Sustained effects of intralymphatic pollen-specific immunotherapy on Japanese cedar pollinosis.

BACKGROUND: Intralymphatic immunotherapy (ILIT) for allergic patients requires only a few intralymphatic injections of the allergen. However, the effectiveness and safety for Japanese cedar pollinosis are unclear. The objectives of this study were to clarify whether and how long ILIT is effective for pollinosis, and its safety. METHODS: In an open pilot investigation followed by a double-blind, placebo-controlled study, patients with Japanese cedar pollinosis received 3 intralymphatic inguinal injections of the pollen extracts before the first pollen season. The symptom medication score (SMS), nasal provocation testing and scoring visual analogue scale (VAS) were assessed after the first-third seasons. RESULTS: (1) Although mild adverse events were induced at the injected site, severe adverse events were not noted. (2) During the latter part of the first season, ILIT-treated patients (n=12) tended to show improved SMS compared to placebo-treated (n=6) without statistical significance. When assessed by nasal provocation testing and VAS scoring after the first season, the effectiveness of ILIT was significant. (3) The effects of ILIT continued until the second or third season. (4) Neither allergen-specific antibodies nor Treg/Breg cells changed in the peripheral blood. CONCLUSIONS: ILIT was safe and effective for Japanese cedar pollinosis. The clinical effects remained for 1-2 years.

Novel scoring system and algorithm for classifying chronic rhinosinusitis: the JESREC Study.

BACKGROUND: Chronic rhinosinusitis (CRS) can be classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). CRSwNP displays more intense eosinophilic infiltration and the presence of Th2 cytokines. Mucosal eosinophilia is associated with more severe symptoms and often requires multiple surgeries because of recurrence; however, even in eosinophilic CRS (ECRS), clinical course is variable. In this study, we wanted to set objective clinical criteria for the diagnosis of refractory CRS. METHODS: This was a retrospective study conducted by 15 institutions participating in the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC). We evaluated patients with CRS treated with endoscopic sinus surgery (ESS), and risk of recurrence was estimated using Cox proportional hazard models. Multiple logistic regression models and receiver operating characteristics curves were constructed to create the diagnostic criterion for ECRS. RESULTS: We analyzed 1716 patients treated with ESS. To diagnose ECRS, the JESREC scoring system assessed unilateral or bilateral disease, the presence of nasal polyps, blood eosinophilia, and dominant shadow of ethmoid sinuses in computed tomography (CT) scans. The cutoff value of the score was 11 points (sensitivity: 83%, specificity: 66%). Blood eosinophilia (>5%), ethmoid sinus disease detected by CT scan, bronchial asthma, aspirin, and nonsteroidal anti-inflammatory drugs intolerance were associated significantly with recurrence. CONCLUSION: We subdivided CRSwNP in non-ECRS, mild, moderate, and severe ECRS according to our algorithm. This classification was significantly correlated with prognosis. It is notable that this algorithm may give useful information to clinicians in the refractoriness of CRS before ESS or biopsy.

Enhanced production and activation of progelatinase A mediated by membrane-type 1 matrix metalloproteinase in human oral squamous cell carcinomas: implications for lymph node metastasis.

We measured the production levels of seven different matrix metalloproteinases (MMP-1, 2, 3, 7, 8, 9 and 13) and two tissue inhibitors of metalloproteinases (TIMP-1 and 2) in the homogenates of human oral squamous cell carcinomas and control normal squamous epithelia by the corresponding sandwich enzyme immunoassay systems. The levels of MMP-1, 2, 3, 8, 9, 13 and TIMP-1 were significantly higher in the carcinoma samples than in the control. Among them, only the production level of MMP-2 was significantly higher in the carcinomas with cervical lymph node metastasis than in those without metastasis (P < 0.05). Gelatin zymography demonstrated that activation ratio of the zymogen of MMP-2 (proMMP-2) is significantly higher in the carcinomas with lymph node metastasis than in those without metastasis (P < 0.05) or normal control (P < 0.01). Quantitative RT-PCR for membrane-types 1, 2 and 3 MMPs (MT1, 2 and 3-MMPs), which activate proMMP-2 in vitro, demonstrated that MT1-MMP is predominantly expressed in the carcinoma tissues, and the expression level is significantly higher in the carcinomas with lymph node metastasis than in those without metastasis (P < 0.05) or the control samples (P < 0.05). Although MT2-MMP and MT3-MMP were detected in approximately 30% of the carcinoma cases, their expression levels were extremely lower compared with that of MT1-MMP. There was a direct correlation between the MT1-MMP expression level and proMMP-2 activation ratio (r = 0.62, P < 0.01). In situ hybridization and immunohistochemistry indicated that carcinoma cells and stromal cells adjacent to carcinoma cell nests express MT1-MMP transcripts and protein. MMP-2 and TIMP-2 were also immunolocalized to the carcinoma cells in the carcinoma samples. By in situ zymography, gelatinolytic activity was demonstrated in the carcinoma cell nests and abolished by the treatment with an MMP inhibitor, BB94. These results suggest that among seven different MMPs, the production of proMMP-2 and its activation mediated by MT1-MMP play an important role in the cervical lymph node metastasis of the human oral squamous cell carcinomas.

