A phase I trial of isolated hepatic perfusion (IHP) using 5-FU and oxaliplatin in patients with unresectable isolated liver metastases from colorectal cancer.

BACKGROUND: Isolated hepatic perfusion (IHP) with melphalan is an established approach for patients with unresectable metastatic liver lesions. This study determined the safety and maximum tolerated dose (MTD) of 5-FU with oxaliplatin via IHP. METHODS: Standard 3 × 3 Phase I design. Subjects with unresectable isolated CRC liver metastases scheduled for HAI pump were eligible. IHP used fixed-dose oxaliplatin with escalating 5-FU doses. Toxicity (CTCAE v 4.0) and response (RECIST), progression-free survival, and overall survival (OS) were assessed. Systemic and IHP plasma PK of 5-FU, anabolites, and platinum were determined. RESULTS: All 12 patients had received ≥ 1 line of pre-IHP chemotherapy. There were 4 grade 3 serious adverse events (33.3 %) and 1 grade 4 event (8.3 %). Also, 2 dose-limiting toxicities occurred at DL2 at 300 mg/m(2), resulting in expansion of DL1 at 200 mg/m(2) 5-FU, the eventual MTD. At 6-month follow-up, 9 patients (82 %) demonstrated partial response, while 2 (18 %) exhibited stable disease. Also, 64 % of patients demonstrated a >50 % decrease in CEA. The 1- and 2-year OS probabilities were 90.9 and 71.6 %, respectively, with median follow-up of 24 months. IHP exposures (AUC0-60 min) were 10.9 ± 4.5 µgPt h/mL, 49.3 ± 30.7 µg h/mL 5-FU (DL1), and 70.5 ± 35.5 µg h/mL 5-FU (DL2). Systemic exposure (AUC0-inf) relative to IHP exposure was negligible for both platinum (1.1 ± 1.5 %) and 5-FU (0.09 ± 0.10 %). CONCLUSIONS: The MTD for IHP was 200 mg/m(2) 5-FU with 40 mg/m(2) oxaliplatin. Systemic exposure to the agents was minimal during IHP. The response and survival observed warrants assessment in a larger phase II trial.

The Pech-de-l'Azé I Neandertal child: ESR, uranium-series, and AMS 14C dating of its MTA type B context.

The Pech-de-l'Azé I skull and mandible are included in the juvenile Neandertal remains from Europe. However, some preserved features in the cranial skeleton seem to distinguish the specimen from other Neandertal children. Unfortunately, the stratigraphic position and dating of this child has never been clear. Our recent work on unpublished archives show that the Pech-de-l'Azé I Neandertal child was discovered at the bottom of layer 6, attributed to the Mousterian of Acheulean tradition type B. These skull and mandible are the first diagnostic human remains (aside from an isolated tooth) attributed to the Mousterian of Acheulian tradition (MTA) type B. Consequently, we confirm that Neandertals were the makers of this Mousterian industry, which is characterized by unusual high frequencies of Upper Paleolithic type tools, elongated blanks and blades. We were able to date the context of the hominid remains by dating layer 6 and the layers above and beneath it using ESR, coupled ESR/(230)Th/(234)U (coupled ESR/U-series), and AMS (14)C. Coupled ESR/U-series results on 16 mammalian teeth constrain the age of the uppermost layer 7 to 41-58ka, and layer 6 to 37-51ka. The wide spread in each age estimate results mainly from uncertainties in the gamma-dose rate. These ages are concordant with AMS (14)C ages of two bones coming from the top of layer 6, which provide dates of about 41.7-43.6ka cal BP. A combination of stratigraphic arguments and dating results for layers 6 and 7 show that the Neandertal child cannot be older than 51ka or younger than 41ka. The lowermost layer 4 is shown to be older than 43ka by the principle of superposition and ESR dating in the immediately overlying layer 5. This study shows that the MTA type B had been manufactured by Neandertals before the arrival of anatomically modern humans in the local region. Additionally, by providing a firm chronological framework for the specific morphometric the features of Pech-de-l'Azé I Neandertal child, this study is a new step toward the understanding of temporal and spatial changes in the ontogenesis of Neandertals in south-western Europe during oxygen isotope stages 5-3.

Laparoscopic hiatal hernia repair in patients with poor esophageal motility or paraesophageal herniation.

