Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning.

Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is curable in less than 50% of patients. Prognostic models based on pre-treatment characteristics, such as the International Prognostic Index (IPI), are currently used to predict outcome in DLBCL. However, clinical outcome models identify neither the molecular basis of clinical heterogeneity, nor specific therapeutic targets. We analyzed the expression of 6,817 genes in diagnostic tumor specimens from DLBCL patients who received cyclophosphamide, adriamycin, vincristine and prednisone (CHOP)-based chemotherapy, and applied a supervised learning prediction method to identify cured versus fatal or refractory disease. The algorithm classified two categories of patients with very different five-year overall survival rates (70% versus 12%). The model also effectively delineated patients within specific IPI risk categories who were likely to be cured or to die of their disease. Genes implicated in DLBCL outcome included some that regulate responses to B-cell-receptor signaling, critical serine/threonine phosphorylation pathways and apoptosis. Our data indicate that supervised learning classification techniques can predict outcome in DLBCL and identify rational targets for intervention.

[Treatment of superior sulcus tumor].

We reported on 34 patients with superior sulcus non-small-cell lung cancer and clinical outcome. It is necessary to select the most appropriate approach from preoperative examination and the degree of infiltration at the chest wall. Recently, various approach and preoperative chemoradiotherapy followed by surgical resection is effective for the treatment of superior sulcus tumor (SST), we should keep challenging for radical resection in mind.

Role of finite populations in determining evolutionary dynamics.

The connection between the finite size of an evolving population and its dynamical behavior is examined through analytical and computational studies of a simple model of evolution. The infinite population limit of the model is shown to be governed by a special case of the quasispecies equations. A flat fitness landscape yields identical results for the dynamics of infinite and finite populations. On the other hand, a monotonically increasing fitness landscape shows "epochs" in the dynamics of finite populations that become more pronounced as the rate of mutation decreases. The details of the dynamics are profoundly different for any two simulation runs in that events arising from the stochastic noise in the pseudorandom number sequence are amplified. As the population size is increased or, equivalently, the mutation rate is increased, these epochs become smaller but do not entirely disappear.

[Analysis of ocular circulatory kinetics in glaucoma by the ultrasonic Doppler method].

In order to analyze ocular circulatory kinetics in relation to the stages of progression of primary open-angle glaucoma, the pulse wave of flow velocity in the central retinal artery was measured by the ultrasonic Doppler method. In eyes with glaucoma, the ratio of blood flow velocity of the central retinal artery (fundus artery: FA) to that of the ophthalmic artery (medial frontal artery: OA) was smaller and, at the same time, the pulse rise time (PRT) of the pulse wave of flow velocity was shorter than in normal eyes, a tendency which increased as the disease progressed. The ratio of FA to OA in terms of velocity [V (FA/OA)] showed a significant inverse correlation with the degree of visual field disorder (Kosaki classification) and the ratio in terms of PRT [T (FA/OA)] showed significant inverse correlation with the C/D ratio of the papilla. An ultrasonic Doppler blood flowmeter with 2 frequencies, attached to an integral spectrum analyzer for indicating the direction of blood flow using real time sonography (Vasoflo-3), was used. The investigation was conducted on 100 eyes with primary open-angle glaucoma in 60 patients aged 20-70 years [28 males and 32 females (mean age 64.3 +/- 12.1)], and 60 eyes in 30 normal subjects of the same age (mean age 58.1 +/- 14.3). These results demonstrated that the ultrasonic Doppler method is useful for the observation of ocular circulatory kinetics in eyes with glaucoma.

[Evaluation of tissue plasminogen activator and plasminogen activator inhibitor-1 in blood obtained from patients of idiopathic central serous chorioretinopathy].

It is postulated that idiopathic central serous chorioretinopathy (ICSC) may be induced by a variety of underlying choroidal diseases capable of producing initially alterations in the permeability of the choriocapillaries. A history of unusual emotional stress frequently accompanies the onset of visual complaints. We have reported that alterations of serum lipids may exert a powerful effect on tissue plasminogen activator (t-PA) levels acting as a risk factor of variable cardioangiopathies. In this study, we evaluated the levels of t-PA activity, t-PA antigen and plasminogen activator inhibitor-1 (PAI-1) in blood from the patients with central serous chorioretinopathy, and compared them with the levels of total cholesterols (TCH), triglycerides (TG), and high-density lipoprotein cholesterol (HDL). t-PA activity levels and HDL were lower than in standard controls but t-PA antigen, PAI-1 antigen, and TG were higher. These facts may be associated with the pathogenesis or pathophysiological features of ICSC.

[Gross anatomical study of veins in the orbit].

The aim of this study is to clarify the major route of venous return in the orbit. Minute dissections were performed in 10 adult cadavers (5 males and 5 females) after being fixed in a 10% formalin solution. The superior ophthalmic vein (SOV) and its ascending anastomotic branch were consistently well-developed (the average maximum diameter: 6.2mm and 3.2mm, respectively) and these two veins formed the main venous channel from the orbital contents. The ascending anastomotic branch ran between the optic nerve and the medial rectus just behind the eyeball and joined the SOV. A large number of veins, including the inferior ophthalmic vein, which originated from the inferior contents of the orbit, drained into the ascending anastomotic branch. Arteries and/or nerves did not accompany their respective veins in the orbit, except for the lacrimal and ethmoidal veins. The posterior end of the SOV was severely narrowed lateral to the aponeurosis of the lateral rectus, while being conspicuously dilated just behind the eyeball. The above findings suggested that the dilated portion of SOV may act as a reservoir of the venous return of the orbit.