The effects of inversed ratio ventilation (IRV) on arterial oxygenation during mechanical ventilation in patients with acute respiratory failure.

We investigated the effects of inversed ratio ventilation by altering the inspiratory:expiratory (I:E) ratio and assessing the time course changes in the intrapulmonary shunting (Qs/Qt) in 14 patients with acute respiratory failure. Stepwise prolongation of the I:E ratio from 1:1.9 to 2:1 and then to 2.6 or 4:1 was applied when PEEP failed to raise the PaO2 above 80 mmHg while breathing oxygen. A significant decrease in Qs/Qt was observed following prolongation of the I:E ratio from 1:1.9 (Qs/Qt = 45 +/- 9%) to 2:1 (Qs/Qt = 29 +/- 9%) but not with further prolongation of the I:E ratio (Qs/Qt = 27 +/- 7%). Improvement of the pulmonary ventilation/perfusion imbalance became more marked with continued IRV and a significant increase in PaO2 was observed at 6 h after initiating prolongation of the inspiratory time (P less than 0.05). There were no significant changes in hemodynamics, PaCO2, or peak inspiratory pressure during IRV. This ventilatory pattern may be indicated when PEEP fails to improve PaO2, but prolongation of the inspiratory time above an I:E ratio of 2:1 did not produce a greater improvement in Qs/Qt and further increases in PaO2 did not occur after more than 10 h of IRV in our 14 patients.

[Comparison of intraocular penetration level of cefuzonam sodium and cefotiam after intravenous and subconjunctival injection].

We investigated the intraocular penetration of a new Cephem type antibiotic: Cefuzonam sodium (CZON) following intravenous and subconjunctival injection. CZON was administered to 28 eyes in 26 patients by 1 g intravenous injection (IV) and to 11 eyes in 10 patients by 20 mg/0.2 ml subconjunctival injection (SCI). The penetration level of CZON by the IV method was from less than 0.0025-3.35 micrograms/ml into aqueous humor, from less than 0.0025-0.315 microgram/mg into iris tissue and 2.7-157.5 micrograms/ml into serum. The penetration level of CZON by the SCI method was from less than 0.0025-12.8 micrograms/ml into aqueous humor, from less than 0.0025-0.0426 microgram/mg into iris tissue and 1.03-18.5 micrograms/ml into serum. The penetration level of CZON into aqueous humor by SCI was higher than by IV administration. In comparison with the penetration level of CZON and Cefotiam (CTM), both aqueous humor and serum levels of CTM were higher than those of CZON. These results suggested that therapeutic levels in aqueous humor effective against gram-positive and gram-negative pathogens were achieved with the 1 g IV and 20 mg SCI of CZON. However levels effective against Staphylococcus epidermidis were only erratically attained.

[Private practitioner & clinical laboratory physicians].

The clinical(laboratory) examiner should know how to accommodate clinical necessity. Instead of the real necessity(patient's needs), the clinical examination is dependent on the physician's own clinical skill. That is clinical laboratory examinations are ordered by the doctor's own clinical experiments and data is judged and analyzed by the mass standardized levels. Each patient's own bias must be ignored. From the medical practitioner's viewpoint(who is running his own clinic), it is desirable to have personal laboratory levels to have person-to-person and tailor-made medical management. Above all, for the futuristic medical examiner, we suggest urgent development of several parameters which will easily describe personal basic laboratory levels. (We applied for the patient of "Vessel Age" as for the new personal basic laboratory level to show atherosclerotic degeneration.)

