Effectiveness of a surveillance program of upper endoscopy for upper gastrointestinal cancers in Lynch syndrome patients.

BACKGROUND AND AIMS: Lynch syndrome (LS) is the most common cause of hereditary colorectal cancer and is associated with an increased lifetime risk of gastric and duodenal cancers of 8-16% and 7%, respectively; therefore, we aim to describe an esophagogastroduodenoscopy (EGD) surveillance program for upper gastrointestinal (GI) precursor lesions and cancer in LS patients. METHODS: Patients who either had positive genetic testing or met clinical criteria for LS who had a surveillance EGD at our institution from 1996 to 2017 were identified. Patients were included if they had at least two EGDs or an upper GI cancer detected on the first surveillance EGD. EGD and pathology reports were extracted manually. RESULTS: Our cohort included 247 patients with a mean age of 47.1 years (SD 12.6) at first EGD. Patients had a mean of 3.5 EGDs (range 1-16). Mean duration of follow-up was 5.7 years. Average interval between EGDs was 2.3 years. Surveillance EGD detected precursor lesions in 8 (3.2%) patients, two (0.8%) gastric cancers and two (0.8%) duodenal cancers. Two interval cancers were diagnosed: a duodenal adenocarcinoma was detected 2 years, 8 months after prior EGD and a jejunal adenocarcinoma was detected 1 year, 9 months after prior EGD. CONCLUSIONS: Our data suggest that surveillance EGD is a useful tool to help detect precancerous and cancerous upper GI lesions in LS patients. To our knowledge, this is the first study to examine a program of surveillance EGDs in LS patients. More data are needed to determine the appropriate surveillance interval.

Cost Effectiveness of Routine Duodenal Biopsy Analysis for Celiac Disease During Endoscopy for Gastroesophageal Reflux.

BACKGROUND & AIMS: Some patients with refractory gastroesophageal reflux disease (GERD) actually have undiagnosed celiac disease. These patients often undergo an esophagogastroduodenoscopy (EGD) to determine the etiology and severity of GERD. Performing routine duodenal biopsy analysis during an EGD could identify patients with celiac disease. We evaluated the cost effectiveness of this approach. METHODS: We performed a systematic search of the MEDLINE database to identify publications through March 2014 on patients who underwent a duodenal biopsy analysis during an EGD for GERD. Data collected were used to construct a decision tree to calculate the cost effectiveness of an EGD with and without celiac disease tests. RESULTS: Among 10,000 patients with refractory GERD who underwent an EGD, we predicted a biopsy strategy would detect 70% of patients with celiac disease if the prevalence of celiac disease was 1% in this cohort. Biopsy analysis at the start of the EGD procedure would increase the remaining quality-adjusted life years (QALYs) by 0.0032, and increase the lifetime cost by $389/patient. Compared with no biopsy, the biopsy strategy cost $55,692.86/case of celiac disease detected, and $121,875/QALY gained. The incremental cost-effectiveness ratio for the biopsy strategy met the threshold of less than $50,000/QALY when 1 of the following parameters was met: when the utility of living with GERD was less than 0.88, when the prevalence of celiac disease in patients with refractory GERD was greater than 1.8%, when biopsy analysis detected celiac disease with more than 98.1% specificity, when the cost of a gluten-free diet was less than $645.85/y, or if the cost of proton pump inhibitor therapy was more than $5874.01/y. CONCLUSIONS: Based on base-case values, it is not cost effective to perform a biopsy analysis to detect celiac disease in patients undergoing an EGD for refractory GERD. However, the approach becomes cost effective when the prevalence of celiac disease in this population is 1.8% or greater.

Increased efficacy of breast cancer chemotherapy in thrombocytopenic mice.

Platelets contribute to homeostasis of the tumor vasculature by helping prevent hemorrhage. Thus, we hypothesized that inducing thrombocytopenia would increase tumor vascular leakiness and facilitate the effective delivery of chemotherapeutic agents to tumors. In a mammary carcinoma murine model, platelet depletion induced bleeding specifically at the tumor site, favoring the accumulation of fluorescently labeled microspheres only in the tumor. Moreover, induction of thrombocytopenia in tumor-bearing mice before injection of paclitaxel increased its intratumoral accumulation and reduced growth of both slow- and fast-growing tumors, compared with mice with normal platelet counts that were treated only with paclitaxel. Histologic analysis confirmed the expectation of an increase in tumor apoptosis and a reduction in tumor proliferation in thrombocytopenic mice receiving chemotherapy. No increased toxicity was seen in other organs or blood cells. Taken together, our results indicate that low platelet count selectively induces leakiness of tumor vessels and favors the delivery of chemotherapy to tumor sites, enhancing its tumoricidal effects.

von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models.

Deep vein thrombosis (DVT) and its complication, pulmonary embolism, are frequent causes of disability and mortality. Although blood flow disturbance is considered an important triggering factor, the mechanism of DVT initiation remains elusive. Here we show that 48-hour flow restriction in the inferior vena cava (IVC) results in the development of thrombi structurally similar to human deep vein thrombi. von Willebrand factor (VWF)-deficient mice were protected from thrombosis induced by complete (stasis) or partial (stenosis) flow restriction in the IVC. Mice with half normal VWF levels were also protected in the stenosis model. Besides promoting platelet adhesion, VWF carries Factor VIII. Repeated infusions of recombinant Factor VIII did not rescue thrombosis in VWF(-/-) mice, indicating that impaired coagulation was not the primary reason for the absence of DVT in VWF(-/-) mice. Infusion of GPG-290, a mutant glycoprotein Ibα-immunoglobulin chimera that specifically inhibits interaction of the VWF A1 domain with platelets, prevented thrombosis in wild-type mice. Intravital microscopy showed that platelet and leukocyte recruitment in the early stages of DVT was dramatically higher in wild-type than in VWF(-/-) IVC. Our results demonstrate a pathogenetic role for VWF-platelet interaction in flow disturbance-induced venous thrombosis.

von Willebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke.

Stroke is a leading cause of death and disability. The only therapy available is recombinant tissue plasminogen activator, but side effects limit its use. Platelets play a crucial role during stroke, and the inflammatory reaction promotes neurodegeneration. von Willebrand factor (VWF), an adhesion molecule for platelets, is elevated in patients with acute stroke. The activity of VWF is modulated by ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13) that cleaves VWF to smaller less-active forms. We recently documented that ADAMTS13 negatively regulates both thrombosis and inflammation. We report that deficiency or reduction of VWF reduces infarct volume up to 2-fold after focal cerebral ischemia in mice, thus showing the importance of VWF in stroke injury. In contrast, ADAMTS13 deficiency results in larger infarctions, but only in mice that have VWF. Importantly, infusion of a high dose of recombinant human ADAMTS13 into a wild-type mouse immediately before reperfusion reduces infarct volume and improves functional outcome without producing cerebral hemorrhage. Furthermore, recombinant ADAMTS13 did not enhance bleeding in a hemorrhagic stroke model. Our findings show the importance of VWF in regulating infarction and suggest that recombinant ADAMTS13 could be considered as a new therapeutic agent for prevention and/or treatment of stroke.