[Ultrasound biomicroscopic imaging diagnosis of the anterior segment of the eye with high-frequency ultrasonic diagnostic equipment].

Micro-imaging displays of the anterior segment of the eye, such as of the anterior chamber angle, iris, ciliary body, ciliary zonule of Zinn, and anterior surface of the crystalline lens, were obtained in human eyes in vivo by means of a recently developed, high-frequency, high-resolution ultrasonic diagnostic unit (30 MHz). Much clearer displays than conventional ultrasonic imaging displays (5-15 MHz) were obtained, showing improved resolution, and greater morphologic diagnostic information was provided. Displays considered useful for making measurements were also provided. The subjects were 20 normal volunteers (35 eyes), 36 patients with glaucoma (58 eyes), 6 patients with uveal diseases (6 eyes), and 28 patients with pseudophakia (32 eyes). The equipment used was a model UX-02 ultrasonic diagnostic unit (RION), and the transducer was the three-element annular array type. The frequency was 30 MHz, the resolution was below 50 microns, and tissue penetration was 6 mm. This method enabled close ultrasound biomicroscopic imaging observations of details of the anterior and posterior chambers of the eyes in vivo and was also useful for clinical diagnosis and elucidation of the cause of glaucoma of various types. It also for the first time enabled evaluation of the position of fixation of an intraocular lens loop in the pseudophakic eyes containing an intraocular lens.

[Total parenteral nutrition and chemotherapy in cancer patients].

A common problem in cancer patients is a significant degree of malnutrition which disturbs and the accomplishment of surgery, chemotherapy and radiotherapy. Most patients with advanced cancer who should be treated with intensive chemotherapy are unable to ingest, digest or absorb sufficiently quantities of food and many antineoplastic agents affect the function of the alimentary tract. Therefore, total parenteral nutrition is a suitable method of nutritional support in these patients. The intravenous administration of nutrients can improve and maintain not only the nutritional status, but also the cell-mediated immunity of patients, and an effective or large doses of agents can be given as a result of increased tolerance. These effects are expected to enhance the potential of tumor response to chemotherapy. At the present time, only a few trials such as pulse TPN and amino acid imbalance therapy have been tried, but a specific nutritional regimen based on the altered metabolism in tumor and host should be developed in future.

[Comparison of continuous venous infusion of 5-FU and FT-207 under total parenteral nutrition].

Yoshida sarcoma-bearing rats were continuously infused with 5-FU at a dose of 20 mg/kg/day, and FT-207 at a dose of 40 mg/kg/day, 100 mg/kg/day or 140 mg/kg/day under TPN. After 4 days, rats were sacrificed and the 5-FU and FT-207 concentrations in their organs were measured. The 5-FU level in the tumor was almost the same at when 5-FU was injected at 20 mg/kg/day and FT-207 at 140 mg/kg/day. This 5-FU level in the tumor was twice and four times higher than that of the group injected with FT-207 at 100 mg/kg/day and 40 mg/kg/day. The 5-FU level in the tumor in all four groups was almost twice as high as that in the stomach, intestine and kidney, 7-10 times higher than that in the liver, and 10-30 times higher than that in serum. The FT-207 levels in the alimentary tract, kidney, tumor and serum were almost the same. The conclusion of our preliminary research is that FT-207 is recommended for use in continuous infusion at 7 times the dose of 5-FU when injected under TPN.

[Continuous venous infusion of 5-fluorouracil (5-FU) under total parenteral nutrition (TPN) in advanced gastric cancer].

Continuous venous infusion of 5-FU was investigated in patients with advanced gastric cancer under TPN. In preliminary research Yoshida Sarcoma-bearing rats were continuously infused with 5-FU at a dose of 20 mg/kg/day under TPN. The 5-FU level in the tumor was 2-5 times higher than that in the kidney, stomach, intestine and liver, and 40-50 times higher than that in serum. Advanced gastric cancer patients were continuously infused with 5-FU at a dose of 500 mg/day under TPN. Serum 5-FU level was constantly maintained at 0.05 mcg/ml during the infusion period. The effects of 5-FU continuously infused with other anticancer agents and TPN were satisfactory with regard to anticancer response and general condition. In conclusion, in advanced cancer, 5-FU is recommended for use in continuous infusion at a dose of 500 mg/day under TPN.

[The metabolic changes and nutritional management following radical surgery of esophageal cancer and total gastrectomy].

The metabolic changes after major surgery such as esophagectomy and total gastrectomy are remarkable. Postoperative levels of plasma catecholamines and glucagon were significantly higher in major surgery than those in the other operations (distal gastrectomy, cholecystectomy, mastectomy, etc). As the consequence of these hormonal changes, resting metabolic expenditure (RME) increased up to 30-40% above the predicted basal metabolic expenditure and blood glucose elevated to a high level. The relationships between RME, N-balance and energy intake after major surgery indicated that the intake of non-protein energy expenditure equal to RME was necessary in order to maintain N-balance. For the administration of enough energy after major surgery, TPN solution composed of glucose 180-240g, fructose 90-100g, xylitol 30-40g and amino acids 68-91g (the approximate weight ratio of G, F and X is 4: 2: 1) was developed since 1975 and in some cases, lipid solution was added as non-protein energy source. This solution was infused immediately after operation and no metabolic complications (hyper glycemia, acidosis, etc) were observed. This nutritional therapy has maintained the nutritional state of postoperative patients and improved our operative results. There are, however, many problems in the nutritional managements of the patients with severe complications and after the discharge of hospital. In the future, special nutritional therapy for these cases should be progressed.