Incidence, clinicopathological features, and clinical outcomes of low HER2 expressed, inoperable, advanced, or recurrent gastric/gastroesophageal junction adenocarcinoma.

BACKGROUND: According to the DESTINY-Breast04 trial, treating patients with breast cancer and low human epidermal growth factor receptor 2 expressions (HER2-low) varies from that of those with no HER2 expression. However, it is interesting to know if HER2-low indicates for anti-HER2 therapy in the gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Hence we conducted this study to assess the incidence, clinicopathological features, and treatment outcomes of patients with HER2-low G/GEJ adenocarcinoma. PATIENTS AND METHODS: This was a single-center, retrospective observational study. Patients with previously untreated G/GEJ adenocarcinoma were classified based on their HER2 status using immunohistochemistry (IHC) with or without in situ hybridization (ISH) as follows: HER2 negative (IHC 0), HER2-low (IHC 1+ or 2+/ISH-), and HER2-positive (IHC2+/ISH+ or 3+). RESULTS: In total, 734 patients with G/GEJ adenocarcinoma were divided into three groups (HER2-negative, n = 410; HER2-low, n = 154, and HER2-positive, n = 170). The intestinal-type histology, peritoneal metastasis, and higher serum carcinoembryonic antigen (CEA) levels differed significantly among patients with negative, low, and positive HER2 statuses: intestinal-type histology (21.0%, 44.2%, and 59.8%, respectively), peritoneal metastasis (56.3%, 44.8%, and 21.8%, respectively), and higher serum CEA level (32.2%, 41.6%, and 56.5%, respectively). Improved survival was observed in the HER2-positive group than in the HER2-negative G/GEJ adenocarcinoma group [hazard ratio (HR) = 0.73, 95% confidence interval (CI) 0.59-0.89; P = 0.002]. However, the prognoses of the HER2-low and HER2-negative groups were similar (HR = 1.01, 95% CI 0.82-1.23; P = 0.843). CONCLUSIONS: Patients with HER2-low G/GEJ adenocarcinoma exhibited intermediate and distinct characteristics than those in the HER2-negative group. Similarly, the HER2-low group's prognosis was worse than that of the HER2-positive group. Therefore developing novel therapeutic strategies targeting HER2-low G/GEJ adenocarcinoma is required.

Whole-Genome Sequencing of the NARO World Rice Core Collection (WRC) as the Basis for Diversity and Association Studies.

Genebanks provide access to diverse materials for crop improvement. To utilize and evaluate them effectively, core collections, such as the World Rice Core Collection (WRC) in the Genebank at the National Agriculture and Food Research Organization, have been developed. Because the WRC consists of 69 accessions with a high degree of genetic diversity, it has been used for >300 projects. To allow deeper investigation of existing WRC data and to further promote research using Genebank rice accessions, we performed whole-genome resequencing of these 69 accessions, examining their sequence variation by mapping against the Oryza sativa ssp. japonica Nipponbare genome. We obtained a total of 2,805,329 single nucleotide polymorphisms (SNPs) and 357,639 insertion-deletions. Based on the principal component analysis and population structure analysis of these data, the WRC can be classified into three major groups. We applied TASUKE, a multiple genome browser to visualize the different WRC genome sequences, and classified haplotype groups of genes affecting seed characteristics and heading date. TASUKE thus provides access to WRC genotypes as a tool for reverse genetics. We examined the suitability of the compact WRC population for genome-wide association studies (GWASs). Heading date, affected by a large number of quantitative trait loci (QTLs), was not associated with known genes, but several seed-related phenotypes were associated with known genes. Thus, for QTLs of strong effect, the compact WRC performed well in GWAS. This information enables us to understand genetic diversity in 37,000 rice accessions maintained in the Genebank and to find genes associated with different phenotypes. The sequence data have been deposited in DNA Data Bank of Japan Sequence Read Archive (DRA) (Supplementary Table S1).

Identification of qRBS1, a QTL involved in resistance to bacterial seedling rot in rice.

