Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial.

BACKGROUND: Erdafitinib is an oral pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved to treat locally advanced/metastatic urothelial carcinoma (mUC) in patients with susceptible FGFR3/2 alterations (FGFRalt) who progressed after platinum-containing chemotherapy. FGFR-altered tumours are enriched in luminal 1 subtype and may have limited clinical benefit from anti-programmed death-(ligand) 1 [PD-(L)1] treatment. This cohort in the randomized, open-label phase III THOR study assessed erdafitinib versus pembrolizumab in anti-PD-(L)1-naive patients with mUC. PATIENTS AND METHODS: Patients ≥18 years with unresectable advanced/mUC, with select FGFRalt, disease progression on one prior treatment, and who were anti-PD-(L)1-naive were randomized 1 : 1 to receive erdafitinib 8 mg once daily with pharmacodynamically guided uptitration to 9 mg or pembrolizumab 200 mg every 3 weeks. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS: The intent-to-treat population (median follow-up 33 months) comprised 175 and 176 patients in the erdafitinib and pembrolizumab arms, respectively. There was no statistically significant difference in OS between erdafitinib and pembrolizumab [median 10.9 versus 11.1 months, respectively; hazard ratio (HR) 1.18; 95% confidence interval (CI) 0.92-1.51; P = 0.18]. Median PFS for erdafitinib and pembrolizumab was 4.4 and 2.7 months, respectively (HR 0.88; 95% CI 0.70-1.10). ORR was 40.0% and 21.6% (relative risk 1.85; 95% CI 1.32-2.59) and median duration of response was 4.3 and 14.4 months for erdafitinib and pembrolizumab, respectively. 64.7% and 50.9% of patients in the erdafitinib and pembrolizumab arms had ≥1 grade 3-4 adverse events (AEs); 5 (2.9%) and 12 (6.9%) patients, respectively, had AEs that led to death. CONCLUSIONS: Erdafitinib and pembrolizumab had similar median OS in this anti-PD-(L)1-naive, FGFR-altered mUC population. Outcomes with pembrolizumab were better than assumed and aligned with previous reports in non- FGFR-altered populations. Safety results were consistent with the known profiles for erdafitinib and pembrolizumab in this patient population.

EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma.

INTRODUCTION: This exploratory analysis evaluated efficacy and safety data for enfortumab vedotin versus chemotherapy over a median follow-up of ∼2 years from EV-301. MATERIALS AND METHODS: Patients with locally advanced/metastatic urothelial carcinoma with prior platinum-containing chemotherapy and disease progression during/after programmed cell death protein 1/ligand 1 inhibitor treatment were randomized to enfortumab vedotin or chemotherapy (docetaxel, paclitaxel, vinflunine). Endpoints were overall survival (primary), progression-free survival (PFS), objective response, and safety. RESULTS: In total, 608 patients were included (enfortumab vedotin, n = 301; chemotherapy, n = 307). With a median follow-up of 23.75 months, 444 deaths had occurred (enfortumab vedotin, n = 207; chemotherapy, n = 237). Risk of death was reduced by 30% with enfortumab vedotin versus chemotherapy [hazard ratio (HR) 0.70 (95% confidence interval [CI] 0.58-0.85); one-sided, log-rank P = 0.00015]; PFS improved with enfortumab vedotin [HR 0.63 (95% CI 0.53-0.76); one-sided, log-rank P < 0.00001]. Treatment-related adverse event rates were 93.9% for enfortumab vedotin and 91.8% for chemotherapy; grade ≥ 3 event rates were 52.4% and 50.5%, respectively. Grade ≥ 3 treatment-related decreased neutrophil count (14.1% versus 6.1%), decreased white blood cell count (7.2% versus 1.4%), and anemia (7.9% versus 2.7%) were more common with chemotherapy versus enfortumab vedotin; maculopapular rash (7.4% versus 0%), fatigue (6.8% versus 4.5%), and peripheral sensory neuropathy (5.1% versus 2.1%) were more common with enfortumab vedotin. Of special interest adverse events, treatment-related skin reactions occurred in 47.3% of patients receiving enfortumab vedotin and 15.8% of patients receiving chemotherapy; peripheral neuropathy occurred in 48.0% versus 31.6%, respectively, and hyperglycemia in 6.8% versus 0.3%. CONCLUSIONS: After a median follow-up of ∼2 years, enfortumab vedotin maintained clinically meaningful overall survival benefit versus chemotherapy, consistent with findings from the EV-301 primary analysis; PFS and overall response benefit remained consistent. Adverse events were manageable; no new safety signals were observed.

