Transabdominal amnioinfusion: An evaluation of its adverse events.

OBJECTIVE: Transabdominal amnioinfusion is beneficial in oligohydramnios, which has high fetal mortality and does not improve with observation alone. However, there are few reports on the maternal adverse events of transabdominal amnioinfusion. This study aimed to evaluate the adverse events of amniocentesis with transabdominal amnioinfusion. STUDY DESIGN: This study is a retrospective cohort study at a single tertiary perinatal center in Japan. A total of 313 procedures in 126 patients who underwent amniocentesis for transabdominal amnioinfusion at our tertiary perinatal institution were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE). Adverse events were retrospectively examined using a 5-grade evaluation based on the CTCAE. Procedurally, a 21-23-G percutaneous transhepatic cholangiography drainage (PTCD) needle was advanced under ultrasound guidance into the amniotic fluid cavity with a gravity-fed infusion of warm saline solution. RESULTS: No maternal deaths were recorded. Only two maternal/fetal adverse events occurred, and grade 4 fetal adverse events requiring pregnancy termination were observed in seven cases. Fetal death occurred in five cases, all with severe oligohydramnios and premature rupture of the membranes. No placental abruption or bleeding occurred before or after delivery. CONCLUSION: Adverse events during transabdominal amnioinfusion were successfully analyzed using CTCAE. We also provided new terminology for evaluating adverse events during amnioinfusion. Our results may encourage obstetricians to perform amnioinfusion in difficult situations, with less concern for severe maternal or fetal adverse events.

Changes in the Intra-Amniotic Pressure following Transabdominal Amnioinfusion during Pregnancy.

OBJECTIVE: The aim of the article was to investigate the changes in intra-amniotic pressure following transabdominal amnioinfusion during pregnancy. DESIGN: This retrospective study included 19 pregnant women who underwent transabdominal amnioinfusion during pregnancy to relieve umbilical cord compression and improve the intrauterine environment or to increase the accuracy of ultrasonography. MATERIALS AND METHODS: We measured and analyzed the changes in intra-amniotic pressure, single deepest pocket, and the amniotic fluid index before and after amnioinfusion. We also determined the incidence of maternal or fetal adverse events, such as preterm premature rupture of membranes, preterm delivery, fetal death within 48 h, placental abruption, infection, hemorrhage, and peripheral organ injury. RESULTS: A total of 41 amnioinfusion procedures were performed for 19 patients. The median gestational age during the procedure was 24.3 weeks. The median volume of the injected amniotic fluid was 250 mL. The median single deepest pocket and amniotic fluid index after amnioinfusion were significantly higher than those before amnioinfusion (4.0 cm vs. 2.65 cm; p < 0.001 and 13.4 cm vs. 6.0 cm; p < 0.001). However, the median (range) intra-amniotic pressure after amnioinfusion was not significantly different compared to that before amnioinfusion (11 mm Hg vs. 11 mm Hg; p = 0.134). Maternal or fetal adverse events were not observed following amnioinfusion. CONCLUSION: Intra-amniotic pressure remained unchanged following amnioinfusion. The complications associated with increased intra-amniotic pressure are not likely to develop if the amniotic fluid index and/or single deepest pocket remains within the normal range after amnioinfusion. Studies of groups with and without complications are warranted to clarify the relationship between the intra-amniotic pressure and incidence of complications.

Successful amnioinfusion for severe fetal growth restriction with umbilical cord complications: two case reports.