Bacterial seedling rot (BSR), a destructive disease of rice (Oryza sativa L.), is caused by the bacterial pathogen Burkholderia glumae. To identify QTLs for resistance to BSR, we conducted a QTL analysis using chromosome segment substitution lines (CSSLs) derived from a cross between Nona Bokra (resistant) and Koshihikari (susceptible). Comparison of the levels of BSR in the CSSLs and their recurrent parent, Koshihikari, revealed that a region on chromosome 10 was associated with resistance. Further genetic analyses using an F5 population derived from a cross between a resistant CSSL and Koshihikari confirmed that a QTL for BSR resistance was located on the short arm of chromosome 10. The Nona Bokra allele was associated with resistance to BSR. Substitution mapping in the Koshihikari genetic background demonstrated that the QTL, here designated as qRBS1 (quantitative trait locus for RESISTANCE TO BACTERIAL SEEDLING ROT 1), was located in a 393-kb interval (based on the Nipponbare reference genome sequence) defined by simple sequence repeat markers RM24930 and RM24944.

A multiple gene complex on rice chromosome 4 is involved in durable resistance to rice blast.

Quantitative trait loci (QTLs) for resistance to rice blast offer a potential source of durable disease resistance in rice. However, few QTLs have been validated in progeny testing, on account of their small phenotypic effects. To understand the genetic basis for QTL-mediated resistance to blast, we dissected a resistance QTL, qBR4-2, using advanced backcross progeny derived from a chromosome segment substitution line in which a 30- to 34-Mb region of chromosome 4 from the resistant cultivar Owarihatamochi was substituted into the genetic background of the highly susceptible Aichiasahi. The analysis resolved qBR4-2 into three loci, designated qBR4-2a, qBR4-2b, and qBR4-2c. The sequences of qBR4-2a and qBR4-2b, which lie 181 kb apart from each other and measure, 113 and 32 kb, respectively, appear to encode proteins with a putative nucleotide-binding site (NBS) and leucine-rich repeats (LRRs). Sequence analysis of the donor allele of qBR4-2a, the region with the largest effect among the three, revealed sequence variations in the NBS-LRR region. The effect of qBR4-2c was smallest among the three, but its combination with the donor alleles of qBR4-2a and qBR4-2b significantly enhanced blast resistance. qBR4-2 comprises three tightly linked QTLs that control blast resistance in a complex manner, and thus gene pyramiding or haplotype selection is the recommended strategy for improving QTL-mediated resistance to blast disease through the use of this chromosomal region.

Thermodynamic investigation of coordination-networked systems of [Mn4] single-molecule magnets under pressure.

Low temperature heat capacity measurements under pressure were performed for tiny single crystals of two-dimensional coordination-networked compounds consisting of [Mn(4)] single-molecule magnets (SMMs) by the ac temperature modulation technique. Systematic variations of the peak temperature and the peak width of the thermal anomalies produced by pressure were clearly detected using two ruthenium oxide resistance chips in the Cu-Be clamp-type cell. A linear increase of the Néel temperature for an ordering set of large SMM spins with S=9 was observed in [Mn(4)(hmp)(6){N(CN)(2)}(2)](ClO(4))(2), while a non-monotonic variation of the peak temperatures and peak shapes was observed in [Mn(4)(hmp)(4)Br(2)(OMe)(2){N(CN)(2)}(2)](ClO(4))(2)·2THF·0.5H(2)O (hmp(-)=2-hydroxymethylpyridinate; N(CN)(2)(-)=dicyanamide as the linker among SMMs). We also report on thermodynamic behavior produced by changing external pressures and magnetic fields. The results are discussed in terms of the tilting angle of Ising axes in the two-dimensional plane.

Penetrating keratoplasty for bullous keratopathy after trabeculectomy.

PURPOSE: To evaluate the results of penetrating keratoplasty (PK) in eyes with bullous keratopathy having previously undergone trabeculectomy. METHODS: We reviewed medical records of patients that had undergone PK for bullous keratopathy having previously undergone trabeculectomy. A total of 34 eyes in 34 patients were included in the study. As a control group, we reviewed the medical records of 26 eyes in 26 patients that had no history of glaucoma and who had undergone PK for bullous keratopathy in the same period at the same institutes. Kaplan-Meier survival analysis was performed to estimate the cumulative probability of successful intraocular pressure (IOP) control, immune reaction-free graft, and graft survival. RESULTS: Visual acuity improved by more than two lines in 30-34 eyes (88%). Log-rank tests showed a statistically significant difference in the cumulative probability of successful IOP control between eyes with functioning blebs and eyes with non-functioning blebs (P=0.0005), but not between the experimental subjects of 34 eyes and the control group (P=0.198). The log-rank test did not show statistically significant differences in the cumulative probability of immune reaction-free grafts and graft failure between the subjects and the control group and between eyes with functioning blebs and eyes with non-functioning blebs. CONCLUSION: The outcomes for PK in bullous keratopathy are good for patients having previously undergone trabeculectomy. Surgical procedures should be performed before PK in eyes with non-functioning blebs even when IOP is controllable with medication.