Nuclear and magnetic spin structure of the antiferromagnetic triangular lattice compound LiCrTe2 investigated by [Formula: see text]SR, neutron and X-ray diffraction.

Two-dimensional (2D) triangular lattice antiferromagnets (2D-TLA) often manifest intriguing physical and technological properties, due to the strong interplay between lattice geometry and electronic properties. The recently synthesized 2-dimensional transition metal dichalcogenide LiCrTe[Formula: see text], being a 2D-TLA, enriched the range of materials which can present such properties. In this work, muon spin rotation ([Formula: see text]SR) and neutron powder diffraction (NPD) have been utilized to reveal the true magnetic nature and ground state of LiCrTe[Formula: see text]. From high-resolution NPD the magnetic spin order at base-temperature is not, as previously suggested, helical, but rather collinear antiferromagnetic (AFM) with ferromagnetic (FM) spin coupling within the ab-plane and AFM coupling along the c-axis. The value if the ordered magnetic Cr moment is established as [Formula: see text]. From detailed [Formula: see text]SR measurements we observe an AFM ordering temperature [Formula: see text] K. This value is remarkably higher than the one previously reported by magnetic bulk measurements. From [Formula: see text]SR we are able to extract the magnetic order parameter, whose critical exponent allows us to categorize LiCrTe[Formula: see text] in the 3D Heisenberg AFM universality class. Finally, by combining our magnetic studies with high-resolution synchrotron X-ray diffraction (XRD), we find a clear coupling between the nuclear and magnetic spin lattices. This suggests the possibility for a strong magnon-phonon coupling, similar to what has been previously observed in the closely related compound LiCrO[Formula: see text].

Intra-articular Localized Haemangioma of the Knee Mimicking Localized Pigmented Villonodular Synovitis: A Case Report.

Intra-articular synovial haemangioma of the knee is a benign tumour. However, diagnostic delay leads to degenerative changes in the cartilage and osteoarthritis due to recurrent haemarthrosis. Therefore, treatment should be performed immediately. We report the case of a localized synovial haemangioma arising from the medial plica in a 38-year old female presenting with pain and restricted range of motion in the right knee joint. Initially, we diagnosed this case as a localized pigmented villonodular synovitis (LPVS) based on MRI and arthroscopic findings and performed only arthroscopic en bloc excision of the mass and synovectomy around the mass for diagnostic confirmation. Fortunately, there was no difference in the treatment approaches for LPVS and localized haemangioma and the synovial haemangioma had not recurred at the 3-month postoperative follow-up with MRI. The patient's clinical symptoms resolved and had not relapsed two years after surgery.

Type 1 Achilles tendon rupture caused by grooming trauma in a young dog.

Achilles tendon rupture is uncommon in small animal practice. A 9-month-old, female, mixed breed dog (weighing 2.2kg) was referred to our hospital with a primary complaint of right hind limb lameness. Complete right Achilles tendon rupture was diagnosed by physical examination and radiography. The tendon was surgically repaired the next day by using a three-loop and single near-far-far-near suture methods. Complete healing was achieved by 97 days post-surgery. This report describes the surgical technique used for complete Achilles tendon rupture repair in a young dog.

A mechanical coil insertion system for endovascular coil embolization of intracranial aneurysms.

Like other fields of medicine, robotics and mechanization might be introduced into endovascular coil embolization of intracranial aneurysms for effective treatment. We have already reported that coil insertion force could be smaller and more stable when the coil delivery wire is driven mechanically at a constant speed. Another background is the difficulty in synchronizing operators' minds and hands when two operators control the microcatheter and the coil respectively. We have therefore developed a mechanical coil insertion system enabling a single operator to insert coils at a fixed speed while controlling the microcatheter. Using our new system, the operator manipulated the microcatheter with both hands and drove the coil using foot switches simultaneously. A delivery wire force sensor previously reported was used concurrently, allowing the operator to detect excessive stress on the wire. In vitro coil embolization was performed using three methods: simple mechanical advance of the coil; simple mechanical advance of the coil with microcatheter control; and driving (forward and backward) of the coil using foot switches in addition to microcatheter control. The system worked without any problems, and did not interfere with any procedures. In experimental coil embolization, delivery wire control using the foot switches as well as microcatheter manipulation helped to achieve successful insertion of coils. This system could offer the possibility of developing safer and more efficient coil embolization. Although we aim at total mechanization and automation of procedures in the future, microcatheter manipulation and synchronized delivery wire control are still indispensable using this system.