Laparoscopic repair for gastroesophageal reflux disease is now an accepted therapy. However, controversy exists with regard to the choice of operation between complete 360-degree Nissen fundoplication versus partial 270-degree Toupe fundoplication. In addition there is some controversy with regard to the proper choice of operation in patients with poor esophageal motility. Another class of hiatal hernia patients are those patients with paraesophageal herniation. Questions regarding the approach to these patients include whether or not to use a reflux procedure at the time of repair and the role of mesh in repair of these large hernias. This retrospective study was undertaken to compare the results of laparoscopic Nissen fundoplication and Toupe fundoplication in patients with both normal and abnormal esophageal motility. In addition the subset of patients with paraesophageal herniation was studied in an effort to ascertain the best surgical approach in these patients. In this study a retrospective analysis was performed on 188 consecutive patients during the period 1995 to 2001. All patients who presented with hiatal hernia surgical problems during this period were included. Endoscopy was performed in all patients with esophageal reflux. Manometry was performed in all patients except those presenting as emergency incarcerations. pH probe testing was performed in those patients in whom it was deemed necessary to establish the diagnosis. Upper gastrointestinal radiographs were used to define anatomy in paraesophageal hernia patients when possible. All patients with esophageal reflux were first treated with a trial of medical therapy. Patients with esophageal reflux and normal esophageal motility underwent 360-degree Nissen fundoplication. Those patients with poor esophageal motility (less than 65 mm of mercury) underwent laparoscopic 270-degree Toupe fundoplication. Patients presenting with paraesophageal herniation underwent laparoscopic repair. When possible esophageal manometry was performed on these patients preoperatively and if normal peristalsis was documented a Nissen fundoplication was performed. If poor esophageal motility was documented before surgery a Toupe fundoplication was performed. Mesh reinforcement of the diaphragmatic hiatus was used if necessary to complete a repair without tension. Patients were followed both by their primary gastroenterologist and their surgeon. Follow-up studies including endoscopy, pH probe, and upper gastrointestinal series were used as necessary in the postoperative period to document any problems as they occurred. Of the 188 patients in the study 141 patients underwent Nissen fundoplication, 21 patients underwent Nissen fundoplication and repair of paraesophageal hernia, 15 underwent Toupe fundoplication, seven underwent Toupe and paraesophageal hernia repair, and four paraesophageal hernia repair alone. One hundred eighty-three patients underwent a laparoscopic operation. Five patients of the 188 underwent an initial open operation-two of these patients because of the size of their paraesophageal hernia. Three of these patients had reoperations of remote operations done years before at other institutions. Twenty-two patients with poor esophageal motility (11.7 %) were included in the study. Fifteen patients required Toupe fundoplication whereas seven patients required Toupe fundoplication and repair of paraesophageal hernias. Mesh repair of paraesophageal hernias was accomplished in ten patients. Patients undergoing Toupe fundoplication had a 13 per cent dysphagia rate less than 4 weeks postoperatively and a 0% dysphagia rate greater than four weeks postoperatively. Patients undergoing Nissen fundoplication had a 16 per cent dysphagia rate less than 4 weeks postoperatively, 2 per cent dysphagia rate greater than 4 weeks postoperatively and no dysphagia at 6 weeks postoperatively. Recurrent symptomatic reflux occurred in 1.4 per cent of Nissen fundoplications and 6.7 per cent of Toupe fundoplications. Of Nissen and paraesophageal repairs 14.2 per cent had reflux and 14.3 per cent of Toupe and paraesophageal repairs had recurrent symptomatic reflux. Overall, complication rate was low. Use of mesh to repair large paraesophageal hernias resulted in a recurrence rate of 0 per cent. There was no instance of infection or bowel fistulization related to the use of mesh. We conclude that laparoscopic Nissen fundoplication in patients with normal esophageal motility is associated with a low rate of dysphagia and a low rate of recurrent reflux. Toupe fundoplication when used in reflux patients with poor esophageal motility is associated with a low rate of dysphagia and an acceptable rate of recurrent reflux. Laparoscop

Induction of tyrosinase gene transcription in human iris organ cultures exposed to latanoprost.