Alveolar bone regeneration using absorbable poly(L-lactide-co-epsilon-caprolactone)/beta-tricalcium phosphate membrane and gelatin sponge incorporating basic fibroblast growth factor.

The aim of this study was to evaluate the effects of combining a porous poly(L-lactide-co-epsilon-caprolactone)/beta-tricalcium phosphate membrane and gelatin sponge incorporating basic fibroblastic growth factor (bFGF) on bone regeneration in mandibular ridges. Four full-thickness saddle-type defects (10 mm long x 5 mm deep) were symmetrically created in both edentulous mandibular alveolar ridges of 6 beagles. The dome-shaped membrane was secured to each defect site, and a gelatin sponge containing 200 microg bFGF was implanted on the left side of each defect (experimental group). Only the membranes (control group) were secured to the defect sites on the right. Three and 6 months later, 3 animals were killed. Bone regeneration was analyzed by soft X-ray photographs, micro-computed tomography (CT) images, and peripheral quantitative CT (pQCT), and then examined histologically. Soft X-ray examination revealed an increase in new bone volume in the experimental group 6 months postoperatively. pQCT showed that immature bone density was higher in the experimental group. Micro-CT images revealed well formed new bone along the original contour of the dome-shaped membrane in the experimental group. Histologically, inflammatory infiltration of tissue surrounding the membranes was slight. These results suggest that combining the poly(L-lactide-co-epsilon-caprolactone)/beta-tricalcium phosphate membrane and bFGF-gelatin sponge is promising for alveolar ridge reconstruction.

Genetic and physical mapping of the partial resistance gene, pi34, to blast in rice.

ABSTRACT Partial resistance to rice blast in the Oryza sativa japonica group cv. Chubu 32 is controlled by Pi34, a major quantitative trait locus (QTL) on chromosome 11, and several uncharacterized QTLs. The objectives of the study were (i) high-resolution genetic and physical mapping of Pi34 and (ii) identification of new QTL imparting resistance to rice blast. Chubu 32 was crossed with a susceptible chromosomal segment substitution line (CSSL) of cv. Koshihikari. From 4,012 of segregating individuals, 213 recombinants in the Pi34 region were screened by using polymerase chain reaction-based markers and tested resistance in the field and greenhouse. The Pi34 locus is located in the 54.1-kb region on the genomic sequence of cv. Nipponbare. We constructed a bacterial artificial chromosome (BAC) library of Chubu 32, selected the clone containing Pi34, and sequenced it. The Pi34 locus consequently was located on an interval of 65.3 kb containing 10 predicted open reading frames (ORFs). Two of these ORFs were predicted only in Chubu 32 and encoded transposable elements. The other eight ORFs were found in both Chubu 32 and Nipponbare and one of them, which encoded an unknown protein, showed significantly different amino acid sequences between two cultivars. The new QTL, Piq6(t), was detected on the short arm of chromosome 6 and the genetic distance of flanking markers was 16.9 centimorgans in Nipponbare. Pi34 and Piq6(t) acted additively on resistance to rice blast but the effect of Piq6(t) was relatively small compared with Pi34.

GP2/THP gene family of self-binding, GPI-anchored proteins forms a cluster at chromosome 7F1 region in mouse genome.

We investigated the genomic organization of pancreatic zymogen granule membrane-associated protein GP2, a GPI-anchored protein exhibiting self-aggregation at acidic pH, in order to construct a gene-knockout mouse. Cloning and analysis of lambda clones encoding GP2 from 129 Svj mouse genomic DNA libraries showed that the GP2 gene spans about 16.8 kb and includes 11 exons. Identifiable functional domains including a signal sequence, an EGF-like motif, a putative condensing ZP domain, a GPI-anchor attachment site, and a transmembrane sequence for GPI anchoring are encoded in separate exons. Using FISH, the GP2 gene was mapped to mouse chromosome 7F1 near the gene for THP, a GP2 homolog expressed in the cells of thick ascending loop of Henle (TALH) in the kidney. Further analysis of the mouse genome revealed that the THP and GP2 genes are adjacent to one another and are separated by only 3.5 kb in the 7F1 locus. Additionally, the overall structure of the THP gene, 16.2kb with 11 exons, was strikingly similar to that of GP2. This finding suggests that the GP2 and THP genes were generated by gene duplication and evolved separately to acquire regulatory elements leading to tissue-specific expression. Comparative analysis revealed that the 5' flanking region of the THP gene is similar to the first intron of NKCC2, a TALH cell-specific ion-transporter gene. The promoter region of the GP2 gene shares cis-elements found in other pancreas-specific genes. Using this genetic information, a GP2 null mutation was successfully introduced into an ES cell line, and an animal model was established without disruption of THP expression.

