Efficacy of percutaneous endoscopic gastro-jejunostomy (PEG-J) decompression therapy for patients with chronic intestinal pseudo-obstruction (CIPO).

BACKGROUNDS: Chronic intestinal pseudo-obstruction (CIPO) is an intractable rare digestive disease manifesting persistent small bowel distension without any mechanical cause. Intestinal decompression is a key treatment, but conventional method including a trans-nasal small intestinal tube is invasive and painful. Therefore, a less invasive and tolerable new decompression method is urgently desired. We conducted a pilot study and assessed the efficacy and safety of percutaneous endoscopic gastro-jejunostomy (PEG-J) decompression therapy in CIPO patients. METHODS: Seven definitive CIPO patients (2 males and 5 females) were enrolled. All patients received PEG-J decompression therapy. The number of days with any abdominal symptoms in a month (NODASIM), body mass index (BMI), serum albumin level (Alb), and small intestinal volume before and after PEG-J were compared in all patients. RESULTS: Percutaneous endoscopic gastro-jejunostomy was well tolerated and oral intake improved in all patients. NODASIM has significantly decreased (24.3 vs 9.3 days/months) and BMI/Alb have significantly increased (14.9 vs 17.2 kg/m2 and 2.6 vs 3.8 g/dL, respectively), whereas total volume of the small intestine has not significantly reduced (4.05 vs 2.59 L, P=.18). Reflux esophagitis and chemical dermatitis were observed in one case but was successfully treated conservatively. CONCLUSIONS & INFERENCES: Percutaneous endoscopic gastro-jejunostomy decompression therapy can contribute greatly to improvement of abdominal symptoms and nutritional status in CIPO patients. Although sufficient attention should be paid to acid reflux symptoms, PEG-J has the potential to be a non-invasive novel decompression therapy for CIPO available at home. However, accumulation of more CIPO patients and long-term observation are needed (UMIN000017574).

Progesterone antagonism of neurite outgrowth depends on microglial activation via Pgrmc1/S2R.

Neuronal plasticity is regulated by the ovarian steroids estradiol (E2) and progesterone (P4) in many normal brain functions, as well as in acute response to injury and chronic neurodegenerative disease. In a female rat model of axotomy, the E2-dependent compensatory neuronal sprouting is antagonized by P4. To resolve complex glial-neuronal cell interactions, we used the "wounding-in-a-dish" model of neurons cocultured with astrocytes or mixed glia (microglia to astrocytes, 1:3). Although both astrocytes and mixed glia supported E2-enhanced neurite outgrowth, P4 antagonized E2-induced neurite outgrowth only with mixed glia, but not astrocytes alone. We now show that P4-E2 antagonism of neurite outgrowth is mediated by microglial expression of progesterone receptor (Pgr) membrane component 1 (Pgrmc1)/S2R, a putative nonclassical Pgr mediator with multiple functions. The P4-E2 antagonism of neurite outgrowth was restored by add-back of microglia to astrocyte-neuron cocultures. Because microglia do not express the classical Pgr, we examined the role of Pgrmc1, which is expressed in microglia in vitro and in vivo. Knockdown by siRNA-Pgrmc1 in microglia before add-back to astrocyte-neuron cocultures suppressed the P4-E2 antagonism of neurite outgrowth. Conditioned media from microglia restored the P4-E2 activity, but only if microglia were activated by lipopolysaccharide or by wounding. Moreover, the microglial activation was blocked by Pgmrc1-siRNA knockdown. These findings explain why nonwounded cultures without microglial activation lack P4 antagonism of E2-induced neurite outgrowth. We suggest that microglial activation may influence brain responses to exogenous P4, which is a prospective therapy in traumatic brain injury.

Acquisition of multidrug resistance in recurrent breast cancer demonstrated by the histoculture drug response assay.

Recurrent breast cancer has a very poor response rate to chemotherapy. To understand the degree of acquisition of multidrug resistance in recurrent disease, 24 recurrent breast tumors and 127 primary tumors were evaluated and compared for chemosensitivity in the histoculture drug response assay (HDRA). The evaluation rate was 98.8%. The HDRA utilizes 3-dimensional culture of human tumors on collagen-gel rafts. Doxorubicin (DXR), 5-fluorouracil (5-FU) and mitomycin C (MMC) were tested as standard agents and cisplatin (CDDP) as a candidate agent on surgical specimen of breast cancer in the HDRA. In vitro drug exposure in the HDRA was for 7 days. At the end of the assay, tumor response was assessed by the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The mean inhibition rates of primary tumors vs. recurrent tumors were 57.9% and 38.6% for DXR (p<0.0005); 59.9% and 42.8% for MMC (p<0.01); 49.0% and 33.4% for 5-FU (p<0.01); and 34.5% and 16.0% for CDDP (p<0.005), respectively. The recurrent cases were pretreated clinically with CAF (cyclophosphamide, DXR and 5-FU), CEF (cyclophosphamide, epirubicin and 5-FU) or CMF (cyclophosphamide, methotrexate and 5-FU). In the CAF and CEF group, the HDRA sensitivity to CDDP was significantly lower in recurrent disease (p<0.005) than that of primary breast cancer suggesting that one agent can induce resistance to another. This is further suggested by the fact that 64.7% of the recurrent cases were resistant to all 4 agents tested as opposed to 27% of the primary cases and that only 5.9% of the recurrent cases were sensitive to three or more agents as opposed to 18% of the primary cases. The correlation of the HDRA results to clinical outcome in the study was 80.0% with 15 cases evaluated consisting of 5 true positives, 3 false positives, 7 true negatives and no false negatives. Thus, the HDRA gives useful clinical information, in particular for the specific individualized treatment design necessary to overcome the multidrug resistance problem of recurrent breast cancer.

