However, when PARP is impaired, cells are noted to become exquisi

However, when PARP is impaired, cells are noted to become exquisitely sensitive to DNA damaging agents such as radiotherapy [14] and [15]. As a result, the clinical development of PARP inhibitors has followed two approaches: 1) combining PARP1/2 inhibition with DNA-damaging agents, such as radiation, to derive additional therapeutic benefit; and 2) targeting tumor

cells with pre-existing defects in double-strand DNA break repair, such as Brease Cancer (BRCA)-deficient cells, which are genetically predisposed to die when PARP activity is lost [16]. ABT-888 is an orally available, small molecule inhibitor of PARP which has been shown to potentiate the effects of alkylators and radiotherapy in xenograft tumor models [17]. Recognizing the therapeutic potential of PARP-1/2 inhibition in PDAC, we have investigated the addition

of veliparib to focused radiation in vitro and in vivo using a novel preclinical pancreatic cancer buy GSI-IX radiation research model [18] and [19]. The PDAC cell line, MiaPaCa-2, stably transfected with the luciferase-aminoglycoside phosphotransferase Dapagliflozin concentration fusion gene under the control of the elongation factor-1α promoter, was kindly provided by Dr. Ralph Graeser, ProQinase GMBH, Freiburg, Germany. Cells were grown in Dulbecco’s modified Eagle’s medium (DMEM; Invitrogen, Carlsbad, CA) supplemented with 10% fetal bovine serum, and 100 units/mL penicillin/streptomycin. Subconfluent cell monolayers were removed using Immune system 0.25% trypsin containing 1 mmol/L EDTA (Invitrogen) and passaged at a ratio of 1:3 or utilized for study. Cells were seeded in triplicate monolayer and treated with varying doses of ionizing radiation using a 137Cs irradiator (5 Gy/min; Mark I, Shepherd and Associates), ABT-888 (Selleck Chemicals, Houston, TX), or a combination of the two. All in

vitro studies were performed in triplicate. When cells were co-treated, ABT-888 was added to the cell suspension 30 minutes prior to irradiation and left until routine media change at 48 hours. Cell viability was determined by the ability to convert a redox dye (resazurin) into a fluorescent end product (resorufin) using the Cell Titer-Blue® Assay (Promega Corporation, Madison, WI) at varying time points after treatment. Treatment doses resulting in 10% (IC10), 20% (IC20) and 50% (IC50) cell death were calculated for ABT-888 and irradiation, respectively. ABT-888 dose enhancement factors were determined after co-treatment with varying irradiation doses. Levels of apoptosis were determined using a chemiluminescent caspase 3/7 assay (G8091, Promega Corporation, Madison, WI) 48 hours after treatment with ABT-888, radiation, or a combination thereof. PARP-1/2 inhibition was quantitated using an enzyme-linked immunosorbent assay for PAR protein (Trevigen, Gaithersburg, MD) after treatment with ABT-888, radiation, ABT-888 plus radiation, or no treatment. Total protein extracts were harvested 6 hours after treatment and PAR levels were determined by chemiluminescence.

As predicted by the standard dam model, erosion continues downstr

As predicted by the standard dam model, erosion continues downstream of the dam until a new stable channel form is achieved (Williams and Wolman, 1984). This new equilibrium will be based on a number of factors such as vegetation, bedrock

controls, bed armoring, or other local control. As such, the eventual stable state of the river will be highly variable and dependent on location. In the Dam-Attenuating reach net channel erosion continues but is reduced and islands and sand bars are metastable in geometry. The disconnect between channel erosion and island stability is likely due to flow regulation by the dam. Dam regulation lowers peak floods and enhances baseflow discharges which can result in a stable channel thalweg (Fig.

3B). Initially, the channel Rigosertib ic50 will Olaparib in vitro excavate the bed, but if the thalweg does not migrate that process is ultimately limited both vertically and horizontally. Consequently, capacity increases because of bed and bank erosion, but islands remain stable laterally. Flows do not often overtop the islands and therefore vertical erosion does not occur. In the River-Dominated Interaction reach the river experiences the beginning of backwater effects of the Oahe Dam. Water velocity slows and the coarsest material is deposited. With peak discharges reduced due to dam operations, this material is not transported and is deposited on the outside Adenosine of the main river channel (forming bank-attached islands). Further downstream, large amounts of sediment accumulate in the Reservoir-Dominated Interaction reach and fills in the historical thalweg resulting in accumulation on the flooded banks (Fig. 4). The inundation, in turn, then causes additional backwater

