Clinicopathological features,diagnosis, and treatment of sessile serrated adenoma/polyp with dysplasia/carcinoma

Sessile serrated adenoma/polyps (SSA/Ps) are early precursor lesions in the serrated neoplasia pathway, which results in BRAF‐mutated colorectal carcinomas with not only high levels of microsatellite instability but also microsatellite stable. SSA/Ps with advanced histology, including cytological dysplasia or minimally invasive carcinomas, are important lesions because SSA/Ps are considered major contributors to “interval cancers” and these lesions can rapidly become dysplastic or invasive carcinomas. Clinicopathologically, SSA/Ps with dysplasia or invasive carcinoma were associated with advanced age, female sex, and proximal colon. Although SSA/Ps with submucosal invasive carcinoma were smaller and invaded less deeply into the submucosal layer than conventional tubular adenomas with submucosal invasive carcinoma, SSA/Ps with submucosal invasive carcinoma frequently had a mucinous component and exhibited a higher potential for lymphatic invasion and lymph node metastasis. In an SSA/P series, endoscopic characteristics, including (semi)pedunculated morphology, double elevation, central depression, and reddishness, may help accurately diagnose SSA/Ps with advanced histology. Removal of SSA/Ps with dysplasia or invasive carcinoma was recommended. Endoscopic treatment such as endoscopic mucosal resection or endoscopic submucosal dissection is useful for those lesions. However, surgical resection with lymph node dissection might be indicated when SSA/Ps with invasive carcinoma are endoscopically suspected, because these have the high risk of lymph node metastasis. Greater awareness may promote further research into improving the detection, recognition, and complete resection rates of SSA/Ps with dysplasia or invasive carcinoma and reduce the interval cancer rates.     

Mucoadhesive Microspheres Containing Amoxicillin for Clearance of Helicobacter pylori

In an effort to augment the anti-Helicobacter pylori effect of amoxicillin, mucoadhesive microspheres, which have the ability to reside in the gastrointestinal tract for an extended period, were prepared. The microspheres contained the antimicrobial agent and an adhesive polymer (carboxyvinyl polymer) powder dispersed in waxy hydrogenated castor oil. The percentage of amoxicillin remaining in the stomach both 2 and 4 h after oral administration of the mucoadhesive microspheres to Mongolian gerbils under fed conditions was about three times higher than that after administration in the form of a 0.5% methylcellulose suspension. The in vivo clearance of H. pylori following oral administration of the mucoadhesive microspheres and the 0.5% methylcellulose suspension to infected Mongolian gerbils was examined under fed conditions. The mucoadhesive microspheres and the 0.5% methylcellulose suspension both showed anti-H. pylori effects in this experimental model of infection, but the required dose of amoxicillin was effectively reduced by a factor of 10 when the mucoadhesive microspheres were used. In conclusion, the mucoadhesive microspheres more effectively cleared H. pylori from the gastrointestinal tract than the 0.5% methylcellulose suspension due to the prolonged gastrointestinal residence time resulting from mucoadhesion. A dosage form consisting of mucoadhesive microspheres containing an appropriate antimicrobial agent should be useful for the eradication of H. pylori.     

A clinical trial of low dose methotrexate therapy in patients with rheumatoid arthritis]

The efficacy and safety of MTX in active RA were evaluated based on patient medical records. The study population consisted of 460 patients with active RA who had received no prior MTX therapy and started it at our hospital between August 1998 and December 2003 (80 men and 380 women with a mean age of 59.3 years). After 24 weeks of MTX therapy, 61.3% of patients showed a 20% improvement, and 30.4% achieved a 50% improvement according to the ACR criteria. The cumulative rate of patients who continued MTX therapy for 48 weeks was 0.567. During the observation period, 260 patients (56.5%) experienced 304 adverse reactions. 52 patients (11.3%) discontinued treatment because of adverse reactions, and 10 patients (2.2%) died. The adverse reactions that occurred in at least 1% of patients were: abnormal hepatic function (31.7%), infection (6.1%), gastrointestinal symptoms (5.0%), stomatitis (3.9%), hematological abnormalities (3.5%), fracture (3.5%), malignant tumor (2.6%), interstitial pneumonia (2.0%), cerebrovascular or cardiovascular disorder (2.0%), headache (1.7%), eruption (1.3%), and alopecia (1.1%). Adverse reactions were more common in the elderly and patients with advanced stage disease. This study reaffirms the therapeutic benefit of MTX, but suggests that careful monitoring is of great importance.     