An endovascular primate model for the production of a middle cerebral artery ischemic infarction.

SUMMARY: An endovascular model for producing and studying middle cerebral artery acute ischemic strokes was developed to avoid the need for an open surgical approach to the middle cerebral, anterior cerebral, posterior cerebral and internal carotid arteries. Endovascular occlusion of these vessels followed by Xenon-CT cerebral blood flow study confirmed the production of a middle cerebral artery distribution infarct in two primates. The methodology, advantages and drawbacks of this model are discussed.

BodyMap: a collection of 3' ESTs for analysis of human gene expression information.

BodyMap is a collection of site-directed 3' expressed sequence tags (ESTs) (gene signatures, GSs) that contains the transcript compositions of various human tissues and was the first systematic effort to acquire gene expression data. For the construction of BodyMap, cDNA libraries were made, preserving abundance information and histologic resolutions of tissue mRNAs. By sequencing 164,000 randomly selected clones, 88,587 GSs that represent chromosomally coded transcripts have been collected from 51 human organs and tissues. They were clustered into 18,722 independent 3' termini from transcripts, and more than 3000 of these were not found among ESTs assembled in UniGene (Build 75). Assessment of the prevalence of polyadenylation signals and comparison with GenBank cDNAs indicated that there was no significant contamination by internally primed cDNAs or genomic fragments but that there was a relatively high incidence (12%) of alternative polyadenylation sites. We evaluated the sensitivity and resolution of expression information in BodyMap by in silico Northern hybridization and selection of tissue-specific gene probes. BodyMap is a unique resource for estimation of the absolute abundance of transcripts and selection of gene probes for efficient hybridization-based gene expression profiling.

[Histoculture drug response assay on non-small cell lung cancer].

We examined the chemosensitivity of non-small cell lung cancer (NSCLC) tissues to CDDP, 5-FU, ADM, MMC, ETP and SN38 using histoculture drug response assay (HDRA). One-hundred and thirty surgical specimens from NSCLC patients who were not given preoperative chemotherapy were used. The inhibition indexes of CDDP, 5-FU, MMC, ADM, ETP and SN38 were 39.1 +/- 18.2%, 48.0 +/- 19.7%, 63.3 +/- 17.7%, 47.6 +/- 22.0%, 36.9 +/- 21.1%, and 37.9 +/- 25.2%, respectively. Inhibition indexes were above the cutoff level, i.e., 'judged sensitive,' in 40 cases (31.3%) for CDDP, 34 cases (27.4%) for 5-FU, 54 cases (44.3%) for MMC, 36 cases (33.0%) for ADM, 29 cases (29.8%) for ETP, and 34 cases (37.4%) for SN38, respectively. In almost one-third of patients, the inhibition indexes of all drugs were under cutoff levels. Correlations between in vitro chemosensitivity data and patient responses to chemotherapy were obtained from 16 evaluable patients, and a 44.4% true positive rate and a 100% true negative rate were observed. Our results with HDRA for NSCLC showed a high incidence of intrinsic multidrug resistance. HDRA may help doctors to avoid non-effective chemotherapy for NSCLC patients.

Disappearance curves for tumor markers after resection of intrathoracic malignancies.

Determination of the standard elimination kinetics of tumor markers will be helpful in the diagnosis of malignancies. We analyzed the disappearance curves for serum tumor marker levels after resection of intrathoracic malignancies. Serum levels of CEA, SLX, AFP, CA 19-9, SCC, TPA and CYFRA were measured several times after surgery in a total of 40 patients. To obtain precise biological half-lives, we applied non-linear least square analysis, taking into consideration the possibility of residual tumor cells. Disappearance curves were monophasic for CEA, SCC, TPA, CYFRA and SLX and biphasic for CA 19-9 and AFP. Temporary elevation of serum levels after surgery was observed for SCC, TPA and CYFRA. The average half-lives of CEA, SLX, SCC, TPA and CYFRA were 1.5 days, 2.7 days, 2.2 hours, 2.5 hours and 1.5 hours, respectively. The average half-life of CA 19-9 was 0.5 days in the first compartment and 4.3 days in the second compartment, while that of AFP was 1.0 days and 6.3 days, respectively. These values will be helpful in the interpretation of serum tumor marker levels after surgery.