effects upstream resulting in additional infilling. The exact location of these processes can shift substantially longitudinally due to fluctuating reservoir levels and upstream dam discharges. Many of the features found in this reach are the result of the creation of deltaic deposits during one season and the subsequent modification as the active process in the location shifts. The Reservoir reach (Lake Oahe) is depositional but, given the lateral extent of the channel due to impoundment, the vertical bed accumulation is small and the morphology remarkably stable through time (Fig. 4 and Fig. 5). Reservoir and delta sedimentation in this reach is reduced significantly due to the trapping of sediment in the upper reservoir (Lake Sakakawea above the Garrison Dam) and regulated dam flows limit storm induced transport. This has the effect of magnifying the sediment sorting, limiting the dynamic response of the delta, and potentially stabilizing its location (relative to a delta without an upstream dam).

The skeletal biology of Marajoarans also is distinctively Amazoni

The skeletal biology of Marajoarans also is distinctively Amazonian, not Andean, as is the associated art (Roosevelt, 1991b). The cultural origin of the Marajo earthworks has

been disputed by natural scientists on the basis of environmental limitation theory, remote sensing, and sediment coring (Rossetti et al., 2009). Their claim is that Marajoara villages must have been placed on natural, not artificial mounds. However, their remote sensing analyses on offsite terrain shed no light on mound contents or stratigraphy, and their only mound investigations were inadequate sampling with a narrow percussion drill, a technique that could not reliably selleck kinase inhibitor distinguish cultural from natural deposits in an artificial mound. Wide-area archeological excavations and trenches cut by looters through sites give clear evidence of superimposed human-built platforms full of cultural structures: floors, fired hearths, black soil middens (see Section ‘Anthropic black soils’), garbage pits, abundant pottery, and cemeteries (Fig. 6) (Bevan

and Roosevelt, 2003, Roosevelt, 1991b and Roosevelt, 2014:1177–1181; Schaan, 2001 and Schaan, 2004). Extensive ground-probing geophysical surveys of the mounds document the same kinds of remains (Fig. 7 and Fig. 8). There is no question that Marajoara mounds are cultural phenomena, and their numbers suggest a much larger population than today. The Marajoara had a mixed subsistence economy: small amounts of hard-seed maize, small

seeds, and gathered and cultivated tree fruits typical of cultural forests: cocosoid palms (Astrocaryum, Acrocomia, Acai, find more Euterpe oleracea), legumes (Inga), fruits (Spondias and Byrsonima), supplemented with large amounts of small fish. Special foods from ceremonial contexts include turtles, very large fish Progesterone (e.g., A. gigas and O. bicirrhosum), and abundant fruits of cultivated Acai palm ( Fig. 9). Despite their sedentary settlement pattern, the mound-dwellers retained access to tall canopied forest for fuel and construction, according to the stable isotope ratios of plant remains. However, open-vegetation plants and crops increase in their food and firewood during the occupation, according to the stable isotopes of human bone and carbonized plants ( Roosevelt, 2000:483–484). Today, the mounds continue to support dense anthropic forest cover, despite surrounding deforestation for cattle pasture. One of the most remarkable prehistoric anthropic effects was the cultural construction of wide areas of fields, transportation ways, and residential mounds in wetlands. Such systems have been studied most in two areas of Amazonia: the Guianas (Fig. 10) (Iriarte et al., 2010, Rostain, 2010, Rostain, 2013 and Versteeg, 2008) and the Bolivian Amazon (Denevan, 1966, Erickson, 1980, Erickson, 2008, Erickson, 2010, Walker, 2004 and Walker, 2012), but new areas keep turning up.

Terrestrial animals, while not nearly as important to the diets o

Terrestrial animals, while not nearly as important to the diets of prehistoric Amerindians as marine fauna, were nonetheless exploited when available. These included native species of iguanas, birds, lizards, and rodents, as well as several which were translocated from South America such as the agouti, opossum, armadillo, guinea pig, and peccary (Giovas et al., 2012). These translocated species never appear to have been moved in great numbers, however, and their general paucity and patchiness suggest they may have been prestige or status oriented GSK1349572 clinical trial foods. It is not known what environmental impacts these