Development of cholinergic chronotropic control in chick (Gallus gallus domesticus) embryos.

In chick (Gallus gallus domesticus) embryos, instantaneous heart rate begins to fluctuate with the appearance of rapid, transient decelerations at around the end of the second week of incubation. Previously, it was shown that instantaneous heart rate decelerations were eliminated by administration of atropine and concurrently heart rate baseline was elevated in late embryos. Because the previous study lacked statistical treatment and there has been recent controversy over the development of tonic vagal control of the heart, we reexamine the hypothesis that transient decelerations of instantaneous heart rate are mediated by vagus nerve and the vagal tone begins to appear at around the end of the second week of incubation. Atropine administration tests were conducted for sixty-seven 11- to 14-day-old and 18-day-old embryos in total. Heart rate decelerations appeared sporadically in three out of ten 12-day-old embryos, but the difference of mode heart rate before and after administration of atropine was not significant. Seven out of nine 13-day-old embryos and all nine 14-day-old embryos showed heart rate decelerations and the difference of mode heart rate before and after atropine administration was significant. In late (18-day-old) embryos, magnitude and frequency of instantaneous heart rate decelerations further increased with additional appearance of transient, irregular accelerations. Administration of varying doses of atropine completely eliminated the heart rate decelerations and elevated the heart rate baseline more markedly than in young embryos, indicating the maturation of vagal tone late in incubation.

The bifunctional rat pancreatic secretory trypsin inhibitor/monitor peptide provides protection against premature activation of pancreatic juice.

BACKGROUND: In the rat, two forms of the pancreatic secretory trypsin inhibitor, PSTI-I and PSTI-II, are secreted into pancreatic juice. It is assumed that their role is to protect the pancreas from premature activation of the protease-rich pancreatic juice. In the small intestine, PSTI-I, also called 'monitor peptide', is thought to have a different role: PSTI-I competes with protein for activated trypsin. In the presence of a protein-rich meal, free PSTI induces a release of cholecystokinine from the intestine. METHODS: To investigate whether its role as monitor peptide is compatible with the inhibitory, protective function in the pancreas, PSTI-I was chemically synthesized and then renatured. RESULTS: The peptide was almost completely trypsin resistant and exhibited a dose-dependent inhibitory activity to bovine and partially purified rat trypsin. Furthermore, experiments with trypsin- and endopeptidase-activated pancreatic juice demonstrated that its inhibitory capacity was sufficient to prevent premature activation. Binding studies of (125)I-labeled PSTI-I with the putative intestinal receptor using isolated membranes indicated the presence of high-affinity binding sites (k(d) = 5 x 10(-8)M). Binding of PSTI-I could be competed with excess PSTI-I or trypsin. In a biological assay system, injections of PSTI-I displayed monitor peptide activity by inducing a dose-dependent trypsinogen release from the pancreas. CONCLUSION: Our experiments support a dual function of PSTI-I: monitoring protein in the gut due to its 'moderate' affinity for trypsin and a protective role in the pancreas.

Feasibility of myocardial dual-isotope perfusion imaging combined with gated single photon emission tomography for assessing coronary artery disease.

