Safety and factors contributing to the difficulty of laparoscopic surgery for rectal cancer treated with preoperative chemoradiotherapy.

BACKGROUND: The safety of laparoscopic surgery for rectal cancer following chemoradiotherapy (CRT) has not been fully established. The aim of our retrospective study was to examine the outcomes and the factors contributing to the difficulty of laparoscopic surgery after CRT. METHODS: Eighty-seven consecutive rectal cancer patients treated with CRT were analyzed. Clinicopathological factors were compared between laparoscopic surgery (n = 57) and open surgery (n = 30) groups, and factors that correlated with operation time and blood loss were analyzed in low anterior resection (LAR) cases in the laparoscopic surgery group (n = 46). RESULTS: There was less blood loss in the laparoscopic surgery group than in the open surgery group (191 vs. 1,043 ml, p = 0.0001), and the operation time in the two groups was similar (329 vs. 322 min, p = 0.8). The rate of conversion from laparoscopic surgery to open surgery was 1.8 %. There was no significant difference in the morbidity rate (laparoscopic surgery 22.8 % vs. open surgery 33.3 %, p = 0.3). All circumferential resection margins were clear. Three-year cumulative rates of local recurrence were as follows: laparoscopic surgery: 1.9 % vs. open surgery: 8.4 % (p = 0.4), and distant recurrence was 28.5 % in laparoscopic surgery vs. 22.7 % in open surgery (p = 0.8) and these rates were not significantly different. In laparoscopic LAR cases, a shorter distance of the tumor from the anal verge was associated with a longer operation time. A high computed tomography Hounsfield units value of the mesorectum (CTV) was associated with increased blood loss in the first 23 cases, but not in the other 23 cases. CONCLUSIONS: Laparoscopic surgery following CRT was safe and feasible. A shorter anal verge was associated with a longer operation time. Blood loss increased in cases with high CTV, but this can likely be mitigated by experience.

Two cases of diverticulitis in patients with Williams syndrome.

Williams syndrome is rare and associated with physical anomalies and mental retardation. It is a disease resulting from a gene deletion of chromosome 7. The main concurrent medical conditions typically associated with Williams syndrome are heart defects such as supravalvular aortic stenosis, mental retardation, and unusual physical characteristics. It is also associated with colon diverticulosis and diverticulitis. In the present article, we report on 2 cases of diverticulitis in patients with Williams syndrome, in whom surgery was performed. In many cases of diverticulitis in patients with Williams syndrome, surgical treatment is indicated. It is important to take diverticulitis into consideration when examining a patient with Williams syndrome presenting with abdominal pain and consider surgical treatment if necessary.

A case of fulminant amebic colitis with multiple large intestinal perforations.

Amebic colitis normally causes mucous and bloody diarrhea stool as predominant symptoms, thus leading to a course of chronic colitis. However, though rare, there exists a fulminating type that causes intestinal perforations due to wide necrosis of the large intestine. We encountered a case of fulminant amebic colitis that lead to death due to multiple large intestinal perforations. The patient was a 72-year-old female. The patient was admitted to our hospital with symptoms of fever, abdominal pain, and diarrhea. She continued to have a fever of over 38 degrees C and increased left abdominal pain. An abdominal computed tomography scan revealed free gas on the abdominal side of the kidney. Therefore, gastrointestinal perforations were diagnosed and surgery was performed. In surgery, many perforated parts were observed from the appendix to the descending colon, and subtotal colectomy was performed. However, sepsis and disseminated intravascular coagulation occurred, and the patient died on the eighth postoperative day.

Hemodynamic effects of dexmedetomidine in patients after cardiac surgery.

AIM: Dexmedetomidine hydrochloride (Prece-dex(R)) is a potent and highly selective central a2-adrenoreceptor agonist. Dexmedetomidine has recently been approved as a new sedative drug, however, its hemodynamic effects on patients just after cardiac surgery has not been established. METHODS: Nineteen patients (14 males and 5 females) who underwent elective cardiovascular surgery were included in this study. The mean age of the patients was 65 years. Coronary artery bypass grafting was performed in 8 patients, aortic valve surgery in 5, mitral valve plus radiofrequency Maze surgery in 3, graft replacement of the ascending aorta in 2 and double valve replacement in 1. After surgery, dexmedetomidine was continuously infused for 3 h in total at a rate of 0.8 mg/kg/h for the initial 1 h and followed by 0.4 mg/kg/h. RESULTS: All patients were well sedated during dexmedetomidine infusion. Dexmedetomidine infusion induced a decrease in systemic blood pressure and systemic vascular resistance index. Heart rate, stroke index, central venous pressure, pulmonary artery pressure and pulmonary artery resistance index remained unchanged. Mixed venous oxygen saturation significantly decreased and arterio-venous O2 content difference increased after the beginning of dexmedetomidine infusion. CONCLUSIONS: Continuous dexmedetomidine infusion did not influence the hemodynamic condition except for the vaso-dilating effect, thus dexmedetomidine was considered to be a viable sedative drug after cardiac surgery.

