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Biomedical subjects

F F Liu

Publications and source records attributed to F F Liu.

At least 19 recordsLinked to original sources

Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group.

PURPOSE: Claims for the value of hyperthermia as an adjunct to radiotherapy in the treatment of cancer have mostly been based on small Phase I or II trials. To test the benefit of this form of treatment, randomized Phase III trials were needed. METHODS AND MATERIALS: Five randomized trials addressing this question were started between 1988 and 1991. In these trials, patients were eligible if they had advanced primary or recurrent breast cancer, and local radiotherapy was indicated in preference to surgery. In addition, heating of the lesions and treatment with a prescribed (re)irradiation schedule had to be feasible and informed consent was obtained. The primary endpoint of all trials was local complete response. Slow recruitment led to a decision to collaborate and combine the trial results in one analysis, and report them simultaneously in one publication. Interim analyses were carried out and the trials were closed to recruitment when a previously agreed statistically significant difference in complete response rate was observed in the two larger trials. RESULTS: We report on pretreatment characteristics, the treatments received, the local response observed, duration of response, time to local failure, distant progression and survival, and treatment toxicity of the 306 patients randomized. The overall CR rate for RT alone was 41% and for the combined treatment arm was 59%, giving, after stratification by trial, an odds ratio of 2.3. Not all trials demonstrated an advantage for the combined treatment, although the 95% confidence intervals of the different trials all contain the pooled odds ratio. The greatest effect was observed in patients with recurrent lesions in previously irradiated areas, where further irradiation was limited to low doses. CONCLUSION: The combined result of the five trials has demonstrated the efficacy of hyperthermia as an adjunct to radiotherapy for treatment of recurrent breast cancer. The implication of these encouraging results is that hyperthermia appears to have an important role in the clinical management of this disease, and there should be no doubt that further studies of the use of hyperthermia are warranted.

Breast Neoplasms

CVS-exposed limb deficiency defects with or without other birth defects: presentation of six cases born during a period of nine years.

We report on six cases with CVS-exposed limb-"reduction" defects born in our hospital during a period of 9 years (1986-1994). Four cases were associated with other birth defects. One had an oromandibular-limb hypogenesis syndrome with a cleft lip and jejunal atresia, a second had an oromandibular-limb hypogenesis (Hanhart) syndrome, a third had severe flexion deformity at the hips and hyperextension at the knees with meconium peritonitis and intestinal obstruction, and a fourth had Poland anomaly. Detailed clinical descriptions, prenatal diagnosis, photographs, and radiographs are presented. Our presentation adds to the information on severe limb abnormalities after CVS and suggests CVS-exposed limb defects may be associated with other birth defects resulting from vascular insufficiency or intrauterine compression. We suggest that detailed post-CVS sonographic followups are necessary for each CVS-exposed case to identify not only the possible fetal limb reduction, but also vascular disruption-type malformations and compressive deformities.

Abnormalities, Multiple

The stress-activated protein kinase pathway mediates cell death following injury induced by cis-platinum, UV irradiation or heat.

BACKGROUND: Stimuli that stress cells, including inflammatory cytokines, ultra-violet irradiation, DNA-damaging chemotherapeutic drugs and heat shock, stimulate a recently identified cytoplasmic signaling system that is structurally related to the mitogen-activated protein kinase pathway. This pathway consists of a cascade of protein kinases including stress-activated protein kinase (SAPK), also termed Jun N-terminal kinase (JNK), and two kinases that activate it, MEKK and SEK/MKK4. Despite rapid progress in delineating the components of this pathway, the cellular consequence of its activation remains to be defined. RESULTS: We have screened cells for defects in SAPK signaling and identified a cell line, previously characterized for its thermotolerance properties, as being more refractive to SAPK activation induced by heat stress than its thermosensitive parental line. Stable expression of dominant inhibiting SEK mutants in thermosensitive parental cells specifically and effectively blocked SAPK activation after heat shock. These lines also became markedly resistant to the cytocidal effects of thermal stress, confirming the phenotype of the thermotolerant line. These cell lines defective in SAPK activation were also resistant to the lethal effects of the DNA-damaging drug cis-platinum. CONCLUSIONS: Experimentally induced stable blockade of SAPK activation in cells with normal thermosensitivity is sufficient to confer resistance to cell death induced by diverse stimuli including heat and the chemotherapeutic agent cis-platinum. These results suggest that activation of the SAPK pathway by diverse cell stressors plays a critical part in mediating the toxicity of these treatments and inducing cell death. SAPK activation in this context could broadly influence cellular response to stress, modulate apoptosis during development or determine the clinical response of tumor cells to cytotoxic therapies.