Relationship between the number of outpatient visits for hypotension in the springtime in Japan, extracted from clinical electronic records, and global solar radiation levels.

Hypotension is commonly reported in springtime when health changes, such as autonomic imbalance, are common and its symptoms may cause difficulties in daily activities. In this study, medical data from 101 outpatient clinic attendees (mean age 43.9 years; 16 males) making their first visit for hypotension symptoms, were compared with meteorological data from the clinic's location. The main symptom of hypotension was giddiness on standing. The most common coexisting conditions were gastrointestinal; e.g. gastro-oesophageal reflux disorder and irritable bowel syndrome. The 7-day moving average of total global solar radiation correlated significantly with the 7-day moving average of the number of patients with hypotension. Discriminant analysis revealed an increase in hypotension consultations in the total global solar radiation moving average range 11-19 MJ/m(2), consistent with the local spring season. Guidance--such as wearing compression stockings during springtime--may help to reduce the occurrence of clinical hypotension in susceptible patients.

Mechanism of the formation of dural arteriovenous fistula: the role of the emissary vein.

Dural arteriovenous fistula (DAVF) can be separated into two types: DAVF which drains through an affected sinus (sinus type) and DAVF with direct reflux to the cortical vein (non-sinus type). The present report attempted to clarify the mechanism of formation and development of DAVF focusing on the emissary vein (EV) hypothesis.First, inflammation occurs at the penetrating point of the EV on the dura due to idiopathic or secondary causes. Local inflammatory reactions induce vessel dilatation and neovascularization, and subsequently create arteriovenous (AV) connections on the arteriole level. Although EV communicating with dural arteries might play a role as draining routes at first, they start to degrade due to compression of enlarged emissary arteries or to a hemodynamic shift to the drainage pathway of least resistance. Following the occlusion of drainage pathway through EV into the sinus or cortical veins may form, resulting in clinically detectable DAVF. The AV shunt then expands to the surrounding dura associated with recruitment of feeders from distant sites induced by expression of angiogenetic factors and a shift in the hemodynamic balance. In sinus type DAVF, the sinus is progressively compartmentalized and finally occludes due to thrombogenesis with activated coagulopathy or to hemodynamic hypertrophy of the sinus wall. This progression results in the mature, aggressive DAVF with drainage impairments. Previous mechanistic hypotheses focusing on sinus hypertension and sinus thromboses cannot explain the pathogenesis of non-sinus type of DAVF. Although the etiology of DAVF may be concerned by the thrombo-occlusive change of sinus, the unique theory presented in this report may enable an understanding of the common etiology of both types of DAVF.

The mechanism of catheter kickback in the final stage of coil embolization for aneurysms: the straightening phenomenon.

The catheter kickback phenomenon often occurs in the last stage of coil packing for cerebral aneurysms. This behavior is considered the result of either a lack of space in the sac or a stiff detaching zone. In order to clarify its mechanism, focused stretch-resistance (SR) coil simulation models were tested. Various commercially available SR coils were inserted into a cylinder or an aneurismal sac made from a silicone tube with a smaller than prescribed diameter. A magnified SR coil model (straight type) of fishing line was created for simulation. Numerical analysis for the changes in coil behavior were verified. All SR coils showed hardening and straightening at the last few millimeters, resulting in catheter kickback. In a magnified coil experiment, straightening was also realized when folding into a narrow cylinder. The SR line coursed in the canal of the first loops and shifted to the outside in the middle portion. Gaps among first coil pitches were enlarged on after insertion into the narrower space. Shortage of the SR line was calculated to reach a maximum of 32%. The straightening phenomenon is due to SR line shortening and subsequent condensation of pitches of the first loops at the coil end. Coil tail flexibility was lost, and the coil behaved as a stiff wire. Straightening is an important factor in the kickback phenomenon. Shorter final SR coils should be selected, and coil designs should be improved.

Methylation in p14(ARF) is frequently observed in colorectal cancer with low-level microsatellite instability.