[Differential effects of isosorbide dinitrate and nitroprusside on pial vessel diameter in cats].

Changes in pial vessel diameter combined with regional cerebral blood flow (CoBF) during infusion of vasodilating drugs, isosorbide dinitrate (ISDN) 5 micrograms/kg/min and nitroprusside (NTP) 5 micrograms/kg/min, compared with haemorrhagic hypotension were studied in cats anesthetized with halothane (1.0%). Pial arteries and veins were measured by image-splitting technique and were each divided into three groups according to the reference diameter: I; < 50 microns, II; 51 < microns < 100, III; 101 < microns. With either drug, the mean blood pressure (mBP) decreased by 10-20%. There was significant decrease in cerebral vascular resistance with ISDN compared with haemorrhagic hypotension while CoBF (H2 clearance) remained unchanged. Dilatation of pial arteries depending on vessel size with ISDN was two-hold compared with haemorrhagic hypotension without any change in all veins. Consistent and significant dilation of veins (I and II) was observed only during NTP infusion. These findings indicate the differential effect of ISDN and NTP on pial arteries and veins.

[Perioperative management of endovascular stent graft placement for abdominal aortic aneurysm].

We retrospectively examined the changes in hemodynamics, oxygen index and renal function along with the complications in 25 patients who had undergone endovascular stent graft placement (ESG) surgery for abdominal aortic aneurysm. During stent graft placement, mean arterial pressure decreased to 58 +/- 8 mmHg by increasing the dose of anesthetics and/or using vasodilators. Except for this intended hypotensive period, mean arterial pressure and heart rate were relatively stable and adequately maintained during surgical manipulation. Oxygenation index was well maintained. A patient with a high preoperative creatinine level underwent prophylactic hemodialysis postoperatively. In other patients except one who died in early postoperative period, both BUN and creatinine levels were kept within normal ranges. Four patients died postoperatively and the causes of the death in two patients are related to the surgical procedure; one with multiple emboli possibly due to released atheloma from the aortic wall during procedure, the other with sepsis due to infected stent graft. Although ESG is a well tolerated procedure, embolism is the most serious complication. Careful preoperative evaluation of the ascending arch and descending aortic wall and monitoring with transcranial doppler are necessary.

[Assessment of ventriculoarterial coupling in humans by transesophageal echocardiography and radial artery pressure tracing].

To investigate coupling between the heart and arterial system in patients undergoing elective non-cardiac surgery, we determined both the ventricular elastance and the effective arterial elastance in two groups of subjects: normal group, 68 subjects without heart disease; and cardiac group, 33 subjects with heart disease. Left ventricular end-systolic (Ves) and end-diastolic (Ved) volumes were determined by transesophageal echocardiography. By assuming that left ventricular end-systolic pressure (Pes) is close to mean arterial blood pressure (MAP) and that x-axis intercept (Vo) is zero, the ventricular elastance (E'max) was approximated as MAP/Ves, and the effective arterial elastance (Ea) as MAP/(Ved-Ves). In 222 (74%) of the 299 measurements obtained in normal group, Ea/E'max was nearly 0.5, which is a condition for a maximal mechanical efficiency, while in 61 measurements (20%) Ea was almost equal to E'max (Ea/E'max = 1), which is a condition for maximal stroke work from a given end-diastolic volume. In contrast, in cardiac group, Ea/E'max was nearly 0.5 in 56 (41%) of the 137 measurements, while in 42 measurements (31%) Ea/E'max was nearly 1. In addition, although the value of Ea/E'max over 2, which represents severe heart failure, was not observed in normal group, Ea/E'max was over 2 in 10 measurements (7%) in cardiac group. Thus, the present results suggest that, as reported previously in awake patients, ventriculoarterial coupling is set toward higher left ventricular work efficiency in surgical patients without heart disease, whereas in patients with heart disease, ventricular and arterial properties are so matched as to maximize stroke work at the expense of the work efficiency.