WIDESPREAD ECZEMA VACCINATUM ACQUIRED BY CONTACTS A Report of an Autopsy Case

A4-moth-old male infant predisposed to allergic dermatitis acquired widespread eczema vaccinatum by contacts with a recently vaccinated sibling. He died of acute purulent peritonitis following a perforation of multiple duodenal ulcers. Fluorescence immunocytochemical and electron microscopic studies on the skin lesions revealed the presence of viral antigens and numerous virus particles compatible morphologically with those of the mature form from the same batch of smallpox vaccine given to the sibling. A large number of virus particles in the developmental form were also predominantly scattered in the cytoplasm of cells at the stratum malpighii of the epidermis as well as in neutrophils and macrophages in the skin lesions. The virus isolation from the skin lesions was done by using the HeLa cells and the human embryonic lung fibroblasts. No abnormal laboratory data were noted in immunoglobulins. On the basis of atrophy of the thymus and other lymphatic tissues and an appearance of large pyroninophilic cells in association with blastoid transformation, the authors discussed a possible participation of the disturbance of cellular immunity secondary to the virus infection in the development of the disease. ACTA PATH. JAP. 29 : 435–455, 1979.     

Immunochemical analysis of two peak M proteinemia derived from structural differences of IgG Fc region

We found M-proteins with two peaks by agarose electrophoresis in the serum of a myeloma patient. The M-proteins were identified as both IgG 1-kappa type, and classified as IgG-F (fast mobility) and IgG-S (slow mobility). 1) The possibility that the two M-proteins were derived from the post translational differences of sugar moieties of the same IgG molecule was unlikely, because no migration changes were observed in IgG-F and IgG-S after the treatment with 4 different sugar enzymes. 2) Fab fractions of IgG-F and IgG-S were analyzed. After papain or pepsin digestion, western blotting with anti-Fab antiserum revealed that the Fab fraction of IgG-F and IgG-S had identical mobility by agarose electrophoresis. However the Fc fractions of IgG-F and IgG-S analyzed by the same procedures with anti-Fe antiserum, were different. 3) Anti-idiotype antiserum prepared in rabbits against IgG-S, or -F, and absorbed by normal IgG and normal human serum showed a fused precipitin line with IgG-F and IgG-S. These findings suggest that two M-proteins with both IgG 1 and kappa type, have the same VH and VL regions but have different constant regions of heavy chain. Since one copy of IgG 1 constant gene is found in each human haploid gene. It is speculated that the switching of the rearranged VDJ gene to constant region gene occurred not only between cis chromosome but also between trans chromosome.     

Granulocytosis associated with malignant neoplasms: a clinicopathologic study and demonstration of colony-stimulating activity in tumor extracts

We studied seven cases of malignant neoplasms, taken from various sites in the body, that were associated with marked granulocytosis. The seven cases were characterized clinically by marked granulocytosis with mature neutrophils, nonspecific inflammatory signs, and a rapid and progressive fatal course of the disease. The elevation of granulocyte count generally paralleled the increase in tumor size. Postmortem examination revealed no evidence of extensive bone marrow metastases or significant suppuration in any case. The bone marrows showed varying degrees of granulocytic hyperplasia with or without a shift to the left in the maturation series. Erythroid cell hyperplasia was observed in some cases, and in one instance there was an increase in immature eosinophils. The spleen showed various degrees of infiltration by neutrophils, from minimal to extremely marked; some spleens had foci of extramedullary hemopoiesis. Colony-stimulating activity was demonstrated in tumor extracts from three of these cases and from the serum in another case. Thus, it is suggested that marked granulocytosis in these patients was caused, at least in part, by colony-stimulating factor produced by the neoplastic cells.     

Two patients with chromosome 6q terminal deletions with breakpoints at q24.3 and q25.3.

We report on 2 patients with de novo terminal deletion of 6q. The first was a 4-month-old boy whose karyotype was 46,XY,del(6)(q24.3); the second a 2-year-old girl whose karyotype was 46, XX, del(6)(q25.3). The main anomalies in both patients included mental retardation, minor craniofacial and cerebral anomalies, and cardiac defects. The characteristic manifestations were imperforate anus in the first patient, and retinitis proliferans and a triatrial heart in the other. Comparison of clinical findings of our 2 patients with those of 18 previously reported patients with similar phenotypes suggests that terminal deletion of the 6q23 or 6q25 band is critical in producing the main anomalies of del(6q) syndrome.     