had on Caribbean island environments, though given their generally low numbers, it may have been limited. Of these animal translocations, only the opossum and agouti persist today. Overall, there is mounting evidence that ancient Amerindians adversely affected their island environments, though the impacts varied through space and time (Fitzpatrick and Keegan, 2007 and Fitzpatrick et al., 2008). Prehistoric impacts were generally dwarfed by what selleck happened after European arrival in A.D. 1492, when the transmission

of diseases, introduction of hundreds of non-native plants and animals from the Old World, large scale human population replacement, intensifying exploitation of marine resources (e.g., whales, sea ZD1839 supplier turtles), and plantation economies devastated local flora and fauna. Regardless, the Caribbean follows a similar pattern seen worldwide, in which even small, pre-industrial populations exacted a toll on previously uninhabited island ecosystems, but some groups seem to have effectively used local resources over the long-term.

With a long tradition of archeological and ecological research, California’s Channel Islands provide important datasets to evaluate long-term human ecodynamics and the nature of Holocene and Anthropocene cultural and environmental developments. Many of the trends apparent on Caribbean and Pacific Islands—including over-harvest, landscape burning and clearing, translocation, as well as long-term continuity in the harvest of some key resources—are also apparent on the Channel Islands. California’s islands, however, were occupied entirely by Native American hunter-gatherers until the 19th century, when sea otters and several pinnipeds were hunted nearly to extinction, Chinese abalone fishers visited the islands, and Euroamerican ranching commenced (see Kennett, 2005). We focus on the Native American hunter-gatherer occupation of the Channel Islands, which provides comparative data that build on the Polynesian and Caribbean examples. The Channel Islands are composed of eight islands that are divided into northern and southern groups and are considerably less isolated than Polynesian and most Caribbean islands.

They had no significant difference in age, sex and smoking status

They had no significant difference in age, sex and smoking status between patients with or without EGFR mutation. In the EGFR wild type patients 50 conducted fusion gene detection.

Of these, 14 had ALK fusion (28%), 2 had ROS1 fusion (4%), and 3 had RET fusion (6%). PCR positive samples were all verified by DNA sequencing. The ALK fusions were: eight E(EML4) exon 13 with A(ALK) exon 20 fusions, four E20 with A20 fusions, one E18 with A20 fusion, and one E6 with A20 fusion. The ROS1 fusions were ROS1 exon 34 with TPM3 exon 8. The three RET fusions were all RET exon Protein Tyrosine Kinase inhibitor 12 with KIF5B exon n15. The patients who harbored fusion gene mutation were listed in Table 2. In the EML4-ALK patients, 11 were under 60 and 8 were none or light smokers. The TPM3-ROS1 and two KIF5B-RET patients were under 60 years old and none-smokers, and one KIF5B-RET patient was a heavy smoker (30 pack-years)

and under 60. There was no significant difference between the patients with and without any one of the fusion genes in sex, and smoking status (p > 0.05), but the patients with fusion gene mutations were younger than those without mutations (median age, 51 vs 61, p = 0.032). Thirty-five of the 50 patients received first-line chemotherapy in this hospital, including 29 carboplatin or cisplatin contained therapies, 2 single drug therapies and 4 TKI targeting EGFR therapies. In these patients, twenty-four did not carry any mutation of three fusion genes, eight were ALK fusion positive and three were RET fusion positive (Table 3). In LDK378 order the last follow-up, three patients did not get disease progression. ORR was 4.2% and 9.1% in patients without and with fusion gene mutation, respectively (p > 0.05); DCR was 50% and 72.7%, respectively (p > 0.05). The median PFS of the EML4-ALK positive patients was 4.2 (95% confidence interals, 1.890-6.510) months vs 2.8 (95% CI, 1.658-3.942) months (p = 0.706) in the EML4-ALK negative patients and in either one

of three genes positive patients it was 4.0 (95% CI, 2.605-5.395) months vs 2.7 (95% CI, 1.551-3.849) months mafosfamide (p = 0.371) in the none-positive patients (Figure 2). Although there was no significant difference between the two cohorts, the results showed a trend that patients with fusion genes had a better chemotherapy response than those without any one of fusion genes in chemotherapy. Cell block (CB) is a method to concentrate and preserve cells in fluid samples for long use. Compared with effusion smears, CB contains more cells to be identified and helps pathologists in decision making. It has been used routinely in pathological classification and also in gene detection. In certain cases it has an advantage to other conventional pathological methods [24]. In advanced-stage patients who cannot have their tissues dissected, CB samples could be an alternative selection.