Calcium-Calmodulin-Dependent Protein Kinases

The effect of heat on Na+/H+ antiport function and survival in mammalian cells.

PURPOSE: Because intracellular pH (pHi) is a determinate of thermosensitivity, it is important to understand the relationship between heat cytotoxicity and the mechanisms responsible for pHi regulation, such as the Na+/H+ antiport. The objective of this study is to elucidate the relationship between heat damage and Na+/H+ antiport activity. METHODS AND MATERIALS: Various cell lines, EMT6, RIF-1, and its thermoresistant variant TR-4, and CCL39, and its variant that lacks the Na+/H+ antiport (PS120), were all heated using a water bath. Parallel assessments of antiport function and pHi were made using the fluorescent dye 2,7-biscarboxyethyl-5(6)-carboxyfluorescein (BCECF). RESULTS: Exposure of EMT6 cells to 43-46 degrees C for 30-60 min caused progressive decline in antiport activity, in parallel with cytotoxicity. When the same degree of cytotoxicity was induced by ionizing radiation, no alteration in Na+/H+ antiport function was observed. Despite a 10-fold lower survival in RIF-1 compared to TR-4 cells after heating, there was no difference in the thermosensitivity of their antiports. Antiport activity in the TR-4 cells, however, was higher than that of RIF-1 cells both before and during heating. Intracellular pH for TR-4 cells decreased minimally during heating, in contrast to a decline of 1 pH unit in RIF-1 cells despite similar relative levels of antiport activity, suggesting that in this pair of cell lines, antiport activity does not play a major pHi regulatory role. PS120 and CCL39 cells and similar survival levels when heated at pHe 7.2 in the presence of NaHCO3, which allows function of the other major regulator of pHi, the Na+ -dependent HCO3-/Cl- exchanger. This occurred despite a drop in pHi in the PS120 cells during heating. A reduced survival was observed, however, in PS120 cells after 43 degrees C for 30-60 min at either pHe 6.5 or pHe 7.2 in the absence of NaHCO3. Intracellular pH was consistently greater for PS120 than CCL39 cells. CONCLUSION: We demonstrated that damage to the Na+/H+ antiport likely reflects early heat-induced change in membrane function, but is not a primary target for heat cytotoxicity. Although there is an association between survival, antiport function, and pHi level under most treatment conditions, the precise role of the Na+/H+ antiport in mediating thermal cytotoxicity remains uncertain.

Animals

Prenatal diagnosis of partial monosomy 3p and partial trisomy 2p in a fetus associated with shortening of the long bones and a single umbilical artery.

The prenatal and postnatal findings of a fetus with partial deletion of 3p25 -> pter and duplication of 2p25.3 -> pter are described. The proband postnatally displayed mental and growth retardation, psychomotor delay, microcephaly, ptosis, micrognathia, a narrow palate, and cryptorchidism. All of these anomalies were consistent with those described in 3p- and partial trisomy 2p syndromes, and also frequently seen in patients with other chromosomal disorders. However, the prenatal sonograms revealed unusual shortening of the long bones, a single umbilical artery, and normal development of the skull. Our case suggests that skeletal growth retardation of the long bones may occur earlier than that of the skull in fetuses associated with chromosomal aberrations such as del(3p)/dup(2p). Shortening of the long bones and a single umbilical artery together with other abnormalities detected by prenatal ultrasound thus warrant a fetal cytogenetic study.

Abnormalities, Multiple

Ultrasound-guided fluid aspiration and prenatal diagnosis of duplicated hydrometrocolpos with uterus didelphys and septate vagina.

We report on a case of duplicated hydrometrocolpos with uterus didelphys, a septate vagina, lower vaginal atresia, a persistent urogenital sinus, left ear agenesis, a single umbilical artery, and an imperforate anus, but without the associated features of McKusick-Kaufman syndrome such as polydactyly and congenital heart defects. Ultrasound-guided fluid aspiration of the fetal intrapelvic cystic mass helped to decompress the distended genital organs, decrease the severity of the urinary tract obstruction, delineate the ultrasonographic image of duplicated hydrometrocolpos to differentiate it from other intrapelvic cystic masses, and obtain fluid for cytological analysis.

Abnormalities, Multiple

Prenatal diagnosis of partial monosomy 13q associated with occipital encephalocoele in a fetus.