Structure-based generation of a new class of potent Cdk4 inhibitors: new de novo design strategy and library design.

As a first step in structure-based design of highly selective and potent Cdk4 inhibitors, we performed structure-based generation of a novel series of Cdk4 inhibitors. A Cdk4 homology model was constructed according to X-ray analysis of an activated form of Cdk2. Using this model, we applied a new de novo design strategy which combined the de novo design program LEGEND with our in-house structure selection supporting system SEEDS to generate new scaffold candidates. In this way, four classes of scaffold candidates including diarylurea were identified. By constructing diarylurea informer libraries based on the structural requirements of Cdk inhibitors in the ATP binding pocket of the Cdk4 model, we were able to identify a potent Cdk4 inhibitor N-(9-oxo-9H-fluoren-4-yl)-N'-pyridin-2-ylurea 15 (IC(50) = 0.10 microM), together with preliminary SAR. We performed a docking study between 15 and the Cdk4 model and selected a reasonable binding mode which is consistent with the SAR. Further modification based on the proposed binding mode provided a more potent compound, N-[(9bR)-5-oxo-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindol-9-yl]-N'-pyridin-2-ylurea 26a (IC(50) = 0.042 microM), X-ray analysis of which was accomplished by the soaking method. The predicted binding mode of 15 in Cdk4 was validated by X-ray analysis of the Cdk2-26a complex.

A novel approach for the development of selective Cdk4 inhibitors: library design based on locations of Cdk4 specific amino acid residues.

Identification of a selective inhibitor for a particular protein kinase without inhibition of other kinases is critical for use as a biological tool or drug. However, this is very difficult because there are hundreds of homologous kinases and their kinase domains including the ATP binding pocket have a common folding pattern. To address this issue, we applied the following structure-based approach for designing selective Cdk4 inhibitors: (1) identification of specifically altered amino acid residues around the ATP binding pocket in Cdk4 by comparison of 390 representative kinases, (2) prediction of appropriate positions to introduce substituents in lead compounds based on the locations of the altered amino acid residues and the binding modes of lead compounds, and (3) library design to interact with the altered amino acid residues supported by de novo design programs. Accordingly, Asp99, Thr102, and Gln98 of Cdk4, which are located in the p16 binding region, were selected as first target residues for specific interactions with Cdk4. Subsequently, the 5-position of the pyrazole ring in the pyrazol-3-ylurea class of lead compound (2a) was predicted to be a suitable position to introduce substituents. We then designed a chemical library of pyrazol-3-ylurea substituted with alkylaminomethyl groups based on the output structures of de novo design programs. Thus we identified a highly selective and potent Cdk4 inhibitor, 15b, substituted with a 5-chloroindan-2-ylaminomethyl group. Compound 15b showed higher selectivity on Cdk4 over those on not only Cdk1/2 (780-fold/190-fold) but also many other kinases (>430-fold) that have been tested thus far. The structural basis for Cdk4 selective inhibition by 15b was analyzed by combining molecular modeling and the X-ray analysis of the Cdk4 mimic Cdk2-inhibitor complex. The results suggest that the hydrogen bond with the carboxyl group of Asp99 and hydrophobic van der Waals contact with the side chains of Thr102 and Gln98 are important. Compound 15b was found to cause cell cycle arrest of the Rb(+) cancer cell line in the G(1) phase, indicating that it is a good biological tool.

Crystallographic approach to identification of cyclin-dependent kinase 4 (CDK4)-specific inhibitors by using CDK4 mimic CDK2 protein.