Effects of nilvadipine, a calcium antagonist, on rabbit ocular circulation and optic nerve head circulation in NTG subjects

PURPOSE: To study the effects of nilvadipine, a Ca2+ antagonist, on tissue circulation in the optic nerve head (ONH), choroid, and retina in rabbits and on the ONH circulation in normal tension glaucoma (NTG) patients. METHODS: Nilvadipine (3.2 microg/kg) or vehicle solution was injected intravenously into urethane-anesthetized rabbits, and the normalized blur value (NB), a quantitative index of in vivo tissue blood velocity, was measured in the choroid and in an area of the ONH and retina free of visible surface vessels before and for 90 minutes after injection, using the laser speckle method. The effects of nilvadipine on the ONH circulation was also studied using the H2 gas clearance method in separate groups of rabbits. Oral nilvadipine (4 mg/d) or placebo was administered to NTG patients in a double-masked manner, and NB in an area of the ONH rim free of visible surface vessels was measured by the same method before and 2, 4, 8, and 12 weeks after administration. RESULTS: The NB obtained from the ONH, choroid, or retina during the experimental period was increased by approximately 10% to 25% in the nilvadipine group compared with the NB in the control group (P < 0.0001, ANOVA), although systemic condition parameters and intraocular pressure (IOP) showed no significant intergroup difference except for a transient decrease in blood pressure in the nilvadipine groups. Blood flow rate in the ONH determined by the H2 gas clearance method also showed an approximately 25% increase in the nilvadipine group. The NB in the ONH of the oral nilvadipine-treated patients was significantly increased, by approximately 20% compared with the placebo-treated patients throughout the follow-up period. No significant intergroup difference was seen in blood pressure, pulse rate, or IOP. CONCLUSIONS: Nilvadipine increased blood velocity and, probably, blood flow in the ONH, choroid, and retina of rabbits. It also increased blood velocity in the ONH of NTG patients.     

Two cases of frosted retinal angiitis with central retinal vein occlusion]

BACKGROUND: Frosted retinal angiitis usually occurs in children, and has a good prognosis. We report two cases of unilateral frosted retinal angiitis in adults. They resulted in visual degradation because of associated central retinal vein occlusion and neovascular glaucoma. CASES: Case 1 was a 36-year-old female. Almost all retinal veins and some retinal arteries had vasculitis in her right eye, and the veins were slightly dilated and sheathed. Case 2 was a 23-year-old female. Angle hypopyon was observed in her left eye. Retinal veins were dilated, meandered, and sheathed. Retinal hemorrhages were also observed. In both cases, systemic steroid therapy gradually improved the retinal vasculitis, but central retinal vein occlusions gradually developed, and in spite of systemic administration of urokinase and panretinal photocoagulation, neovascular glaucoma developed, and visual acuity became degraded in both cases. CONCLUSION: Two cases of frosted retinal angiitis complicated by retinal vein occlusion were reported. Careful observation of retinal blood flow is necessary in frosted retinal angiitis in adults.     

Somatic mutations of epidermal growth factor receptor in colorectal carcinoma.

PURPOSE: Somatic mutations of the epidermal growth factor receptor (EGFR) gene may predict the sensitivity of non-small cell lung carcinoma to gefitinib. However, no mutations have been reported for colorectal carcinoma. We therefore analyzed EGFR mutations in colorectal adenocarcinomas by the combined use of laser microdissection and sequencing of genomic DNA. EXPERIMENTAL DESIGN: We examined 11 representative colorectal adenocarcinoma cell lines and 33 clinical samples of colorectal carcinoma. In the clinical cases, we carefully dissected only carcinoma cells from frozen sections by laser microdissection. After DNA extraction and PCR, we examined EGFR mutations by sequencing genomic DNA. RESULTS: None of 11 colorectal carcinoma cell lines exhibited somatic mutations, but 4 of 33 clinical tumors (12%) exhibited mutations in the EGFR kinase domain. This may be the first report of somatic mutations in colorectal adenocarcinoma. CONCLUSIONS: Our findings suggest that a distinct minority of colorectal adenocarcinomas exhibit somatic mutations of EGFR, and these tumors may be susceptible to gefitinib treatment.