BACKGROUND: There is no established treatment for fetal growth restriction during pregnancy. We report two cases that represent an example of an amnioinfusion-based management strategy for severe fetal growth restriction with umbilical cord complications. CASE PRESENTATION: We encountered two cases of fetal growth restriction with abnormal fetal Doppler velocity. In one case, fetal ultrasound revealed a hypercoiled umbilical cord with a single umbilical artery and oligohydramnios, while fetal Doppler revealed a reversed end-diastolic flow in the umbilical artery and reversed a-waves of the ductus venosus. Umbilical cord compression was confirmed at 22 weeks and 2 days of gestation, and nine amnioinfusions were performed to relieve the umbilical cord compression. A cesarean section was performed at 31 weeks and 2 days of gestation because of severe preeclampsia. The Asian infant is now a normally developed 6-month-old. In another Asian case, fetal ultrasound revealed a hypercoiled cord, while fetal Doppler revealed a reversed end-diastolic flow in the umbilical artery and intermittent reversed a-waves of the ductus venosus. Umbilical cord compression was confirmed at 24 weeks and 5 days of gestation, and seven amnioinfusions were performed. A cesarean section was performed at 31 weeks and 1 day of gestation because of nonreassuring fetal status. At the age of 1 month, the Asian infant was stable on respiratory circulation. In both cases, fetal Doppler findings improved significantly following amnioinfusions. CONCLUSIONS: Amnioinfusion is a symptomatic treatment for umbilical cord compression. However, to determine the therapeutic effect of amnioinfusion, complete resolution of the umbilical cord compression should be ascertained by ultrasonography.

Relationship between higher intra-amniotic pressures in polyhydramnios and maternal symptoms.

OBJECTIVES: Our study aimed to analyze the differences in intra-amniotic pressures in patients with polyhydramnios with and without symptoms. STUDY DESIGN: We recruited patients with pregnancies in which amnioreduction was performed for polyhydramnios in the Department of Fetal-Maternal Medicine at Nagara Medical Center between April 2017 and August 2018. Amnioreduction was performed for severe polyhydramnios with maternal symptoms [symptomatic group] or polyhydramnios without maternal symptoms [asymptomatic group] such as abdominal distension, dyspnea, or threatened premature labor. We measured the intra-amniotic pressure after every 200 ml volume reduction during the amnioreduction. RESULTS: A total of 27 patients who underwent amnioreduction were classified into symptomatic (66.7%, 18/27) and asymptomatic (33.3%, 9/27) groups. Gestational age, amniotic fluid index at the time of amnioreduction, and the volume of amniotic fluid removed were not significantly different between the symptomatic and asymptomatic groups [median 32.4 weeks vs. 33.1 weeks, median 38.0 cm vs. 39.0 cm, and median 1500 ml vs. 2500 ml, respectively]. However; the intra-amniotic pressure before amnioreduction was significantly higher in the symptomatic group than in the asymptomatic group [median 15.0 mmHg (range, 10-27) vs. 10.0 mmHg (range, 6.0-13); p < 0.005]. After amnioreduction, these pressures decreased significantly to median 9.0 mmHg (range, 5.0-13) (p < 0.001) in the symptomatic and 7.0 mmHg (range, 4.0-11) (p < 0.05) in the asymptomatic group. The median intra-amniotic pressure gradually decreased and reached a plateau during the amnioreductions in both groups. CONCLUSIONS: With polyhydramnios, the intra-amniotic pressure was significantly higher in the symptomatic group than in the asymptomatic group. Therefore, uterine pressure tolerance might vary according to the individual. In addition, intra-amniotic pressure monitoring might enhance the safety during amnioreduction procedures to avoid drastic and potentially harmful pressure changes.

Minor contribution of CYP3A5 to the metabolism of hepatitis C protease inhibitor paritaprevir in vitro.