Genetic alteration of one or more components of the p16(INK4A)-CDK4,6/cyclin D-retinoblastoma pathway is found in more than half of all human cancers. Therefore, CDK4 is an attractive target for the development of a novel anticancer agent. However, it is difficult to make CDK4-specific inhibitors that do not possess activity for other kinases, especially CDK2, because the CDK family has high structural homology. The three-dimensional structure of CDK2, particularly that bound with the inhibitor, has provided useful information for the synthesis of CDK2-specific inhibitors. The same approach used to make CDK4-specific inhibitors was hindered by the failure to obtain a crystal structure of CDK4. To overcome this problem, we synthesized a CDK4 mimic CDK2 protein in which the ATP binding pocket of CDK2 was replaced with that of CDK4. This CDK4 mimic CDK2 was crystallized both in the free and inhibitor-bound form. The structural information thus obtained was found to be useful for synthesis of a CDK4-specific inhibitor that does not have substantial CDK2 activity. Namely, the data suggest that CDK4 has additional space that will accommodate a large substituent such as the CDK4 selective inhibitor. Inhibitors designed to bind into this large cavity should be selective for CDK4 without having substantial CDK2 activity. This design principle was confirmed in the x-ray crystal structure of the CDK4 mimic CDK2 with a new CDK4 selective inhibitor bound.

Suppressive effect of N-(benzyloxycarbonyl)-L-phenylalanyl-L-tyrosinal on bone resorption in vitro and in vivo.

The suppressive effect of N-(benzyloxycarbonyl)-L-phenylalanyl-L-tyrosinal on bone resorption was examined in vitro and in vivo. This synthetic peptidyl aldehyde was found to be a potent and selective cathepsin L inhibitor in our screening for cysteine protease inhibitors. In the pit formation assay with unfractionated rat bone cells, 1.5 nM of this compound markedly inhibited parathyroid hormone-stimulated osteoclastic bone resorption. In addition, intraperitoneal administration of this peptidyl aldehyde (2.5-10 mg/kg) for 4 weeks suppressed bone weight loss dose dependently in the ovariectomized mouse, experimental model of osteoporosis. Hydroxyproline measurement of the decalcified femurs from these ovariectomized mice suggested that this compound acts as a bone resorption suppressor through the inhibition of collagen degradation.

[Cultured human monocytes activated by cytokines or lipopolysaccharide induce fibronectin].

We studied the effects of cytokines such as IL-1 alpha, IL-6 and TNF alpha, and lipopolysaccharide (LPS) on cultured human monocytes. Increased fibronectin (FN) production, as a indicator of the activation of monocytes, was observed with any cytokines or LPS stimulation those were added in the culture medium. These increased FN production by cytokines showed a dose dependent fashion, and 4 hours culture with these cytokines was enough to obtain the amount of FN measured with radioimmunoassay. The combination of sub-optimal dose of cytokines (IL-1 alpha + IL-6, IL-1 alpha, IL-6 + TNF alpha), that could not induce substantial amount of FN with any single cytokine, also could induce FN by cultured monocytes. The specificity of cytokines for the FN production by cultured monocytes was confirmed by the neutralization using monoclonal antibodies specific for each monokines. Northern blot analysis with cDNA specific for FN confirmed the expression of FN mRNA in cultured monocytes stimulated with cytokines or LPS. Cytokine network plays an essential role for immune and inflammatory reaction, and FN has been shown to induce monokines through VLA-5 receptor on cultured monocytes. Our data suggests that monocytes may not always require high concentration of cytokines for the activation of monocytes in vitro, and that the synergistic action of low concentration of cytokines for the activation was enough for the progression of immune or inflammatory reaction.

[A case of Sjögren's syndrome complicated with cryoglobulinemia, nephrogenic diabetes insipidus, and renal tubular acidosis].

A 68-year-old woman had been complained of xerostomia since she was 30 years old. Further symptoms of polyuria, polyposia and insomnia had been developed since she was 35 years old. The biopsy material from a minor salivary gland demonstrated the infiltration of lymphocytes into mesenchyme which was compatible with Sjögren's syndrome. She admitted to our hospital because of myalgia in bilateral gastrocnemius and petechiae in both lower extremities in addition to the complaints described above. Complete blood cell counts on admission revealed hemoglobin 9.7 g/dl, platelet count 12.5 x 10(4)/microliters, and white blood cell count 3,300/microliters. Marked polyuria, polyposia (more than 5,000 ml/day, respectively) and low urine gravity (1.005) were observed, although the serum creatinine level showed normal value. Serologic examination showed that the elevation of total serum protein concentration (9.5 g/dl) with marked elevation of serum IgG level (6,190 mg/dl). Her immunoglobulins contained cryoglobulin (cryocrit 20%), and immunoelectrophoresis demonstrated the existence of IgG-kappa monoclonal protein. A positive anti-nuclear antibody at 1:320 dilution, a positive rheumatoid factor and a positive antibody to SS-A (Ro) were also observed. The serial studies of blood gas analysis could not demonstrated the presence of metabolic acidosis. Together with the result of elevated plasma antidiuretic hormone level and results of vasopressin test, Fishberg's concentrating test and the tests of the overload of NH4Cl or bicarbonate, she was diagnosed Sjögren's syndrome with both diabetes insipidus and subclinical renal tubular acidosis. She was initially medicated with prednisolone (40 mg/day, orally), then she was given six courses of intravenous cyclophosphamide (750 mg/body/month).(ABSTRACT TRUNCATED AT 250 WORDS)