Colorectal cancer (CRC) can be classified as high-level microsatellite instability (MSI-H), low-level MSI (MSI-L) and microsatellite stable (MSS) depending on levels of MSI. MSI-H CRC relies on a distinct molecular pathway due to the mismatch repair (MMR) deficiency and shows methylation in multiple gene promoters. The genetic pathway leading to MSI-L is unknown, although higher levels of promoter methylation are observed in this group compared with MSS CRCs. This study explored how promoter methylation affects MSI phenotype, by analysing the methylation status of eight CRC-related promoters, MSI phenotype and KRAS/BRAF mutations in a series of 234 CRCs. Promoter methylation of p14(ARF) was significantly related to MSI-L CRC with KRAS mutation. The MSI-H phenotype was related to methylation of MLH1 as expected, while the MSS phenotype was related to methylation of p16(INK4a) and O(6)-methylguanine-DNA methyltransferase, although this was not statistically significant. Thus, promoter methylation of p14(ARF) could be a significant alteration leading to CRC with MSI-L.

Can periprocedural hypotension in carotid artery stenting be predicted? A carotid morphologic autonomic pathologic scoring model using virtual histology to anticipate hypotension.

SUMMARY: Periprocedural hypotension, which frequently occurs during carotid artery stenting (CAS), is an important risk factor for complications such as stroke or death after CAS. To determine if a scoring model can be established to predict periprocedural hypotension (systolic blood pressure < or = 90 mm Hg) and prolonged periprocedural hypotension (requiring vasopressor for > 3 hours) in CAS, we conducted a prospective cohort study of patients undergoing interventional treatment of cervical carotid artery stenosis in an urban tertiary referral hospital from April 2006 to April 2007. Forty-eight stenotic lesions in 45 consecutive patients treated with CAS were included in the study. Multivariate analysis showed three independent risk factors of periprocedural hypotension; "fibrous plaque on Virtual Histology" (P = 0.029), "stenotic lesion involving both the common carotid artery and internal carotid artery on angiogram" (P = 0.004), and "patients without history of diabetes mellitus" (P = 0.020). Further, "distance between carotid bifurcation and point of minimum lumen size < or = 10 mm on angiogram" (P = 0.003) was an independent risk factor of prolonged periprocedural hypotension. Carotid morphologic autonomic pathologic score (carotid MAPS), determined by adding one point for each of those risk factors (total 0 to 4), had good discrimination for both periprocedural hypotension (area under receiver operating characteristic curve: ROC AUC = 0.876; SE 0.053) and prolonged periprocedural hypotension (ROC AUC = 0.811; SE 0.066). Carotid MAPS is useful for predicting periprocedural hypotension and prolonged periprocedural hypotension during CAS.

No duplicate KRAS mutation is identified on the same allele in gastric or colorectal cancer cells with multiple KRAS mutations.

Codon 12 and 13 mutations in 170 colorectal cancer (CRC) and 66 gastric cancer (GC) specimens were analysed by an 'enriched' polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. All identified mutations were verified by direct sequencing of the second PCR products. Among the 170 CRC specimens, mutations were identified in 47 (28%) and 13 (7.6%) cases in codons 12 and 13, respectively. In the 66 GC specimens examined, however, mutations in codons 12 and 13 were only detected in two (3.0%) and one (1.5%) cases, respectively. Mutations in both codon 12 and 13 were found in 3/170 (1.8%) CRCs and 1/66 (1.5%) GCs. Duplicate mutations were never identified in the same allele, which was confirmed by direct sequencing of the second amplified products. The majority of colorectal and gastric cancer cells with KRAS mutations are homogeneous because they have the same KRAS mutation. A few colorectal or gastric cancers, however, showed heterogeneity, as verified by the fact that single mutations were identified in the same allele.

Oesophageal squamous cell carcinoma may develop within a background of accumulating DNA methylation in normal and dysplastic mucosa.

BACKGROUND: Oesophageal squamous cell carcinoma (OSCC) often arises from preceding dysplastic lesions in the oesophageal epithelium. However, the molecular changes occurring in premalignant lesions are not well understood. An epigenetic change is an example of OSCC that may occur within the epithelium. AIM: To investigate the methylation status of multiple promoters in cancer-derived DNA, as well as in the background epithelium of OSCC, including dysplastic lesions and non-neoplastic mucosa. The normal epithelium from patients without cancer was also examined. The findings were correlated with the mutational status of p53. PATIENTS AND METHODS: 56 patients with advanced OSCC, 21 patients with intraepithelial neoplasia (IEN), 56 patients with a background of non-neoplastic epithelium, adjacent to the OSCC, and 42 normal control epithelia from healthy volunteers were studied. The promoter methylation status of SFRP1, SFRP2, DCC, APC, p16(INK4a), p14(ARF), MINT1, MINT2, MINT31, CACNA1G, COX2, DAPK, hMLH1 and MGMT was examined by methylation-specific single polymerase chain reaction or combined bisulphite restriction analysis. The mutation of p53 by direct sequencing was assessed. RESULTS: DNA methylation was observed in OSCC and in its background epithelium. The frequency of CpG island methylation increased from a baseline level in the background non-neoplastic epithelium, through IEN, to advanced OSCC. However, mutations in p53 were almost exclusively observed in IEN and OSCC. More extensive DNA methylation was seen in the neoplastic lesions (OSCC or IEN) having a p53 mutation than in those with wild-type p53. CONCLUSION: DNA methylation is present at low levels in the non-neoplastic oesophageal epithelium and appears to contribute to the progression of the dysplasia-carcinoma sequence in OSCC carcinogenesis.