OBJECTIVE: Topical administration of latanoprost sometimes induces gradual iris darkening. The present study was undertaken to determine if latanoprost can increase transcription of the gene for tyrosinase, an important enzyme in the biosynthesis of melanin. Results from brown, hazel, and blue irides were compared. METHODS: Iris tissue was isolated from 30 pairs of postmortem human donor eyes, and 2 iris segments from each eye were incubated in tissue culture medium supplemented with 200nM latanoprost acid or vehicle for 7 days. Tyrosinase messenger RNA (mRNA) was determined using real-time polymerase chain reaction analysis (TaqMan quantitative polymerase chain reaction). Results for tyrosinase mRNA were normalized according to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA in each sample. RESULTS: Tyrosinase mRNA expression was similar in blue and hazel irides, and ranged from 0.7-fold to 12.6-fold greater than GAPDH expression. In contrast, control brown iris culture tyrosinase expression ranged from 6.4-fold to 265-fold greater than GAPDH expression. Induction of tyrosinase mRNA by latanoprost was below threshold in all the blue iris cultures (n = 8 pairs), present in 1 of 9 hazel iris cultures, and present in 5 of 13 brown iris cultures. Mean induction in the responding hazel iris cultures was 1.40-fold. Mean induction among the responding brown iris cultures was 2.97-fold. CONCLUSIONS: These observations support the view that iris darkening associated with latanoprost treatment reflects induction of tyrosinase expression. Moreover, they suggest that the probability that latanoprost will increase tyrosinase expression is directly related to the magnitude of tyrosinase expression before treatments are initiated. CLINICAL RELEVANCE: The variability of iris darkening with latanoprost may reflect natural variation in the basal transcription of tyrosinase.

Feasibility of using GFP-expressing Escherichia coli, coupled with fluorimetry, to determine protozoan ingestion rates.

The feasibility of using a live Escherichia coli population, which had been engineered to express the green fluorescent protein (GFP), coupled with fluorimetry, was tested as a means for determining protozoan ingestion rates. Its potential use was based on evidence that once cells are acidified, e.g. in a food vacuole, the fluorescence is lost. Of the 29 protozoa tested, over 85% ingested the GFP-expressing E. coli and a detailed experiment with the ciliate Tetrahymena pyriformis was carried out, principally to assess the performance of the live bacterium against two commonly used surrogate prey, i.e. fluorescently labelled bacteria (FLB) and fluorescently labelled microspheres (FLMs). A decrease in GFP-expressing E. coli fluorescence and, hence, concentration, was recorded by fluorimetry and epifluorescence microscopy, with calculated ingestion rates being equivalent. A higher ingestion rate was determined by counting the number of fluorescent E. coli within the ciliate over 120 s, but this was equivalent to that obtained for the stained E. coli using the same direct method of analysis. However, the ciliate was shown to process the stained and unstained E. coli cells differently, with only the latter resulting in an increase in ciliate abundance.

Second stage of a genome scan of schizophrenia: study of five positive regions in an expanded sample.

In a previous genome scan of 43 schizophrenia pedigrees, nonparametric linkage (NPL) scores with empirically derived pointwise P-values less than 0.01 were observed in two regions (chromosomes 2q12-13 and 10q23) and less than 0.05 in three regions (4q22-23, 9q22, and 11q21). Markers with a mean spacing of about 5 cM were typed in these regions in an expanded sample of 71 pedigrees, and NPL analyses carried out. No region produced significant genomewide evidence for linkage. On chromosome 10q, the empirical P-value remained at less than 0.01 for the entire sample (D10S168), evidence in the original 43 pedigrees was slightly increased, and a broad peak of positive results was observed. P-values less than 0.05 were observed on chromosomes 2q (D2S436) and 4q (D4S2623), but not on chromosomes 9q or 11q. It is concluded that this sample is most supportive of linkage on chromosome 10q, with less consistent support on chromosomes 2q and 4q. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:864-869, 2000.

Laparoscopic repair of bilateral inguinal hernias in a patient with müllerian agenesis.

OBJECTIVE: To report a case of laparoscopic repair of bilateral inguinal hernias in a patient with müllerian agenesis. DESIGN: Case report. SETTING: Hospital. PATIENT(S): An 18-year-old woman with müllerian agenesis who presented with symptomatic inguinal hernias containing ovaries. INTERVENTION(S): Laparoscopic repair of bilateral inguinal hernias. MAIN OUTCOME MEASURE(S): Hernia repair was accomplished laparoscopically. RESULT(S): Outpatient laparoscopic repair of bilateral inguinal hernias with reduction of ovaries was performed using an extraperitoneal approach without complication. CONCLUSION(S): Laparoscopic approach of inguinal hernias can be an option for surgical repair in patients with müllerian agenesis even when the hernias contain ovaries.

Genome scan of schizophrenia.