[Surgical treatment of lung cancer with chest wall invasion].

From January 1986 to May 1998, 45 lung cancer patients with chest wall invasion (P3) underwent resection (40 male, 5 female), (median age 63.2 yrs (30-79)). Histological types were squamous cell carcinoma in 20, adenocarcinoma in 14, large cell carcinoma in 7, adenosquamous cell carcinoma in 2, and unknown in 2. Operative methods of lung resection were total pneumonectomy in 2, bilobectomy in 3, lobectomy in 38, and partial lung resection in 2. Resection was regarded as complete in 35 and incomplete in 10 patients. Thirty one patients had negative lymph nodes (N0), 9 had peribronchial or hilar lymph node metastases (N1), and 5 had mediastinal lymph node metastases (N2). The extent of tumor invasion to chest wall was P3a (invasion within parietal pleura) in 11, P3b-c (invasion to intercostal muscle) in 16, P3d (invasion to rib) in 18, patients. 5-year survival rate was totally 19.7%. Cisplatin based chemotherapy and concurrent thoracic radiation following surgery (CCRT) was performed in latest nine P3d cases. Partial response was observed in 5 of 9 cases (response rate 56%) and viable tumor cell in the primary site was not seen histologically in 5 of 9 cases. Three year survival rate was 46.9% for CCRT(+) 11.1% for CCRT(-). Acturial 5-year survival rate in P3a-d was 19.76%. P3d cases had poor survival, but CCRT improved prognosis of P3d cases.

[Induction chemotherapy based on histoculture drug response assay for a patient with advanced thymic cancer--a case report].

Histoculture drug response assay (HDRA) was applied to a biopsy specimen of advanced thymic cancer from a 68 years-old male patient. HDRA revealed that the tumor was not sensitive to CDDP but highly sensitive to 5-FU, ADM and MMC, which were administered as induction chemotherapy. The tumor regressed to 14% of the pretreatment size and was able to be completely resected with right and left brachiocephalic veins, superior vena cava, pericardium, right phrenic nerve and a part of right lung. Histologically, only a few small cancer nests remained in the fibrous tissue. The patient is alive and disease free 32 months after surgery. This result suggests that HDRA is useful to select anticancer agents which are sensitive to a rare kind of carcinoma such as thymic cancer.

Analysis of the early postoperative serum carcinoembryonic antigen time-course as a prognostic tool for bronchogenic carcinoma.

BACKGROUND: The serum kinetics of carcinoembryonic antigen (CEA) after resection of lung carcinoma are not well characterized. Its prognostic implications remain unclear. This study was designed to clarify the correlation between postoperative CEA time-course and patient prognosis. METHODS: The authors analyzed early postoperative CEA time-course in 31 lung carcinoma patients using nonlinear least square analysis with the following three equations: Equation 1: C(t) = C(0); Equation 2: C(t) = C(0)exp(-kt); and Equation 3: C(t) (C(0)PLAT)exp(-kt) + PLAT, in which t: postoperative day; C(t): postoperative CEA; PLAT: postoperative CEA at plateau; C(0): CEA at postoperative Day zero; and k: rate constant of elimination. The equation that yielded the least Akaike's information criterion was adopted as the best fitting regression equation for each patient. When Equation 3 was adopted, postoperative CEA production (PROD) was calculated as PLAT multiplied by k. RESULTS: Equations 1, 2, and 3 were adopted for 16 (Group 1), 0, and 15 (Group 2) patients, respectively. In Group 1, no decrease in serum CEA level after surgery was detected and CEA production appears to have been little or none. In Group 2, biologic CEA half-life was 1.1 +/- 0.7 days and was not useful for predicting patient prognosis. Tumor recurrences were observed in 9 of the Group 2 patients 19 +/- 9 months postoperatively and there was no significant difference in PLAT or PROD between patients with and without recurrence. Early recurrence within 6 months after surgery was recognized in 5 (early-REC) of the 15 Group 2 patients, in whom there was a tendency for PLAT to be higher than in the other 10 patients without recurrence (early-NON) (early-REC: 3.8 +/- 4.9 ng/mL; early-NON: 1.5 +/- 1.1 ng/mL; P = 0.08). PROD was significantly higher in early-REC than in early-NON (early-REC: 3.5 +/- 4.2 ng/mL/day; early-NON: 0.8 +/- 0.4 ng/mL/day; P < 0.05). CONCLUSIONS: Although PROD is more sensitive than PLAT, both parameters appear to be useful as prognostic tools for predicting early recurrence after resection of lung carcinoma. This is probably because they represent the number of residual tumor cells immediately after surgery.