3) Again, the scoring cutoff was determined by the non-averaged,

3). Again, the scoring cutoff was determined by the non-averaged, replicate MFI values, resulting in a more stringent analysis (i.e. MFI values of the three different assay runs for the normal patient samples were not averaged before determining cutoff). Results are shown in Supplementary Fig. 3. Despite this stringent cutoff, all five previously known p53-positive samples (based on ELISA in Fig. 2) remained positive on the VeraCode™ beads in this rigorous inter-assay setting. Furthermore, the two additional p53-positives

picked up only by the VeraCode™ assay (and not ELISA) shown in Fig. 2 (single assay), also remained positive in this rigorous inter-assay setting. The average inter-assay CV was 20% across all sample-protein pairs (see error bars in Supplementary Fig. 3 for more detail). Finally, as an additional metric of inter-assay reproducibility, linear regression JNK inhibitor analysis of two separate assay runs of SD-208 in vivo the 94 samples for two different

TAAs (assayed in multiplex) showed R2 values ≥ 0.96 in both cases (Supplementary Fig. 4; p53, as well as insulin-like growth factor 2 mRNA binding protein 2 [IGF2BP2] (Reuschenbach et al., 2009)). Next, to show compatibility of the VeraCode™ based assay with multiple biomarker classes and to increase the overall diagnostic sensitivity for CRC beyond TAAs alone, we combined three distinct biomarkers, i) autoantibodies against the aforementioned p53 TAA, as well as detection of serum Rutecarpine levels of ii) carcinoembryonic antigen (CEA) and iii) the cytokine

GDF15. While CEA is very well known as a CRC biomarker for disease monitoring and prognostics, its diagnostic use alone or as part of a biomarker panel is currently under investigation ( Creeden et al., 2011 and Su et al., 2012). GDF15 (MIC-1) is perhaps not as well as established for CRC, however, several recent studies suggest it may be useful as a prognostic and diagnostic marker ( Xue et al., 2010, Wallin et al., 2011 and Brown et al., 2012). First, we sought to demonstrate that sandwich immunoassay detection of non-antibody serum protein biomarkers could also be achieved on the VeraCode™ system. As with the p53 TAA, this was done by comparison to conventional ELISA. In this case CEA was used as a model system (with 52 CRC and 25 normal serum/plasma samples). For the VeraCode™ assay, an anti-CEA capture antibody was attached to the bead surface. Following incubation with the serum/plasma samples to capture the CEA, detection was with a biotin labeled anti-CEA antibody followed by a fluorescently labeled streptavidin. ELISA (sandwich immunoassay format) was simply performed using a commercially available kit (see Materials and methods). Results are shown in Fig. 3. Clear agreement is apparent between the two assays as seen by the overlaid bar graphs in Fig. 3A.

The aim of this study is to describe the HDR-IORT-DP technique an

The aim of this study is to describe the HDR-IORT-DP technique and report on the preliminary clinical outcomes of patients treated with this approach. Beginning in 2007, the DP technique was introduced for HDR-IORT cases at Memorial Sloan–Kettering Cancer Center; thus the treatment plans for all patients Rapamycin who received IORT after January 2007 were reviewed to identify IORT plans using DP. A total of 207 patients with locally advanced or recurrent neoplasms, who underwent IORT between January 12, 2007 and August 25, 2010 were identified. Among this group, 16 patients (7.7%) received HDR-IORT-DP

and comprised our study group: 13 patients had recurrent colorectal cancer, 2 patients had recurrent cancer of the head and neck region, and 1 had a gynecologic malignancy. All patients in this group had undergone surgical resection and EBRT previously and had areas within the field that were identified by the surgeon to be at higher risk of microscopic residual disease or were adjacent to critical structures such as the ureter, where adequate selleck chemicals llc shielding could not be achieved owing to geometric constraints. DP was indicated in these cases to either achieve modulation of the dose and delivery

of a concomitant boost to higher-risk areas within the resection bed, while delivering a lower dose to the regions closest to normal structures or to achieve even more conformal dosimetry to a more complicated geometric region within the square or rectangular treatment region created