The pre- and postnatal findings of a fetus with a de novo del(13)(pter-->q21:) and an occipital encephalocoele are described. Maternal serum alpha-fetoprotein (AFP) screening at 19 weeks' gestation demonstrated a high level of 2.5 multiples of the median (MOM) and ultrasonography at 27 weeks' gestation showed severe intrauterine growth retardation, cardiomegaly, an occipital encephalocoele, and a calvarial defect. Genetic amniocentesis revealed a karyotype of 46,XX,del(13)(pter-->q21:). The proband postnatally displayed additional abnormalities such as microphthalmia, hypertelorism, large low-set ears, and micrognathia. We discuss the association of central nervous system (CNS) malformations with 13q deletions and emphasize that pregnancies with neural tube defects warrant cytogenetic analysis, especially when additional fetal abnormalities and neonatal dysmorphism are observed.

Adult

The relationship between thermosensitivity and intracellular pH in cells deficient in Na+/H+ antiport function.

BACKGROUND AND PURPOSE: We have demonstrated previously the relationship between intracellular pH (pHi) level and heat survival in mammalian cells. To explore this in further detail, we studied thermosensitivity in CCL 39 and their variant PS120 cells, which lack Na+/H+ antiport function. MATERIALS AND METHODS: CCL39 and PS120 cells were heated with or without amiloride, or 5-(N-ethyl(-N-isopropyl) amiloride (EIPA), inhibitors of Na+/H+ antiport function. Antiport activity and pHi measurements were made using the fluorescent dye 2,7-biscarboxyethyl-5(6)-carboxyfluorescein (BCECF). A clonogenic assay was used to assess survival after heating. RESULTS: Enhanced cytotoxicity was observed when CCL39 cells were heated with either EIPA (15 microM) or amiloride (2.5 mM) at pHe7.3 in the presence of NaHCO3. Under the same conditions, thermal enhancement of PS120 cells was observed only with amiloride at 2.5 mM. When the cells were heated at pHe 6.5 in bicarbonate-free medium, both EIPA and amiloride enhanced thermal cytotoxicity in CCL39 cells, but only the higher dose of amiloride sensitized the variant PS120 cells. Surviving fraction was related to pHi, but the data fell into two clusters, depending on whether or not both Na+/H+ antiport and the Na(+)-dependent HCO3-/Cl- exchangers were functioning. CONCLUSIONS: We confirm that Na+/H+ antiport function can mediate thermosensitivity, and corroborate a linear correlation between pHi level and log survival after heating, but suggest that this relationship is complicated by other factors such as membrane exchanger function, and extracellular pH levels during heating.

Amiloride

Prenatal diagnosis and perinatal aspects of abdominal wall defects.

We retrospectively reviewed 27 cases of omphalocele and 15 cases of gastroschisis occurring among 62, 572 deliveries between 1987 and 1994. All cases had undergone prenatal sonographic examinations at a mean gestational age of 28 weeks. In cases of omphalocele, 59.3% (16/27) of fetuses were associated with multiple malformations and 16% (4/25) had chromosomal abnormalities. Among the 4 cases with an abnormal karyotype, three cases were associated with extracorporeal livers and two cases were associated with umbilical cord cysts. Prenatal ultrasound examinations during the second and third trimesters were able to detect 66.7% (18/27) of the cases of omphalocele and 66.7% (10/15) of the cases of gastroschisis. Failure in correctly diagnosing abdominal wall defects by prenatal ultrasound occurred mostly in cases associated with small defects, ruptured omphalocele, multiple fetal anomalies, intrauterine fetal death, twin pregnancies, or cases referred in late gestation. A comparison of perinatal data between omphalocele and gastroschisis reveals fetuses with omphalocele carry higher risks of associated malformations, chromosomal abnormalities, prematurity, and neonatal death. Although fetuses with gastroschisis have higher incidences of oligohydramnios and small for gestational age, the fetal prognosis after pediatric surgery is good.

Abdominal Muscles

Prenatal detection of the separation of the great toe, toe syndactyly, and large bilateral choroid plexus cysts in a fetus with trisomy 18.

Prenatal sonographic presentation of toe deformities is associated with fetal aneuploidies. This report presents a second-trimester fetus with large bilateral choroid plexus cysts, clenched hands, separation of the great toe, toe syndactyly, abnormal double maternal serum biochemical screening results, and trisomy 18. We suggest a careful ultrasound screening of the fetal limbs and other organs once a choroid plexus cyst has been identified. If abnormal sonographic findings are present, or if the results of the maternal serum biochemical screening are abnormal, karyotyping should be recommended.