OBJECTIVE: The goal of this study was to identify chromosomal regions likely to contain schizophrenia susceptibility genes. METHOD: A genomewide map of 310 microsatellite DNA markers with average spacing of 11 centimorgans was genotyped in 269 individuals--126 of them with schizophrenia-related psychoses--from 43 pedigrees. Nonparametric linkage analysis was used to assess the pattern of allele sharing at each marker locus relative to the presence of disease. RESULTS: Nonparametric linkage scores did not reach a genomewide level of statistical significance for any marker. There were five chromosomal regions in which empirically derived p values reached nominal levels of significance at eight marker locations. There were p values less than 0.01 at chromosomes 2q (with the peak value in this region at D2S410) and 10q (D10S1239), and there were p values less than 0.05 at chromosomes 4q (D4S2623), 9q (D9S257), and 11q (D11S2002). CONCLUSIONS: The results do not support the hypothesis that a single gene causes a large increase in the risk of schizophrenia. The sample (like most others being studied for psychiatric disorders) has limited power to detect genes of small effect or those that are determinants of risk in a small proportion of families. All of the most positive results could be due to chance, or some could reflect weak linkage (genes of small effect). Multicenter studies may be useful in the effort to identify chromosomal regions most likely to contain schizophrenia susceptibility genes.

Polyclonal Ki-67 expression in transitional cell carcinoma of the bladder.

The proliferation kinetics of 101 cases of transitional cell carcinoma (TCC) and seven cases of transitional cell carcinoma-in-situ of the bladder were assessed following staining with polyclonal Ki-67 antibody (pKi-67). Labeling indices ranged from 49% to 60.2% with a mean value of 22.2% for all cases. A significant association between pKi-67 indices, tumor grade and tumor stage was observed, with significant differences between pKi-67 indices of Grade 1 and 3 tumors and Grade 2 and 3 tumors. Significant differences in labeling indices were also found between superficial (Ta) tumors and both musculoinvasive (T2/T3a) tumors and those infiltrating the perivesical fat (T3b). pKi-67 indices for carcinoma-in-situ were similar to those noted for Grade 1 TCC. No difference in pKi-67 index was found when tumors were classified according to the morphology of the tumor invasion front. It is concluded that pKi-67 index is a useful marker for tumor progression for vesical TCC and that this immunohistochemical stain may assist clinical assessment of the potential behaviour of tumors in individual cases.

Luminal epithelial antigen (LEA.135) expression correlates with tumor progression for transitional carcinoma of the bladder.

Luminal epithelial antigen (LEA.135) expression has been shown to have prognostic significance in breast carcinoma, however its relationship to tumor progression in other forms of malignancy is unknown. This study evaluates LEA.135 expression in bladder transitional cell carcinoma (TCC) and compares the findings with tumor stage and grade, and polyclonal Ki-67 derived cell cycle activity. LEA.135 expression was evaluated by immunohistochemical staining using the streptavidin-biotin method. Staining distribution was graded 0 to 4 and the results were compared with World Health Organisation tumor grade, UICC TNM stage and fraction of actively cycling cells showing positive pKi-67 immunohistochemical staining. In normal bladder epithelium, LEA.135 staining was confined to the luminal surface of superficial epithelium. In lower grade, superficial TCC LEA.135 overexpression was noted and there was a progressive loss of expression in tumors of higher grade (p = 0.0001) and advanced stage (p = 0.0001). No LEA.135 staining was seen in carcinoma-in-situ. Loss of LEA.135 expression correlates with tumor progression for bladder TCC.

Multiple pancreatic abscesses due to Candida albicans following ERCP.

A report is presented of a patient who developed multiple abscesses of the pancreas due to Candida albicans following an Endoscopic retrograde chole-pancreatography (ERCP) for acute pancreatitis. He was not immunocompromised, debilitated and had not had recent surgery. There was complete radiological and clinical resolution of the abscess on prolonged treatment with amphotericin alone. Only a few cases of candidal abscess of the pancreas have been reported, none of them having occurred after an ERCP.

Latex allergy in patients with spina bifida.

Latex recently has been associated with severe intraoperative IgE-mediated anaphylactic reactions. Pediatric patients with meningomyelocele (spina bifida) appear to be specifically at risk for this type of reaction. This article provides background information on the etiology of latex allergies, identifies some commonly used dental products containing latex, recommends some alternatives to use, and suggests precautions the dental practitioner should take when treating high-risk individuals such as spina bifida patients.