The clinical feasibility of both dual-isotope single photon emission tomography (SPET) and gated SPET have been described. The present study evaluates the feasibility of combining gated SPET with exercise 201Tl/rest 99mTc-tetrofosmin dual-isotope SPET corrected for scatter. Ninety-one patients with known or suspected coronary artery disease underwent cardiac catheterization and coronary angiography. Twenty-nine of them underwent exercise 201Tl/rest 99mTc-tetrofosmin dual-isotope SPET with a second 201Tl injection 3 h after the initial 201Tl injection (protocol 1). We then segregated a Bull's eye polar map into three coronary artery territories and quantified the relative regional uptake. The remaining 62 patients underwent exercise 201Tl/rest 99mTc-tetrofosmin dual-isotope SPET combined with gated SPET. We visually evaluated exercise and rest images from the three coronary artery territories. Left ventricular (LV) function was assessed globally by means of the LV ejection fraction and regionally by means of visual scoring analysis, compared with left ventriculography (LVG). The correlation between rest 99mTc-tetrofosmin and 201Tl reinjection images in 87 areas of coronary artery territory (r=0.89, P<0.01) and in 13 infarcted areas (r =0.94, P<0.01) was very close in protocol 1. The overall values for vessel-related sensitivity, specificity and accuracy were 88%, 79% and 82%, respectively, in protocol 2. The correlation between gated SPET and LVG was significant and linear with respect to the LV ejection fraction (r=0.77, P<0.01). The wall motion score from visual evaluation in gated SPET revealed a close overall agreement with LVG (concordance rate, 88%; kappa, 0.670). Exercise 201Tl/rest 99mTc-tetrofosmin dual-isotope SPET with scatter correction for assessing the coronary artery disease offers excellent diagnostic accuracy and the additional gated SPET provides useful information about LV function similar to that for LVG. This sequential protocol requires only 2 h to generate much useful clinical information.

Analysis of the C-terminal structure of urinary Tamm-Horsfall protein reveals that the release of the glycosyl phosphatidylinositol-anchored counterpart from the kidney occurs by phenylalanine-specific proteolysis.

Tamm-Horsfall protein (THP), also known as uromodulin, is a major glycoprotein synthesized in the kidney. THP is expressed on the luminal surface of the membrane with the glycosyl phosphatidylinositol (GPI) anchor and excreted in urine at a rate of 50-100 mg per day. Although THP is the most abundant urinary protein, the function of THP remains unclear. In addition, little is known about the mechanism by which large amounts of THP are actively released into the urinary fluid. In this study, we examined the C-terminal structure of highly purified THP derived from human urine. Carboxypeptidase Y efficiently degraded urinary THP, indicating that the C-terminal structure of the protein contains an amino acid residue with a free carboxyl moiety. These results are consistent with our previous finding that urinary THP does not bind anti-CRD antibody. We obtained peptides from the complete digestion of urinary THP with lysylendopeptidase. We purified the most C-terminal peptide with p-phenylene diisothiocyanate-controlled pore glass (DITC-CPG) beads. N-terminal sequence analysis indicated the peptide begins with Tyr 520 and ends between E539 and E576. Direct C-terminal amino acid sequencing of highly purified urinary THP gave a sequence of -X-(Q)-G-(R)-F, corresponding to amino acids 544-548, -S-Q-G-R-F. We therefore conclude that urinary THP is generated by a proteolytic cleavage between F548 and S549, 66 amino acids upstream of a possible GPI-anchor attachment site. Because the sequence of THP, including the cleavage site, is highly homologous to that of GP2, a GPI-anchored protein within the pancreas, and both THP and GP2 are abundantly found as soluble forms in the excreted fluids, a common mechanism may exist governing the proteolytic release of GPI-anchored membrane proteins.

Biophysical characterization of lipopolysaccharide and lipid A inactivation by lactoferrin.

The interaction of bacterial endotoxins (LPS Re and lipid A, the 'endotoxic principle' of LPS) with the endogenous antibiotic lactoferrin (LF) was investigated using various physical techniques and biological assays. By applying Fourier-transform infrared (FTIR) spectroscopy, we find that LF binds to the phosphate group within the lipid A part and induces a rigidification of the acyl chains of LPS. The secondary structure of the protein - as monitored by the amide I band - is, however, not changed. Concomitant with the IR data, scanning calorimetric data indicate a sharpening of the acyl chain phase transition. From titration calorimetric and zeta potential data, saturation of LF binding to LPS was found to lie at a [LF]:[LPS] ratio of 1:3 to 1:5 M from the former and 1:10 M from the latter technique. X-ray scattering data indicate a change of the lipid A aggregate structure from inverted cubic to multilamellar, and with fluorescence (FRET) spectroscopy, LF is shown to intercalate by itself into phospholipid liposomes and may also block the lipopolysaccharide-binding protein (LBP)-induced intercalation of LPS. The LPS-induced cytokine production of human mononuclear cells exhibits a decrease due to LF binding, whereas the coagulation of amebocyte lysate in the Limulus test exhibited concentration-dependent changes. Based on these results, a model for the mechanisms of endotoxin inactivation by LF is proposed.