[IgD-lambda type multiple myeloma associated with IgG-kappa type benign monoclonal gammopathy].

A 76-year-old man was admitted to Kisen hospital because of lumbago and chest pain. Laboratory examinations revealed a chronic renal failure with marked elevation of the serum BUN (48.8 mg/dl) and creatinine levels (8.2 mg/dl). The serum electrophoresis demonstrated a hypergammaglobulinemia with M peaks. An immunoelectrophoresis demonstrated monoclonal IgD-lambda and IgG-kappa proteins in the serum, and lambda-type Bence Jones protein in the urine (0.4 g/day). Bone marrow smears revealed an abnormal proliferation of atypical plasma cells (43%). A systemic X-ray examination of the skeletal system showed systemic osteoporosis without punched out lesion. The patient was diagnosed as having IgD-lambda type multiple myeloma and IgG-kappa type benign monoclonal gammopathy by quantifying concentration of two M proteins (1,160 mg/dl in IgD, 1,179 mg/dl in IgG, respectively). A combination chemotherapy with melphalan and prednisolone was administered monthly for multiple myeloma, and hemodialysis for the renal failure was performed 3 times a week. A marked improvement of his laboratory findings including a diminution of the serum IgD-lambda M-protein was obtained. On the other hand, IgG-kappa M-protein level was unchanged. Two M-protein levels showed a different behavior after the combination chemotherapy. Although the patient died of congestive heart failure, the partial remission of multiple myeloma has been maintained for 16 months with chemotherapy.

Ectopic calcinosis possibly due to 1 alpha (OH) vitamin D3 in a patient with systemic lupus erythematosus.

A 30-year-old woman with systemic lupus erythematosus (SLE) developed ectopic calcinosis. She had been receiving prednisolone since 1980 with the addition of vitamin D3 in 1986. Despite this therapy, her renal function had gradually deteriorated. Right gonalgia was noted in September 1991. X-ray findings revealed calcinosis of the arteries of the femur, poplitea, cubitus, hands, and feet. Her finger pads and joint sacs were also involved. Calcinosis seen in SLE has only rarely been reported, and that observed in association with vitamin D intoxication or arteriosclerosis has a different distribution of calcium deposits. The use of vitamin D3 in our patient with renal disability may have induced calcinosis with a unique distribution.

Interstitial pneumonitis possibly due to mitoxantrone.

A 41-year-old patient with chronic myelogenous leukemia in the accelerated phase was treated with mitoxantrone. She developed pyrexia 7 days after receiving the third administration of mitoxantrone. After 3 more days, she experienced dry cough and dyspnea. Bilateral fine crackles were audible, but no signs of heart failure were found. A chest X-ray film revealed diffuse reticulogranular infiltrates bilaterally. An increase in the prednisolone dosage led to an improvement. Specimens of the bronchoalveolar lavage revealed an increase in CD4-/CD8- lymphocytes. The peripheral lymphocytes also expressed neither CD4 nor CD8. Specimens of a transbronchial lung biopsy disclosed thickening of the alveolar wall with infiltration of lymphoid cells.

[Surgical enucleation for renal cell carcinoma. A case report].