[A long-term survival case of advanced gastric cancer undergoing radical gastrectomy by second-look operation after successful chemotherapy (CDDP, MMC, 5-FU)].

A 55-year-old woman with gastric cancer underwent laparotomy and was found to have an unresectable tumor characterized by S3 (invasion of the pancreas), N3, P0 and H0. She was then treated by combined administration of cisplatinum, mitomycin C and 5-fluorouracil. A remarkable response (CR) was confirmed by upper gastrointestinal roentgenography and endoscopy. Upon reoperation about 8 weeks after chemotherapy, a successful radical total gastrectomy with R2 (partially R3) lymphnode dissection was performed. Histological examination of the specimens, including the stomach and lymphnodes, revealed no cancer cells in any region (pCR). She had been given UFT and PSK for 4 years 4 months after reoperation. She has lived for 5 years 2 months after reoperation without any signs of recurrence or metastases.

[Advanced gastric cancer successfully resected following cisplatin therapy. A case report].

A case of unresectable advanced gastric cancer (portion A, Min, S3 infiltrating into pancreas, N3, por., Borrmann III-type, hen's egg size) was treated with cis-dichlorodiammine platinum (CDDP) at a dosage of 30 mg/day for five days every month following surgery. After three courses of administration, examinations revealed that the tumor had disappeared and an evaluation of complete response was made. Four months later, a second-look operation was performed. It was found that the cancer was less than thumbsize and was able to be resected radically. No significant side effects were observed during CDDP therapy.

[Successful treatment of advanced gastric cancer by combined cisplatinum, mitomycin C and 5-FU administration. A case report].

A 55-year-old woman with gastric cancer underwent laparotomy and was found to have an unresectable tumor at the MC region, characterized by S3 (invasion into the pancreas), N3, P0, H0, Borrmann-II and moderately differentiated tubular adenocarcinoma. She was then treated by combined administration of cis-dichlorodiammine platinum (CDDP), mitomycin C and 5-fluorouracil (5-FU). A complete response was confirmed by upper gastrointestinal roentgenography and endoscopy. Upon reoperation 4 months after the initial laparotomy, a successful total radical gastrectomy with R2 (partially R3) lymph node dissection was performed. Histological examination of the specimens, including the stomach and lymph nodes, revealed no cancer cells in any region.

[A case of congenital laryngeal web with subglottic stenosis].

A severe case of congenital laryngeal web with subglottic stenosis was reported. The patient had weak crying after birth and stridor was noticed from one month old. He had tracheostomy at two month old and the incision of the web was attempted under laryngomicrosurgery with CO2 LASER, although the attempt failed due to combined subglottic stenosis. The "trough method" was applied at the age of one year. The web was incised and subglottic granulation including the excessive cartilaginous tissue was removed through a laryngotracheal fissure. A piece of silicone membrane was inserted between the vocal cords preventing from adhesion and a silicone tube stent was also inserted into the subglottic space and trachea to keep the laryngotracheal space open widely. After one month and a half, the silicon membrane and silicon tube were removed and a silicon T-tube was inserted instead of the silicon tube. The anterior wall of the laryngotracheal space was closed using a hinge flap. The patient can vocalize and does not complain of dyspnea at present, one year after the removal of the T-tube.

[Matrix metalloproteinase-2 concentrations in squamous cell carcinoma of the head and neck and its clinical significance].

Tumor cells degrade extracellular matrix components (ECM) to invade surrounding tissues. Cancer cells are known to produce various ECM-degrading enzymes including matrix metalloproteinases (MMPs), serine proteinases and cathepsins. Type IV collagen is one of the major components of the basement membrane, and it composes the structural scaffold of these specialized sheets of the ECM. The enzymatic degradation of type IV collagen is initiated by MMPs, in particular MMP-2 (a 72 kDa type IV collagenase) and MMP-9 (a 92 kDa type IV collagenase) which play a key role in cancer invasion and metastasis. In this study, we investigated MMP-2 concentrations and the activity of type IV collagenase in cancer tissue homogenate in 21 cases with head and neck carcinomas and 6 cases with normal mucosa. MMP-2 concentrations did not differ between normal mucosa and tumor tissue without lymphnode metastases. Type IV collagenase activity in normal mucosa was below the detection limit. MMP-2 concentrations had no relation to tumor size, however MMP-2 concentrations in tumor tissue with lymphnode metastases were higher than that in cases without lymphnode metastasis (35.8 +/- 20.5, 20.0 +/- 9.7 ng/mg protein, respectively). However, there was no correlation between MMP-2 concentrations and type IV activity in tumor tissues. These results suggest that MMP-2 plays an important role in tumor invasion and metastasis, so MMP-2 could be a useful biological tumor marker for metastasis and prognosis.