Acute necrotizing eosinophilic myocarditis successfully treated by high dose methylprednisolone.

Acute necrotizing eosinophilic myocarditis is the most severe form of eosinophilic myocarditis, or hypersensitivity myocarditis, and is characterized by rapidly progressive congestive heart failure followed by fulminant clinical deterioration that is nearly always fatal. A 55-year-old previously healthy patient with acute necrotizing eosinophilic myocarditis was diagnosed by early myocardial biopsy and successfully treated with corticosteroids. Throughout his hospitalization, the eosinophil count in the peripheral blood remained normal (56-201/mm3). Early stage corticosteroid therapy can have dramatic effects in acute necrotizing eosinophilic myocarditis and early diagnosis by endomyocardial biopsy is recommended.

A new extraction method for Acinetobacter species ODB-L2 rough form lipopolysaccharide from culture broth.

The Gram-negative bacterium Acinetobacter species ODB-L2 produces lipopolysaccharide (LPS) in culture broth. The LPS could not be purified by conventional extraction methods using 90% phenol/water or 90% phenol/chloroform/petroleum ether mixed solvent. Extraction was achieved employing an admixture of chloroform, ethanol, and 4 M HCI solution. The LPS was purified from dissolving the crude extracts in 90% phenol and LPS sediment formed by addition of methanol. The LPS was characterized by chemical, biochemical, and physicochemical methods as rough form 3-hydroxydodecanoic acid rich LPS.

Physico-chemical analysis of lipid A fractions of lipopolysaccharide from Erwinia carotovora in relation to bioactivity.

Highly purified bisphosphoryl, monophosphoryl and dephosphoryl lipids A from Erwinia carotovora with different acylation patterns were characterized physico-chemically. Applying matrix assisted laser desorption/ionization mass spectrometry, the purity of the lipid A fractions was determined, and from monolayer measurements the molecular space requirement was estimated. Fourier transform infrared spectroscopy allowed the elucidation of the gel to liquid crystalline phase transition of the acyl chains as well as the determination of the tilt angle of the diglucosamine backbone with respect to the acyl chain direction applying dichroitic measurements with attenuated total reflectance. With synchrotron radiation small-angle X-ray diffraction the supramolecular aggregate structure was determined, and with fluorescence resonance energy transfer spectroscopy the lipopolysaccharide binding protein induced intercalation of lipid A into a phospholipid matrix corresponding to that of the macrophage membrane was investigated. From the results, a clear dependence of the physico-chemical parameters on the particular lipid A structure can be followed. Furthermore, these parameters correlate well with the biological activities of the various lipids A as deduced from their ability to induce biological activity (Limulus assay and cytokine induction in mononuclear cells). These results contribute to a closer interpretation of the physico-chemical prerequisites for endotoxic activity as found for enterobacterial lipid A.

Conditions for solubilization of Tamm-Horsfall protein/uromodulin in human urine and establishment of a sensitive and accurate enzyme-linked immunosorbent assay (ELISA) method.

Tamm-Horsfall protein (THP), also referred to as uromodulin, is a major glycoprotein produced by kidney cells. The level of THP in urine is an indicator of renal function. THP levels are difficult to quantify accurately, because the protein forms aggregates in the pH and ion concentrations found in urine. Here, we describe conditions by which THP can be solubilized and kept soluble during measurement using Triton X-100, EDTA, and alkaline pH. Establishing conditions for precise quantification of THP by enzyme-linked immunosorbent assay (ELISA) will aid in studying the functions of THP.

Gamma knife radiosurgery for growth hormone-secreting pituitary adenomas invading the cavernous sinus.

The authors assessed whether gamma knife radiosurgery is effective for patients with acromegaly where the pituitary tumors invaded the cavernous sinus. Radiosurgery was performed on 9 patients (average of 20 Gy to the tumor margin), 8 of whom had already undergone transsphenoidal surgery and/or craniotomy with occasional medication of octreotide to reduce tumor size as well as hormonal levels. All tumors have been well controlled so far with follow-up periods ranging from 12 to 69 months (mean: 42). No complications occurred. Forty percent of the patients showed hormonal normalization at 2 years, with the median being 31 months. Similarly, 50% of the patients demonstrated normalization of GH and IGF-I at 36 months. We conclude that gamma knife radiosurgery is a safe and effective tool to treat these tumors invading the cavernous sinus.