We present a case of bilateral synchronous renal cell carcinoma treated with surgical enucleation. Urological consultation was asked to evaluate masses of the kidneys, which were detected during a diagnostic imaging on a 58-year-old man with hepatic disorder. Excretory urograms showed definite bilateral upper pole renal masses. Bilateral selective renal angiograms disclosed neovascularity in the small masses. Surgical enucleation of the left renal tumor by a flank approach was performed. The surgical specimen being 3.5 by 2.5 by 2 cm (29 g) was pseudoencapsulated and was identified renal cell carcinoma of the clear cell type, grade 1. INF alpha, pathologically. Seven weeks after, a pseudoencapsulated tumor of 3 by 2.5 by 2 cm (16 g) in the right upper pole was removed by simple enucleation. The pathological diagnosis was renal cell carcinoma of clear cell type, grade 2, INF alpha. The patient is well without evidence of recurrent or any residual disease at 21 months after the second operation. Renal function remains with in normal limits (CCr 110 ml/min). Of our collected cases of bilateral synchronous renal carcinomas treated by bilateral conservative surgery, clinical data are available for 11. Including our case, a total of 12 cases are reviewed.

[Successful high-dose methylprednisolone therapy in a patient with primary myelofibrosis].

We are presenting a patient with primary myelofibrosis who responded to the High-Dose methylprednisolone therapy (1 g/day for 3 days). Three and a half years ago, a 55-year-old male was admitted to our hospital because of severe erythroblastic anemia, thrombocytopenia, splenomegaly and "dry tap" of bone marrow aspiration. Bone marrow biopsy revealed a marked fibrosis without any blastoid cell proliferations. Since a thrombocytopenia was progressive and refractory to the ordinary therapy, high-dose methylprednisolone therapy was performed which was followed by an administration of activated vitamin D3. After the therapy, hematologic improvements were achieved within a month (RBC: 284 x 10(4)/microliters----413 x 10(4)/microliters, WBC: 3,000/microliters----11,500/microliters, Plat.: 7,000/microliters----20,000/microliters). Three months after the therapy, the bone marrow biopsy and 113In scintigraphy were performed. These tests also proved marked improvement of histological features of the bone marrow and a decrease of uptake of 113In to the spleen, respectively. The patient continues to be in good condition and he is free from any medications at present time.

Functional T-cell subset defined by cluster formation with EB virus transformed B-cells.

This study compares functional properties of T-cells capable of forming clusters with EB virus transformed B lymphoblastoid cells (B-LCL) as accessory cells (A-cells). T-cell functional properties examined include T-cell activation, interleukin 2 (IL-2) production and cell proliferation. In addition, functional properties were compared with the presence or absence of surface markers. T-cells were divided into those that formed clusters with the B-LCL (clustered T-cells) and those that failed to form clusters (nonclustered T-cells). Each subpopulation of T-cells was also incubated with B-LCL and Concanavalin A (Con A) to test for changes in proliferative capabilities. Functional studies indicated that IL-2 activity was higher in the culture supernatant fluids from clustered T-cells than nonclustered T-cells. Spontaneous proliferation of clustered T-cells was equivalent to proliferation of clustered T-cells stimulated with Con A or human IL-2. However, weak spontaneous proliferation by non clustered T cells was enhanced after culturing with Con A or human IL-2. The nonclustered T-cells also produced less IL-2 in cultures containing both B-LCL or Con A. Quantification of T-cell surface markers showed that the expression of Tac antigen was greater on the clustered T-cells than on the nonclustered T-cells. These data suggest that functionally different T-cell subsets can be identified and isolated by their capacity to form clusters with B-LCL A-cells.

Increased vascular permeability in the thymus of the autoimmune New Zealand mouse.

The thymus glands of non-autoimmune BDF1 and C3H mice and autoimmune NZB/WF1 mice were studied histologically at intervals ranging from one hour to 60 days after systemic administration of carbon. In NZB/WF1 mice over 9 weeks of age, many circulating carbon-laden macrophages were seen to have penetrated the walls of blood vessels, and to have then entered the thymic parenchyma. Carbon was also taken up by many perivascular macrophages stretched out along blood vessels and by many resident tissue macrophages scattered throughout the thymic parenchyma. In contrast, no carbon was seen at any time in the extravascular tissues of the thymus in BDF1 and C3H mice of comparable age. These results indicate a great increase in the permeability of blood vessels in the thymus of NZB/WF1 mice. This increase in carbon permeability occurs both in the cortex and the medulla, particularly at the corticomedullary junction. There is little increase in the permeability to carbon in NZB/WF1 mice at the age of 4 weeks, suggesting that the increase in vascular permeability begins between the ages of 4 and 9 weeks. The possible role of this greatly increased blood vessel permeability in the thymus on the aetiology and pathogenesis of autoimmune disease is discussed.

Tolerance of agrochemicals in food.

The virtually safe level of the agrochemical residue in food is statistically discussed.