Abnormalities, Multiple

Influence of heat on Na(+)-dependent HCO3-/Cl- exchanger function in a thermoresistant cell line.

During previous studies on the relationship between thermosensitivity and intracellular pH (pHi) regulation in mammalian cells, we observed that the thermoresistant TR-4 cells appeared to be resistant to manipulations of the Na+/H+ antiport, one of the two primary membrane regulators of pHi. We hypothesized that this might be due to up-regulation of the alternate pHi regulator, the Na(+)-dependent HCO3-/Cl- exchanger, in the TR-4 cells. We have now evaluated the effect of heat exposure on the function of the Na(+)-dependent HCO3-/Cl- exchanger in both the parent RIF-1 and the thermoresistant variant TR-4 cells. We also assessed thermosensitivity of the cell lines under conditions of either pHe 7.2 or 6.8, with NaHCO3, with or without the addition of DIDS, an inhibitor of HCO3-/Cl- exchanger function. After 2h of heating at 43 degrees C, relative exchanger function declined to around 50% for the TR-4 cells and 10% for the RIF-1 cells. DIDS (0.2 mM) enhanced thermal cytotoxicity in both cells lines, by around 1 log when the cells were heated at neutral conditions, and by around 1.5 log when the condition became acidic. Results from pHi measurements during heating reflected the clonogenic survival data in that lower pHi levels were associated with the conditions when DIDS was present. We conclude that in the TR-4 cells, the Na(+)-dependent HCO3-/Cl- exchanger appears to be a more important regulator of pHi than the Na+/H+ antiport.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid

Partial duplication of 3q and distal deletion of 11q in a stillbirth with an omphalocele containing the liver, short limbs, and intrauterine growth retardation.

We describe a female stillbirth with duplication of 3q21-->qter and deletion of 11q23-->qter resulting from an unbalanced segregation of a maternal t(3;11) reciprocal translocation. The proband had some of the clinical features consistent with those seen in patients with dup(3q) syndrome or distal del(11q) syndrome. Prenatal sonographic examination showed short limbs, intrauterine growth retardation, and an omphalocele containing the liver.

Chromosome Aberrations

Cytogenetic evaluation of cystic hygroma associated with hydrops fetalis, oligohydramnios or intrauterine fetal death: the roles of amniocentesis, postmortem chorionic villus sampling and cystic hygroma paracentesis.

BACKGROUND: Pregnancies complicated by fetal cystic hygroma in the second and third trimesters are often associated with hydrops fetalis, oligohydramnios or intrauterine fetal death which may make genetic assessment more difficult. We investigated the roles of amniocentesis, postmortem chorionic villus sampling and cystic hygroma paracentesis in cytogenetic evaluation of cystic hygroma under such circumstances. METHODS: Thirty-five fetuses of cystic hygroma associated with hydrops fetalis, oligohydrammos, or intrauterine fetal death were studied. All fetuses were delivered at Mackay Memorial Hospital, Taipei, Taiwan between January, 1987 and July, 1995. Data collected included maternal age, prenatal sonograms, gestational age at diagnosis, fetal karyotypes and diagnostic procedures. RESULTS: Of 35 fetuses, all had hydrops fetalis, 19 had suffered IUFD at the time of diagnosis, and 10 had severe oligohydramnios. Cytogenetic studies were performed via amniocentesis, postmortem chorionic villus sampling, or cystic hygroma paracentesis. Successful karyotyping was achieved in 32 fetuses and the karyotype of 45,X was found in 24 fetuses. In cases with IUFD, successful karyotyping rates on cells from amniotic fluid, chorionic villi and cystic hygroma fluid were 88.9% (8 of 9), 69.2% (9 of 13) and 20% (1 of 5), respectively, whereas, in cases with living hydropic fetuses, successful karyotyping was achieved in 12 of 12 amniotic fluid and 5 of 5 cystic hygroma fluid samples. CONCLUSIONS: Amniocentesis is a better method for cytogenetic evaluation of fetal cystic hygroma associated with intrauterine fetal death than postmortem chorionic villus sampling and cystic hygroma paracentesis. However, in the case with a living hydropic fetus and oligohydramnios, cystic hygroma paracentesis appears to be a practical alternative for cytogenetic assessment.

Adult

The relationship between intracellular pH and heat sensitivity in a thermoresistant cell line.