by the HAM applicator. At the time of HDR-IORT-DP, patients were undergoing radical resection with expected close margins owing to locally advanced/recurrent nature of the tumors. Final resection margins were negative (R0) in 12 patients (75%) and microscopically positive margins (R1) in 4 patients (25%). Patient and treatment characteristics are shown in Table 1. The HDR-IORT-DP was delivered using the HAM applicator, a flexible pad of silicone rubber that has 8-mm thickness and 22 cm in length (Fig. 1). Multiple catheters (3–24) are embedded parallel to each other spaced 10-mm apart, while a fixed source-to-tissue distance of 5 mm is maintained. All procedures were performed in a dedicated shielded operating room. The HDR-IORT-DP technique can be summarized as follows: After filipin tumor resection, the decision to proceed with IORT is based on the radiation oncologist’s and the surgeon’s impression of the risk for close or microscopically positive margins. If deemed necessary, the area at risk is mapped out by the surgeon and radiation oncologist, and the HAM applicator is chosen with the number of channels to cover the target area appropriately. A sterile, transparent, and flexible template that mimics the HAM applicator and varies in number of channels from 3 to 24 is used to define the “DP” regions within the treatment area (Fig. 2).

39 It is not hard to imagine that,

with the shear enormit

39 It is not hard to imagine that,

with the shear enormity of such an exposure and possibility of unintentional (or intentional) discharge of these weapons, arming individuals in schools will actually have the unintended consequence of increasing risk to our children. One premise for arming individuals in our schools is that it will act as a deterrent. Such might be the case if the felonious use of a firearm in a school was a rational event. It is not. Another potential unintended consequence Ponatinib of ensuring an armed presence in our schools is the “up arming” of a potential shooter at a school to match or exceed the weapons perceived to exist in the target school. Such a possibility would increase the likelihood of additional casualties. The practice of arming teachers in the schools might also place these well-meaning educators in the way of perpetrators who have the advantage of planning. Not 1 of the 62 mass shootings in the last 30 years was stopped by an armed civilian.40In the absence of data supporting the salutary benefits of armed personnel in schools, APSA does NOT support a standard practice of arming teachers, parents, or other officials in the school setting. A meaningful reduction in the burden of firearms injury and death in the pediatric population will not happen with a single action

nor will it happen quickly. But, the lack of a “magic bullet” is not click here a reason to abandon common-sense efforts to limit the access and exposure to firearms

for children. The systematic and dramatic reduction in motor-vehicle–related injuries and death in both the adult and pediatric populations should serve as a model for success. Through modifications in the environment (roads), adoption of safety measures (seatbelts), modification of behavior (use of seatbelts), and modifications of vehicle design (eg, airbags)—a public health approach—change was realized. Former Congressman Jay Dickey, who helped author the bill restricting federal funding for firearms research, recently commented “…like motor vehicle injuries, violence exists in a cause-and-effect 3-oxoacyl-(acyl-carrier-protein) reductase world; things happen for predictable reasons. By studying the causes of a tragic—but not senseless—event, we can help prevent another.”41 With more than 300,000,000 guns in circulation in the United States, we as an Association and we as a nation need to develop ways to live safely in a world with guns. There are no guarantees that these measures would have prevented the tragedy at Sandy Hook, or the next Sandy Hook. But, what if they did? APSA believes that inaction is irrational and indefensible. This organization strongly supports the continuation of legislative, public health and policy recommendations detailed here in an effort to reduce the impact of gun violence on our children and youth.

The 5-HT2A receptor has been shown to be widely distributed throu

The 5-HT2A receptor has been shown to be widely distributed throughout the spinal cord and is present at presynaptic and postsynaptic sites therein. This receptor subtype shows dense labelling in lamina II inner and is therefore ideally located for modulation of spinal nociceptive processing. With regards to primary afferent neurones, 5-HT2A receptors are mainly localised in small and medium sized DRG neurones with most 5-HT2A receptor immunolabeled cells expressing the TRPV1 receptor, thus indicating their nociceptive www.selleckchem.com/products/Bortezomib.html nature (Doly et

al., 2004 and Van Steenwinckel et al., 2009). It is a G-protein coupled receptor positively coupled to phospholipase C, leading to an increase in phosphotidylinositol and intracellular calcium. In vitro electrophysiological recordings have shown a long lasting synaptic facilitation of superficial dorsal horn neurones mediated by 5-HT acting at 5-HT2 receptors ( Hori et al., 1996). Taken together, these data would

implicate an excitatory role for the 5-HT2A receptor in spinal nociceptive transmission. The findings from behavioural studies are mixed. For instance, spinal administration of the mixed 5-HT2A/C agonist, (±)-2,5-dimethoxy-4-iodoamphetamine, (DOI), increased the behavioural response to formalin injection, an effect reversed by ketanserin (Kjorsvik et al., 2001), and DOI induced pain-like behaviours such as licking and biting, in line with a pronociceptive role for 5-HT2 receptors (Eide and Hole, 1991). Similarly, blocking spinal Bleomycin manufacturer 5-HT2A receptors inhibited the formalin response (Nishiyama,