Paritaprevir (PTV) is a non-structural protein 3/4A protease inhibitor developed for the treatment of hepatitis C disease as a fixed dose combination of ombitasvir (OBV) and ritonavir (RTV) with or without dasabuvir. The aim of this study was to evaluate the effects of cytochrome P450 (CYP) 3A5 on in vitro PTV metabolism using human recombinant CYP3A4, CYP3A5 (rCYP3A4, rCYP3A5) and human liver microsomes (HLMs) genotyped as either CYP3A5*1/*1, CYP3A5*1/*3 or CYP3A5*3/*3. The intrinsic clearance (CLint, Vmax/Km) for the production of a metabolite from PTV in rCYP3A4 was 1.5 times higher than that in rCYP3A5. The PTV metabolism in CYP3A5*1/*1 and CYP3A5*1/*3 HLMs expressing CYP3A5 was comparable to that in CYP3A5*3/*3 HLMs, which lack CYP3A5. CYP3A4 expression level was significantly correlated with PTV disappearance rate and metabolite formation. In contrast, there was no such correlation found for CYP3A5 expression level. This study represents that the major CYP isoform involved in PTV metabolism is CYP3A4, with CYP3A5 having a minor role in PTV metabolism. The findings of the present study may provide foundational information on PTV metabolism, and may further support dosing practices in HCV-infected patients prescribed PTV-based therapy.

Amnioinfusion for variable decelerations caused by umbilical cord compression without oligohydramnios but with the sandwich sign as an early marker of deterioration.

We report prophylactic amnioinfusion (AI) for variable decelerations in umbilical cord compression without oligohydramnios as an early sign of deterioration. We performed a transabdominal AI in cases without oligohydramnios using the ultrasonography findings of umbilical cord compression (i.e. sandwich sign [SWS]) and variable decelerations (VD) in a foetal heart rate. Thirteen cases and 21 AIs were analysed. Nine (69%) cases were of a foetal growth restriction and 4 (31%) had umbilical hyper-coiled cords. VD frequency (p < .0001), umbilical artery pulsatility index (PI) (p < .01) and ductus venous PI (0.66 vs. 0.48; p < .05) significantly decreased, and an umbilical venous (UV) flow volume (121 vs. 197 ml/min/kg; p < .05) significantly increased after AI. The umbilical artery diastolic blood flow abnormalities and UV pulsation improved. In conclusion, AI improves the umbilical cord compression even without oligohydramnios. The SWS is an important marker of deterioration to severe oligohydramnios and latent foetal damage. IMPACT STATEMENT What is already known on this subject? Antepartum variable decelerations due to umbilical cord compression are significantly associated with the deceleration in labour. In particular, foetal hypoxia leads to other adverse events such as foetal distress, hypoxic-ischemic encephalopathy, and pulmonary arterial hypertension after birth. Amnioinfusion has been shown to be effective in patients who also have oligohydramnios. What do the results of this study add? Amnioinfusion may be effective in the cases with ultrasonography findings of umbilical cord compression (i.e. sandwich sign) and in cases with variable decelerations in foetal heart rate, but without oligohydramnios. What are the implications of these findings for clinical practice and/or further research? Amnioinfusion may be helpful to prevent adverse events including oligohydramnios and anhydroamnios.

Changes in Intra-Amniotic, Fetal Intrathoracic, and Intraperitoneal Pressures with Uterine Contraction: A Report of Three Cases.

Intra-amniotic, fetal intrathoracic, and intraperitoneal pressures during pregnancy have been previously investigated. However, to our knowledge, changes in these pressures during uterine contractions have not been reported. Herein, we present three cases of polyhydramnios, fetal pleural effusion, and fetal ascites, in which intra-amniotic, fetal intrathoracic, intraperitoneal pressures increased with uterine contractions. These pressure increases may affect the fetal circulation. We suggest that managing potential premature delivery (e.g., with tocolysis) is important in cases with polyhydramnios and excess fluid in fetal body areas, such as the thorax, abdomen, and heart. The results of this preliminary study on intrafetal pressure measurements will be useful in performing fetal and neonatal surgeries in the future.

Prenatal diagnosis of funisitis: two case reports.