To explore further the relationship between intracellular pH (pHi) and thermosensitivity, we compared survival and pHi levels in RIF-1 cells and a thermoresistant variant, TR-4 cells, while heating under different conditions of acid or neutral extracellular pH (pHe). We also added 5-(N-ethyl-N-isopropyl) amiloride (EIPA), a potent inhibitor of one of the major membrane regulators of pHi, the Na+/H+ antiport, and/or removed NaHCO3 to inactivate the alternate membrane regulator of pHi, the HCO3-/Cl- exchanger. At pHe 7.3 with NaHCO3, EIPA (15 microM) did not enhance the cytotoxicity of heat in either cell line. At pHe 6.8 with NaHCO3, EIPA enhanced thermal cytotoxicity for RIF-1 cells only, but without NaHCO3, at pHe 6.8 or 6.5, EIPA treatment during heating resulted in a significant decrease in survival of TR-4 cells also. Measurements of pHi levels immediately after heating correlated with the survival data, demonstrating a linear relationship between pHi and log surviving fraction for both cell lines. This relationship, however, is different between the two cell lines in that the TR-4 cells are more resistant to reduction in pHi with heating, and for any given pHi level to demonstrate a higher correlation is different for the two cell lines, suggesting a difference in the relationship between pHi and log surviving fraction between the TR-4 and RIF-1 cells.

Amiloride

Concurrent papillary and squamous carcinoma in a thyroglossal duct cyst: a case report.

Carcinomas of thyroglossal duct cysts are rare. Most are papillary carcinomas; only about 5% are squamous cell carcinomas. Only one case of mixed papillary and squamous cell carcinoma of a thyroglossal duct cyst has been reported so far. The authors present a second case, that of a 38-year-old man who was first seen with a midline neck lump. It was diagnosed clinically as a thyroglossal duct cyst and was locally excised. Pathological examination showed both a concurrent papillary carcinoma and a squamous cell carcinoma. Treatment consisted of a near-total thyroidectomy, ablative radioactive iodine and adjuvant external radiation therapy. The authors review the literature and explain the rationale behind their choice of treatment.

Adult

Prenatal diagnosis of omphalocele associated with umbilical cord cyst.

BACKGROUND: To study the cytogenetics, ultrasound findings, biochemical screening, perinatal outcome, and associated abnormalities in cases of omphaloceles associated with umbilical cord cysts. METHODS: From 1988 to 1994, three cases of omphaloceles with umbilical cord cysts were identified at Mackay Memorial Hospital. We compared the clinical data of our three cases with six other cases in the published literature. RESULTS: Two cases of omphaloceles with umbilical cord cysts were affected with trisomy 18. One had bilateral choroid plexus cyst, intrauterine growth retardation, low levels of maternal serum alpha-fetoprotein and free beta-human chorionic gonadotropin, and the other had cleft lip and palate, single umbilical artery and intrauterine growth retardation. An elevated level of maternal serum alpha-fetoprotein was found in the case with normal karyotype. Elevated levels of amniotic fluid alpha-fetoprotein were found in two cases. Rupture of the umbilical cord cyst and disruption of the umbilical cord occurred in one case at delivery. Based on the gross and microscopic examinations, the cord cysts we observed are likely to be pseudocysts. CONCLUSION: The umbilical cord cysts most commonly associated with omphaloceles are pseudocysts and allantoic cysts. Among our three cases and the six other cases published in the literature, four out of these nine cases were trisomy 18. Prenatal diagnosis of omphaloceles or umbilical cord cysts by ultrasound warrants cytogenetic analysis and detailed sonogram to rule out the possible combination of both abnormalities and trisomy 18. If an omphalocele is associated with a large umbilical cord cyst and a normal karyotype, cesarean section is recommended to prevent the dilemma of intrauterine vascular compromise of umbilical blood flow during labor.

Abnormalities, Multiple

Phylloides tumor of the breast: a report of 14 cases.

The objective of this retrospective study is to determine the role of radiation therapy in the management of benign phylloides tumors. Fourteen patients with a diagnosis of benign phylloides tumor (PT) and registered at the Princess Margaret Hospital are included in the study. Definitive surgery consisted of either lumpectomy in seven patients or mastectomy in the other seven patients. One patient died of her disease, and the remaining patients had no evidence of disease at last follow-up (median 38.4 months). Among these 13 patients, 4 had at least one recurrence and the recurrence rate was higher for the group who underwent lumpectomy (43% compared with 28%). One patient was treated by lumpectomy and adjuvant radiation therapy, and had no subsequent recurrence (follow-up time 35.5 months). The role for radiation therapy in the management of this disease remains unclear.

Adult