a novel gene responsible for colon cancer progression in a significant proportion of sporadic cancers. Identification of the precise gene and causative genetic change in the kindred will be an important next step to understanding cancer progression and metastasis.

The marine alkaloid naamidine A promotes caspase-dependent apoptosis in tumor cells.

Apoptosis is important for normal development and removal of damaged cells. Evasion of apoptosis by cancer cells is one of the key characteristics of many tumor types. Thus, discovering agents that promote apoptosis in tumor cells could have great therapeutic value. Marine natural products have demonstrated great potential as anticancer agents, and the proapoptotic activity of some of these products is emerging as a potentially useful property for cancer treatments. Using a tumor xenograft assay in rodents, we previously found that the marine alkaloid naamidine A is a potent antitumor agent. In this study, we further characterize the mechanism of action of naamidine A. In cultured tumor cells, we find that naamidine A induces cell death, which is accompanied with annexin V staining, disruption of the mitochondrial membrane potential, and cleavage and activation of caspases 3, 8, and 9, all of which are hallmarks of apoptosis. Furthermore, naamidine A-induced cell death is caspase dependent. We also find that under conditions where naamidine A inhibits tumor xenograft growth, it induces activation of caspase 3, suggesting that apoptosis is part of its antitumorigenic activity in vivo. Apoptosis is not dependent on extracellular signal-regulated kinase 1/2, previously characterized molecular targets of naamidine A, nor does it require functional p53. Our studies support the continued study of naamidine A and its target(s) for the potential development of better clinical treatments for cancer.

Colonic adenoma risk in familial colorectal cancer--a study of six extended kindreds.

OBJECTIVES: Most colorectal cancers (CRCs) arise from adenomatous polyps, but the effects of CRC family history on adenoma risk are not well known. This issue is clinically relevant since several medical societies currently recommend earlier and more rigorous colorectal screening for individuals with a strong family history of CRC. METHODS: Colonoscopies were performed in 236 first-, second-, and third-degree relatives of 40 index CRC cases from six large kindreds selected from a large population database. The kindreds were selected for significantly greater risk of CRCs compared with the overall population. Known hereditary colon cancer syndromes were clinically and genetically excluded. RESULTS: Thirty-seven percent of relatives were found to have adenomas on colonoscopy. The average age of diagnosis for colon cancer was 63 yr and advanced adenomas 56 yr. Independent predictors of adenomatous polyps in the relatives were advancing age (P < 0.0001), male gender (P < 0.001), and greater degree of relation to CRC cases (P < 0.01). There was no significant predilection of colorectal tumors for the right or left colon. A higher degree of relationship to CRC cases was a significant predictor of having simple and advanced adenomas, but not hyperplastic polyps after adjustment for age and gender. CONCLUSIONS: These data support the current recommendations for colonoscopy starting before the age of 50 yr in individuals with a strong family history of CRC.

Oncologists' current opinion on the treatment of colon carcinoma.

Colorectal cancer is a major global health problem with more than a million new cases diagnosed worldwide in 2005. In the United States, this malignancy is the third most common with 145,000 new cases and the second most lethal with 56,000 deaths in 2005. Unfortunately, preclinical diagnostic screening in the U.S. population is less than 30-40 percent. The last decade has ushered in exciting new advances for medical oncologists caring for patients with colorectal cancer. The older cytotoxic chemotherapy drug 5-fluorouracil underwent new formulation, and two new drugs, oxaliplatine and irinotecan, were investigated as adjunctive therapies. Finally, targeted therapies, including monoclonal antibodies against vascular endothelial growth factor (bevacizumab) and the epidermal growth factor receptor (cetuximab), are now standard treatment for metastatic colorectal carcinoma. Systemic adjuvant chemotherapy can be lifesaving in patients with locally advanced colorectal carcinomas, which represent 60-70 percent of cases. For patients with metastatic colorectal cancer, the survival rate has doubled. With more effective drugs in the therapeutic armamentarium, new controversies have arisen. Questions regarding the best schedules for classical cytotoxic chemotherapy were largely answered by contemporary clinical trials. The potential of molecular genetic markers for prognosis or prediction of drug-specific toxicity and efficacy have been explored, but their utility for clinical practice is still being investigated. We will review the rapidly changing, state-of-the-art combination chemotherapy for adjuvant and metastatic disease. We will discuss in detail the c-ERBB family of tyrosine kinases as therapeutic targets in colorectal cancer.

Drug evaluation: Volociximab, an angiogenesis-inhibiting chimeric monoclonal antibody.

PDL Biopharma Inc (formerly Eos Biotechnology Inc) and Biogen Idec Inc are developing volociximab, an angiogenesis-inhibiting chimeric mAb that targets AAB1, a component protein of alpha5/beta1 integrin, for the potential treatment of solid tumors, including renal cell carcinoma. Two phase II clinical trials evaluating volociximab in solid tumors are underway. Volociximab is also under investigation for the treatment of age-related macular degeneration.