Thomas E. Clancy

Hydrated silicate minerals on Mars observed by the Mars Reconnaissance Orbiter CRISM instrument

Phyllosilicates, a class of hydrous mineral first definitively identified on Mars by the OMEGA (Observatoire pour la Mineralogie, L’Eau, les Glaces et l’Activitié) instrument, preserve a record of the interaction of water with rocks on Mars. Global mapping showed that phyllosilicates are widespread but are apparently restricted to ancient terrains and a relatively narrow range of mineralogy (Fe/Mg and Al smectite clays). This was interpreted to indicate that phyllosilicate formation occurred during the Noachian (the earliest geological era of Mars), and that the conditions necessary for phyllosilicate formation (moderate to high pH and high water activity) were specific to surface environments during the earliest era of Mars’s history. Here we report results from the Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) of phyllosilicate-rich regions. We expand the diversity of phyllosilicate mineralogy with the identification of kaolinite, chlorite and illite or muscovite, and a new class of hydrated silicate (hydrated silica). We observe diverse Fe/Mg-OH phyllosilicates and find that smectites such as nontronite and saponite are the most common, but chlorites are also present in some locations. Stratigraphic relationships in the Nili Fossae region show olivine-rich materials overlying phyllosilicate-bearing units, indicating the cessation of aqueous alteration before emplacement of the olivine-bearing unit. Hundreds of detections of Fe/Mg phyllosilicate in rims, ejecta and central peaks of craters in the southern highland Noachian cratered terrain indicate excavation of altered crust from depth. We also find phyllosilicate in sedimentary deposits clearly laid by water. These results point to a rich diversity of Noachian environments conducive to habitability.

Whole exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer

Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two patients with prostate cancer, including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were present in matched tissue. Moreover, we identified 10 early trunk and 56 metastatic trunk mutations in the non-CTC tumor samples and found 90% and 73% of these mutations, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.

Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations

Lynch syndrome or hereditary non‐polyposis colorectal cancer is caused by mutations of DNA mismatch repair (MMR) genes. The extracolonic tumour spectrum includes endometrial, ovarian, gastric, small bowel, pancreatic, hepatobiliary, brain, and urothelial neoplasms. Families were referred on the basis of clinical criteria. Tumour immunohistochemistry and microsatellite testing were performed. Appropriate patients underwent sequencing of relevant exons of the MMR genes. Proven and obligate mutation carriers and first‐degree relatives (FDRs) with a Lynch syndrome spectrum cancer were considered mutation carriers, as were a proportion of untested, unaffected FDRs based on the proportion of unaffected relatives testing positive in each age group. Kaplan–Meier analysis of risk to 70 years was calculated. One hundred and eighty‐four Lynch syndrome spectrum extracolonic cancers in 839 proven, obligate, or assumed mutation carriers were analysed. Cumulative risk for females of an extracolonic tumour is 47.4% (95% CI 43.9–50.8). The risk to males is 26.5% (95% CI 22.6–30.4). There was no reduction in gynaecological malignancies due to gynaecological screening (examination, transvaginal ultrasound scan, hysteroscopy and endometrial biopsy). Males have a higher risk of gastric cancer than females (p = 0.0003). Gastric cancer risk in those born after 1935 does not justify surveillance. These penetrance estimates have been corrected for ascertainment bias and are appropriate for those referred to a high‐risk clinic.

Prostaglandin E2 enhances pancreatic cancer invasiveness through an Ets-1-dependent induction of matrix metalloproteinase-2

Accumulating evidence suggests an important role for cyclooxygenase-2 (COX-2) in the pathogenesis of a wide range of malignancies. Here we tested the hypothesis that the COX-2 product prostaglandin E2 (PGE2) increases cellular invasive potential by inducing matrix metalloproteinase-2 (MMP-2) expression and activity through an extracellular signal-regulated kinase (ERK)/Ets-1-dependent mechanism in pancreatic cancer. PANC-1 and MIAPaCa-2 pancreatic cancer cells were treated with PGE2 or rofecoxib, a selective COX-2 inhibitor. MMP-2 expression and activity were assayed using Western blot analysis and zymography, respectively. MMP-2 promoter activity was analyzed with a luciferase-based assay. Ets-1 activity was analyzed using gel shift assay. Ets-1 expression was specifically silenced using RNA interference. Cellular invasive and migratory potentials were determined using a Boyden chamber assay with or without Matrigel, respectively. Exogenous PGE2 induced MMP-2 expression and activity and increased ERK1/2 phosphorylation, Ets-1 binding activity, and MMP-2 promoter activity. PGE2 also increased cellular migratory and invasive potentials. The mitogen-activated protein kinase kinase inhibitor PD98059 and Ets-1 silencing each abolished PGE2-induced increases in MMP-2 expression. PD98059 and Ets-1 silencing each abrogated the effect of PGE2 on cellular invasive potential but not on cellular migratory potential. Rofecoxib suppressed MMP-2 expression and activity, Ets-1 binding activity, MMP-2 promoter activity, and cellular migratory and invasive potentials. These results suggest that PGE2 mediates pancreatic cancer cellular invasiveness through an ERK/Ets-1-dependent induction of MMP-2 expression and activity. They also suggest that COX-2 inhibition may represent a strategy to inhibit invasive potential in pancreatic cancer.