Cell preparation of Enterococcus faecalis strain EC-12 prevents vancomycin-resistant enterococci colonization in the cecum of newly hatched chicks.

The use of antimicrobials in broilers is considered to be a cause of the appearance of vancomycin-resistant enterococci (VRE). Once VRE penetration occurs, whatever its origin, it is difficult to expel the enterococci from the intestine because of their multiple resistance, whether natural or acquired. In this study, we evaluated the prevention of VRE colonization by the dietary supplementation of a cell-wall preparation of Enterococcus faecalis strain EC-12 (EC-12) in newly hatched broilers that were challenged by experimental infection with VRE. The chicks were fed a basal diet supplemented with 0.05% (wt/wt) EC-12 powder for 15 d. The control group and that administered Lactobacillus sp. were fed the basal diet. The VRE challenge was administered orally when the chicks were 2 d old (d 0). Dietary EC-12 reduced VRE colonization in the intestine from d 3 to 14. Total IgA in the cecal digesta and total IgG in the serum were higher on d 14 in the EC-12 treatment group. However, VRE-specific and EC-12-specific antibodies were not affected in serum. Hence, it appeared that dietary EC-12 stimulated the gut immune system and reinforced the immune reaction against the VRE challenge to accelerate its defecation from the chick intestine.

Prevention of inflammation-mediated acquisition of metastatic properties of benign mouse fibrosarcoma cells by administration of an orally available superoxide dismutase.

Weakly tumorigenic and nonmetastatic QR-32 cells derived from a fibrosarcoma in C57BL6 mouse are converted to malignant cells once they have grown after being coimplanted with a gelatine sponge which induces inflammation. We administered a newly developed peroral superoxide dismutase (SOD), oxykine, and as control vehicle, gliadin and saline, starting 2 days before the coimplantation and continued daily throughout the experiment. In the oxykine group, tumour incidence was lower (41%) than in the gliadin or saline group (83 and 79%, respectively). The inhibitory effect of oxykine was lost when an individual component of oxykine was administered, that is, SOD alone and gliadin alone. The effect was also abolished when administered by intraperitoneal route. When perfused in situ with nitroblue tetrazolium, an indicator of superoxide formation, the tumour masses from gliadin and saline groups displayed intense formazan deposition, whereas, those from oxykine group had less deposition. Enzymatic activity of SOD was also increased in oxykine group. Arising tumour cells in gliadin and saline groups acquired metastatic phenotype, but those in oxykine group showed reduced metastatic ability. These results suggested that the orally active SOD derivative prevented tumour progression promoted by inflammation, which is thought to be through scavenging inflammatory cell-derived superoxide anion.

Optic nerve and spinal cord manifestations of malignant atrophic papulosis (Degos disease).

A fatal case of malignant atrophic papulosis (Degos disease) with optic nerve and spinal cord involvement is described. Magnetic resonance imaging (MRI) of the optic nerve showed abnormal signal enhancement on fat suppressed T1 weighted images after intravenous meglumine gadopentetate infusion. On T2 weighted sagittal images, a sawtooth pattern was observed over seven vertebral segments of the spinal cord. On necropsy, a severe loss of myelinated nerve fibres in the left optic nerve was seen, with thrombotic obstruction of the central retinal artery. Spongy degeneration was observed in all levels of the spinal cord, with patchy and motheaten patterns caused by thromboses and endothelial proliferation in subarachnoid vessels. Findings on MRI were consistent with findings on pathological examination.

Dynamic gadolinium-enhanced fat-suppressed T1-weighted MRI (chemical shift selective images) for remitting seronegative symmetrical synovitis with pitting edema.