2005) and reduced spinal FOS activation in a paw incision model (Silveira et al., 2010). In direct contrast to the aforementioned studies, intrathecal administration of 5-HT2A/2C receptor agonists reversed the behavioural pain-like responses to formalin and chronic constriction nerve injury. These effects were reversed by pretreatment with intrathecal administration of ketanserin, therefore implicating spinal 5-HT2A receptors in mediating the antinociceptive effects of 5-HT (Sasaki et al., 2001 and Sasaki et al., 2003), and 5-HT2A receptor induced spinal acetylcholine release and consequent antinociception was demonstrated (Kommalage Fossariinae and Hoglund, 2005) In rat models of chemotherapy and HIV-therapy induced neuropathy, however, a significant increase in 5-HT2AR immunoreactivity was seen in the superficial layers of the lumbar dorsal horn and an epidural injection of a selective 5-HT2A receptor antagonist dose-dependently decreased the thermal and mechanical hypersensitive behaviours; furthermore 5-HT2A receptor knockout mice did not develop HIV-therapy or chemotherapy-induced neuropathic pain behaviours whereas control littermates displayed a neuropathy comparable to that observed in rats (Thibault et al., 2008).

Patients with inflammatory bowel disease (IBD) (an acronym that i

Patients with inflammatory bowel disease (IBD) (an acronym that includes both ulcerative colitis [UC] and Crohn’s colitis [CC]) are at risk to develop dysplasia in the cryptal epithelium, polypoid and nonpolypoid adenomatous growths, and selleck screening library IBD-independent sporadic polypoid and nonpolypoid adenomas. All these lesions may proceed to colorectal carcinoma (CRC). Information concerning the histogenesis of CRC in IBD is derived from studies done in patients with UC. At present, 7 alternative pathways have been proposed:

(1) from UC-dependent histologically detected dysplastic gland, referred to as dysplasia in flat mucosa in the literature; (2) from UC-dependent adenomatoid neoplastic growths1; (3) from UC-independent, age-dependent, sporadic adenomas1; (4) from gut-associated lymphoid tissue (GALT)2; (5) from nonpolypoid (UC-dependent and UC-independent) adenomas3; (6) from UC-dependent discrete villous dysplastic changes4; or (7) from apparently nondysplastic mucosa (de novo carcinomas). 1 Histologically detected dysplasia in IBD

may be found in colorectal glands exhibiting parallel tubules IDH inhibitor or bifurcations; in those instances, the dysplasia is initially found in the basal aspect of the crypts and progresses gradually toward the superficial aspect of the crypts (base-to-surface progression). In mucosa with advanced atrophy without crypts, dysplasia may be found in the superficial epithelium. A recent search in the literature revealed that most of the publications on flat adenomas in IBD concerned dysplasia in flat mucosa, flat dysplasia, flat dysplastic tissue, or flat low-grade dysplasia. These terms Thalidomide should not be confused with nonpolypoid adenomas, as these adenomas

are also flat dysplasias albeit showing a circumscribed clustering of abnormal crypts lined with dysplastic cells. It is crucial to distinguish between these 2 different histologic alterations, as cases of nonpolypoid adenomas are even today being referred to in the literature as flat adenomas. In this article the term “flat” is reserved for nonpolypoid adenomas. In 1975, Mr Bussey from the St. Mark’s Hospital, London, UK published a monograph on colectomy specimens from patients with familial adenomatous polyposis (FAP). The caption in one of the illustrations reads as follows: “a lesion consisting of adenomatous tubules, which have not produced any thickening of the mucosa”. This appears to be the first description of nonpolypoid (flat) colonic adenomas in FAP.5 In 1985, Muto and colleagues6 launched the colonoscopic-histologic concept “flat adenoma-carcinoma sequence”, uncovering thereby an alternative route to sporadic colorectal carcinogenesis. Hurlstone postulated that the variability in histologic diagnostic criteria used by Western and Japanese pathologists have made comparative studies difficult.