Post−Gastric Bypass Hyperinsulinism With Nesidioblastosis: Subtotal or Total Pancreatectomy May Be Needed to Prevent Recurrent Hypoglycemia

Symptomatic hyperinsulinemic hypoglycemia and pancreatic nesidioblastosis have recently been described in a small series of patients after gastric bypass surgery for morbid obesity. In the limited published reports of patients with this condition, hyperinsulinism and nesidioblastosis have been managed with distal or subtotal pancreatectomy, with the extent of resection guided by calcium angiography. However, nesidioblastosis may involve the pancreas diffusely, and limited pancreatic resections may predispose patients to further hypoglycemic episodes. We have treated two patients with refractory hyperinsulinism and symptomatic hypoglycemia after successful gastric bypass surgery. One patient underwent an approximately 80% pancreatectomy with good results but subsequently experienced recurrent drop attacks and fainting from hyperinsulinism; a completion pancreatectomy via a pancreaticoduodenectomy was then required. A second patient had profound hyperinsulinemic hypoglycemia and was treated successfully with a subtotal (95%) pancreatectomy. Our experience, the third published report of post-gastric bypass nesidioblastosis, suggests that the risk of recurrent symptomatic hyperinsulinism after limited pancreatectomy is significant and relative euglycemia may be achieved with subtotal or total pancreatectomy.

The spectrum of abdominal injuries associated with the use of seat belts

Several recent reports have described abdominal injuries occurring as a result of seat belt use, raising concerns about seat belts as an agent of injury in motor vehicle crashes. The purpose of this study was to characterize the distribution of abdominal injuries after motor vehicle crashes in belted and unbelted patients admitted to trauma centers. The mortality was higher in unbelted than belted patients (7% vs. 3.2%, respectively, p less than 0.0001). Unbelted patients also had significantly more frequent and more severe head injuries (50.0% vs. 32.9%, respectively, p less than 0.001). The incidence of abdominal injury was equal in both unbelted patients (13.9%), but the spectrum of organs injured was different in the two groups. Gastrointestinal tract injuries (stomach, small bowel, colon and rectum) were significantly more frequent in belted vs. unbelted patients (3.4% vs. 1.8%, respectively, p = 0.001). The frequency of liver and spleen injuries was the same in both groups. This study demonstrates that in patients admitted to trauma centers after motor vehicle crashes, belted and unbelted patients have an equal incidence of abdominal injury, but belted and unbelted patients have a different spectrum of injuries. Hollow viscus injuries are more common in belted crash victims. Seat belt use was associated with significantly fewer head injuries and deaths. Physicians evaluating trauma victims after motor vehicle crashes should be aware of the fact that the types of abdominal injuries may vary substantially depending on seat belt use.

Alkaline Phosphatase Predicts Survival in Patients with Metastatic Neuroendocrine Tumors

The clinical course of patients with metastatic neuroendocrine tumors is highly variable. While some patients experience an indolent clinical course over many years, other patients may rapidly succumb to their disease. Little is known about prognostic factors in these patients, making decisions regarding their management more difficult.We performed a retrospective analysis of 137 patients with metastatic neuroendocrine tumors referred to our institution for treatment. Potential prognostic factors were evaluated using multivariate survival analysis. The median overall survival of patients in our cohort was 6.0 years, although the range of survival times was broad (48 days to 23.4 years). Alkaline phosphatase levels above normal were predictive of shorter survival in both univariate and multivariate analysis. Elevated chromogranin A levels were also associated with shorter survival in univariate analysis; in a multivariate analysis, however, this correlation was no longer significant. There was no association between survival and gender, primary tumor site, or presence or absence of carcinoid syndrome. Elevated alkaline phosphatase is a robust adverse prognostic factor for survival in patients with metastatic neuroendocrine tumors and may be superior to chromogranin A in this setting. Close monitoring of alkaline phosphatase levels may be useful when considering initiation or changes of therapy in patients with metastatic neuroendocrine tumors.

Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer

Bacteria go the distance in cancer The bacterial species Fusobacterium nucleatum is associated with a subset of human colorectal cancers, but its role in tumorigenesis is unclear. Studying patient samples, Bullman et al. found that F. nucleatum and certain co-occurring bacteria were present not only in primary tumors but also in distant metastases. Preliminary evidence suggests that the bacterium is localized primarily within the metastatic cancer cells rather than in the stroma. Antibiotic treatment of mice carrying xenografts of F. nucleatum–positive human colorectal cancer slowed tumor growth, consistent with a causal role for the bacterium in tumorigenesis. Science, this issue p. 1443 The same bacteria present in primary tumors of patients with colorectal cancer are also present in liver metastases. Colorectal cancers comprise a complex mixture of malignant cells, nontransformed cells, and microorganisms. Fusobacterium nucleatum is among the most prevalent bacterial species in colorectal cancer tissues. Here we show that colonization of human colorectal cancers with Fusobacterium and its associated microbiome—including Bacteroides, Selenomonas, and Prevotella species—is maintained in distal metastases, demonstrating microbiome stability between paired primary and metastatic tumors. In situ hybridization analysis revealed that Fusobacterium is predominantly associated with cancer cells in the metastatic lesions. Mouse xenografts of human primary colorectal adenocarcinomas were found to retain viable Fusobacterium and its associated microbiome through successive passages. Treatment of mice bearing a colon cancer xenograft with the antibiotic metronidazole reduced Fusobacterium load, cancer cell proliferation, and overall tumor growth. These observations argue for further investigation of antimicrobial interventions as a potential treatment for patients with Fusobacterium-associated colorectal cancer.

CEACAM6 Is a Novel Biomarker in Pancreatic Adenocarcinoma and PanIN Lesions

Objective:The purpose of this study was to test the hypothesis that CEACAM6 expression is an indicator of adverse pathologic features and clinical outcome in pancreatic adenocarcinoma. Summary Background Data:Previously, we have demonstrated carcinoembryonic antigen–related cell adhesion molecule 6 (CEACAM6) to be an oncoprotein that plays an important role in the biology of pancreatic adenocarcinoma. Suppression of CEACAM6 expression reduces tumorigenesis and metastasis in vivo. Methods:A tissue microarray was constructed using tumor specimens obtained from 89 consecutive patients who had undergone pancreatic resection for pancreatic adenocarcinoma with curative intent. A second microarray containing 54 pancreatic intraepithelial neoplasia (PanIN) lesions was constructed using tissues from a separate cohort of 44 patients. Both arrays were immunostained using a specific anti-CEACAM6 monoclonal antibody. Tumoral CEACAM6 expression was dichotomized into negative and positive immunoreactivity groups. The log-rank test was used to evaluate univariate associations of CEACAM6 expression with prognosis. Survival curves were derived using the Kaplan-Meier method. Results:Tumoral CEACAM6 expression was detected in 82 (92%) pancreatic adenocarcinoma specimens. CEACAM6 expression was more prevalent in high-grade than in low-grade PanIN lesions (P = 0.0002). Negative tumoral CEACAM6 expression was associated with absence of lymph node metastases (P = 0.012), lower disease stage (P = 0.008), and longer postoperative survival (P = 0.047). Conclusions:CEACAM6 is a novel biomarker for pancreatic adenocarcinoma. CEACAM6 warrants further evaluation as both a prognostic factor and a therapeutic target in pancreatic cancer.

Current Management of Acute Pancreatitis

Acute pancreatitis may vary in severity, from mild, self-limiting pancreatic inflammation to pancreatic necrosis with life-threatening sequelae. In the majority of the more than 185,000 patients who develop acute pancreatitis each year in the United States, the process is limited tomild parenchymal edema without distant organ dysfunction and an uneventful recovery.1 Although the overall mortality rate with acute pancreatitis is 2–10%, this is primarily related to patients with more severe disease. Approximately 10– 30% of patients develop severe illness with pancreatic inflammation progressing to pancreatic and peripancreatic necrosis. The severity of the local response can lead to development of the systemic inflammatory response syndrome (SIRS) and multiorgan failure, with considerable morbidity and mortality.2,3 The management of patients with mild acute pancreatitis is generally standardized and is primarily limited to identification and management of etiologic factors, resuscitation, and supportive care. Patients with severe and necrotizing pancreatitis require more intensive therapy, possibly including aggressive surgical management for debridement of infected pancreatic necrosis or to address other local complications of the disease. The precise indications for surgery in these patients have been controversial, although in recent years many investigators have adopted a more conservative stance toward early intervention.4,5 This review provides current diagnostic and therapeutic strategies in acute pancreatitis, with particular attention to recent developments in our understanding of severity assessment, nutrition, prophylactic antibiotics, indications for and timing of surgery, and the role of minimally invasive techniques.