Massive hepatic necrosis in toxemia of pregnancy.

Hepatic rupture and infarction associated with toxemia of pregnancy usually occur in multiparous women close to 30 years of age. The most important presenting symptom is right upper-quadrant abdominal pain. Sonography is the most expedient way of making the diagnosis of either rupture or hemorrhagic necrosis, but computed tomography is more sensitive. Elevated transaminase levels and thrombocytopenia or disseminated intravascular coagulation may occur acutely but resolve quickly. Termination of pregnancy is the cornerstone of any treatment plan. Many cases may not require operative treatment other than inspection. In others, surgical hemostasis will be lifesaving. We describe four preeclamptic women, two with ruptured subcapsular hematomas and two with hemorrhagic infarction. Radiological and laboratory evidence of liver damage and recovery are presented.

Doramectin, a new avermectin highly efficacious against gastrointestinal nematodes and lungworms of cattle and pigs: two studies carried out under field conditions in Germany.

Two field studies were carried out to confirm the efficacy of doramectin in cattle and pigs in Europe. A total of 40 cattle harbouring naturally acquired infections of gastrointestinal nematodes, including Ostertagia spp., Oesophagostomum spp., Cooperia spp., Haemonchus spp., Nematodirus spp. and Trichuris spp., were allocated to a treated or a control group (20 animals/group), and 100 harbouring naturally acquired infections of gastrointestinal nematodes and lungworms, including Oesophagostomum spp., Metastrongylus spp., Ascaris suum and Trichuris suis, were allocated to either a treated (60 pigs) or a control (40 pigs) group. Animals in the treated groups received an injection of doramectin at 200 micrograms/kg (1 ml/50 kg) for cattle or 300 micrograms/kg (1 ml/33 kg) for swine. Animals in the control groups received saline at 1 ml/50 kg for cattle or 1 ml/33 kg for swine. The cattle were injected by the subcutaneous route in the lateral mid-line of the neck and the pigs were injected intramuscularly in the neck. Faecal egg counts were determined for all animals on days--7, 0, 7, 14 and 21 of the studies, where day 0 was the day of treatment. The mean daily weight gain of doramectin-treated animals was significantly higher than that of the control animals over the 21 days of the studies (P < 0.0007 for cattle and P = 0.0001 for swine). At 21 days after treatment, the mean faecal egg counts of the doramectin-treated animals were significantly lower than those of the control animals and were reduced by 100% as compared with pretreatment levels. No adverse reaction to treatment was observed in any animal during either study.(ABSTRACT TRUNCATED AT 250 WORDS)

Association between primary dentition wear and clinical temporomandibular dysfunction signs.

Dental wear facets often are considered indicators of temporomandibular dysfunction (TMD). Dental wear facets are common in children, but their association with TMD signs is unknown. A reproducible, clinical evaluation of TMD signs for young children shows no statistically significant association between primary dentition wear facets and clinical signs of TMD (P less than or equal to 0.05). Wear facets in young children do not appear to warrant TMD evaluation or treatment.

Incidental finding of an intranasal foreign body discovered on routine dental examination: case report.

A nasal foreign body was discovered radiologically on an initial dental examination of a young child. The child was a candidate for dental rehabilitation, using nasotracheal intubation under general anesthesia. The parents were unaware of the object's presence, and the child had no nasal symptoms. The child was referred to the Otolaryngology-Head and Neck Surgery Service to have the object removed; this was accomplished successfully without sequelae on an outpatient basis. Dentists and physicians who treat children should be alert to the possible presence of intranasal objects in their patients.

A quality assessment of the effects of a hydrogenous filter on a p(66)Be(40) neutron beam.

Recent measurements in a p(62)Be(36) neutron therapy beam have shown that the quality of the in-phantom beam changes with depth. This variation can be ascribed to the presence of a relatively large low-energy neutron component emanating from the neutron source. As part of the pre-clinical calibration programme at a newly commissioned neutron therapy facility, radiobiological and microdosimetric observations were made to determine the magnitude of this effect on a p(66)Be(40) beam and to evaluate the hardening effect of a hydrogenous filter. The reported data identify a correlation between the two assays and quantify a linear relationship between y* and filter thicknesses less than or equal to 6 cm. Using the data obtained in the study, a filter thickness was selected to comply with clinical requirements. By employing lineal energy spectra, it is demonstrated that subtle changes in beam quality may be quantified in a reproducible manner without resorting to time-consuming radiobiological studies.