[Study of matrix metalloproteinase-2 and -9 in thyroid papillary cancer].

Metastasis of cancer starts with the penetration of cancer cells through the membrane surrounding the cancer focus into the stroma (extracellular matrix). The focal membrane consists of mainly type-IV collagen. An immunochemical study of 28 patients with benign thyroid nodular diseases and 27 patients with papillary carcinoma revealed the fragmentation of type-IV collagen in 4 patients with papillary carcinoma. Matrix metalloprotease (MMP)-2 and MMP-9 are the major enzymes which decompose type-IV collagen, and they have been suggested to be related to cancer metastasis. Therefore, we conducted biochemical and immunohistochemical studies to determine the relationship between these MMPs and the degree of malignancy in thyroid diseases. The concentration of MMP-2 in the serum of patients with papillary carcinoma and patients with benign nodules was 526.0 +/- 96.6 and 522.7 +/- 114.6 ng/ml, respectively, and that of MMP-9 was 53.8 +/- 40.3 and 39.9 +/- 36.0 respectively. There was no significant difference between the two groups in the concentration of either enzyme. The concentration of TIMP-2 in the serum was below the detectable level. On the other hand, the concentration of MMP-2 in the tissue of papillary carcinoma, benign nodules and normal tissue was 12.1 +/- 8.1, 5.7 +/- 4.3, and 0.6 +/- 0.5 ng/mg tissue protein, respectively, and that of MMP-9 was 4.2 +/- 4.1, 2.1 +/- 1.7, and 0.4 +/- 0.3 ng/mg tissue protein, respectively. Concentrations of both enzymes were significantly higher in the papillary carcinoma tissue. Immunohistochemical studies revealed a diffuse granular distribution of MMP-2 in the cytoplasm of the tumor cells. These findings imply that MMP-2 and MMP-9 are related to the degree of malignancy of cancer, especially metastasis.

[Value of upper gastrointestinal endoscopic examination of head and neck cancer patients].

Between January 1995 and March 1999, we performed the upper gastrointestinal endoscopic examinations on 287 patients with head and neck cancers and detected 23 cases (8%) of esophageal cancer and 8 cases (2.8%) of gastric cancer, showing how frequently esophageal cancer occurs in head and neck cancer. The esophageal cancer involved the oral cavity in 8 cases (9.5%), the oropharynx in 3 cases (8.6%), the hypopharynx in 10 cases (19.6%), and the larynx in 2 cases (2%). Esophageal cancer occurred most frequently in hypopharyngeal cancer, particularly the pyriform sinus type and the postcricoid type. We conclude that upper gastrointestinal endoscopic examination, including Lugol staining, is necessary in head and neck cancer patients.

[Experimental study on quantitative evaluation of fatty liver by computed tomography].

Biochemical, histological and CT examinations of the liver were performed in 32 rabbits on significance of measuring CT values in the diagnosis of fatty liver. In 2 groups of rabbits, in which 2g/kg/day and 4g/kg/day of fat emulsion were administered intravenously for 4 weeks respectively, post-treatment reduction in CT value of light degree was observed. In a group, in which 8g/kg/day were given, there was a sufficient reduction in CT value for giving diagnosis of fatty liver of moderate degree. Significant correlation was found between changes in CT value of the liver on the one hand and contents of triglyceride, total cholesterol and cholesterol ester in the liver on the other hand, while there was, no significant correlation between changes in CT value and contents of phospholipid, protein and water. Significant correlation was found between changes in CT value of the liver and degrees of histological fat accumulation in the liver cells. It has been evidenced experimentally that prolonged administration of fat emulsion may cause fatty liver, and that measurement of CT values of the liver is a non-aggressive method of diagnosing fatty liver.