A 75-year-old man suddenly suffered from polyarthralgia and pitting edema in his distal extremities. Laboratory tests revealed inflammation, negative rheumatoid factor, and positive B7 human leukocyte antigen typing. Severe synovitis was observed in dynamic gadolinium-enhanced fat-suppressed (DGEFS) T1-weighted images of his right hand. Our diagnosis was remitting seronegative symmetrical synovitis with pitting edema (RS(3)PE syndrome). He responded dramatically to low-dose corticosteroids, after which his synovitis remarkably improved as observed with DGEFS imaging. DGEFS imaging is useful for distribution of synovitis in patients with RS(3)PE syndrome as well as assessing the efficacy of treatment.

Deletion analysis of the sapovirus VP1 gene for the assembly of virus-like particles.

Human sapovirus (SaV) strains are agents of gastroenteritis. They cannot be grown in cell culture. In this study, constructs containing SaV N- and C-terminal-deleted recombinant capsid proteins (rVP1) were expressed in a baculovirus expression system to allow us to better understand the sequence requirements for the formation of virus-like particles (VLPs). Only proteins derived from N-terminal-deleted rVP1 constructs that began 49 nucleotides downstream assembled into VLPs, which included both small and native-size VLPs. Our results were similar to those reported in a rabbit hemorrhagic disease virus (RHDV) N- and C-terminal-deleted rVP1 expression study but were distinct from those reported in a norovirus N- and C-terminal-deleted rVP1 expression study, suggesting that SaV and RHDV may have similar expression requirements.

BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum.

BACKGROUND AND AIMS: Mutations in BRAF have been linked with colorectal cancers (CRC) showing high level microsatellite instability (MSI-H). However, the distribution of BRAF mutations in MSI-H cancers remains to be clarified with respect to precursor lesions and the CpG island methylator phenotype (CIMP). METHODS: Forty three hyperplastic polyps (HP), nine mixed polyps (MP), five serrated adenomas (SA), 28 conventional adenomas (AD), 18 hereditary non-polyposis colorectal cancers (HNPCC), and 127 sporadic CRC (46 MSI-H and 81 non-MSI-H) were collected from patients undergoing colectomy for either CRC or hyperplastic polyposis. Twenty five of 57 serrated lesions were derived from four patients with hyperplastic polyposis. HP were further subdivided according to recently documented morphological criteria into 27 classical HP and 16 variant lesions described as "sessile serrated adenoma" (SSA). All tumours were screened for BRAF activating mutations. RESULTS: The BRAF mutation was more frequent in SSA (75%) and MP (89%) than in classical HP (19%), SA (20%), and AD (0%) (p<0.0001), and also in sporadic MSI-H cancers (76%) compared with HNPCC (0%) and sporadic non-MSI-H cancers (9%) (p<0.0001). The BRAF mutation was identified more often in CIMP-high serrated polyps (72%) and CIMP-high CRC (77%) than in CIMP-low (30%) and CIMP-negative (13%) polyps (p = 0.002) as well as CIMP-low (18%) and CIMP-negative (0%) CRC (p<0.0001). CONCLUSIONS: The BRAF mutation was frequently seen in SSA and in sporadic MSI-H CRC, both of which were associated with DNA methylation. Sporadic MSI-H cancers may originate in SSA and not adenomas, and BRAF mutation and DNA methylation are early events in this "serrated" pathway.

Allelic imbalance and microsatellite instability in plasma DNA released from polyclonal pancreatic adenocarcinoma.

Evidence of circulating soluble DNA in blood-stream of cancer patients has emerged. Because the plasma DNA is largely derived from cancer cells, genetic analysis of plasma DNA is important to understand the molecular events occurred in cancer patient. Seven microsatellite markers in the soluble plasma DNA from patients with pancreatic adenocarcinoma and other pancreato-biliary malignant tumors were examined for microsatellite instability (MSI) and allelic imbalance (AI). A variety of genetic alterations including MSI and AI were detected in the plasma DNA. Some alterations were detected before recurrence of the tumor was verified. Analysis of five primary pancreatic adenocarcinomas by microdissection revealed that the heterogeneous nature of pancreatic tumors is associated with both MSI and AI in the same tumor. The presence of altered plasma DNA including MSI and/or AI from the same pancreatic cancer patient may be important evidence for the presence of these alterations in heterogeneous primary tumors. Analysis of plasma DNA could become one of the diagnostic or therapeutic measures for this type of pancreatic adenocarcinoma.