Acute funisitis is characterized by the infiltration of fetal neutrophils from the umbilical vessels into Wharton's jelly and presents as fetal inflammation. However, no reports about its prenatal diagnosis using ultrasonography have been published. We encountered one case of oligohydramnios at 26 weeks and another case of threatened premature delivery at 27 weeks of gestation with ultrasonographic findings of non-uniform thickening of Wharton's jelly, a heterogeneous internal echo, and a high echoic line of the umbilical vessel wall. Acute funisitis was diagnosed, and the postpartum histopathological examination revealed severe funisitis in both cases. To our knowledge, this is the first case report of prenatal diagnosis of funisitis determined using ultrasonography. When we find such ultrasonographic features under the circumstances of intrauterine infection, severe funisitis should be included in the differential diagnosis.

[Microarray analysis of tumor xenograft model].

We carried out gene expression profiling of forty human tumor cells for research choice method of the most fitting anticancer drug, using unsupervised hierarchal clustering analysis. This clustering analysis is based on a tumor growth inhibition panel of nine antitumor drugs (MMC, CDDP, ACNU, CPT-11, CPA, FT-207, UFT, 5'-DFUR and ADM) for forty human cancers. These cancers(eleven stomach, seven colon, six breast, three pancreas, five lung, two esophageal carcinomas, one liver, one renal cell carcinoma, one uterus, two ovarian, and one melanoma) have been maintained by serial s. c. passages in nude mice of the same sex of donor patients. Nine antitumor drugs were divided into two groups, a 5-FU-related drug group (5'-DFUR, FT-207 and UFT) and another group. On the other hands, forty cells were clustered into four groups. By using GeneChip (Hu95Av2, Affymetrix), we investigated gene expression profiling of the matched tumor cells and selected specific genes in each group. Interestingly, a pathway analysis revealed that expressions of p53-related genes were up-regulated in the 5-FU-sensitive groups. This result suggested that chemosensitivity was predicted by gene expression profiling of tumor cells. We considered that microarray analysis would be a good tool for further tailor-made medications.

Antitumor activity of a dual epidermal growth factor receptor and ErbB2 kinase inhibitor MP-412 (AV-412) in mouse xenograft models.

Although epidermal growth factor receptor (EGFR) kinase inhibitors are effective for the treatment of non-small cell lung cancer (NSCLC), the emergence of mutations resistant to these inhibitors, such as T790M, has become a clinical problem. Recently, ErbB2 mutations have also been identified in a small number of NSCLC patients. Therefore, novel therapies to overcome these mutations are desirable. We describe the antitumor activity of MP-412 (AV-412), a dual EGFR/ErbB2 kinase inhibitor, against three lung cancer models with EGFR and ErbB2 mutations and also against various human xenografts with overexpression of these receptors. MP-412 inhibited phosphorylation of EGFR and its downstream signaling in NCI-H1650 and NCI-H1975 cell lines, which harbor the E746-A750 deletion and L858R + T790M point mutations, respectively, in EGFR. MP-412 inhibited the growth of these cell lines in vitro and in vivo, whereas the precedent kinase inhibitors lapatinib, erlotinib, and gefitinib were ineffective against NCI-H1975 cells in vivo. Furthermore, MP-412 inhibited ErbB2 signaling in the NCI-H1781 cell line, which harbors the G776V,C insertion in ErbB2, and correlated with its antiproliferation activity. When its antitumor spectrum was further explored in several cancer types overexpressing EGFR or ErbB2, MP-412 showed potent activity in KPL-4 and DU145 xenografts, in which lapatinib was ineffective. MP-412 also inhibited tumor models in which conventional chemotherapies were less effective. These results suggest that MP-412 is a potent dual inhibitor with the potential for treating solid cancers that overexpress EGFR or ErbB2, including NSCLC cells harboring mutations resistant to the first generation of kinase inhibitors.

MEN4901/T-0128, a new camptothecin derivative-carboxymethyldextran conjugate, has potent antitumor activities in a panel of human tumor xenografts in nude mice.

PURPOSE: The purpose of the present study was to evaluate the antitumor activity and pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human tumor xenografts in comparison with irinotecan (CPT-11) and T-2513. EXPERIMENTAL DESIGN: We have determined the antitumor activity of MEN4901/T-0128, CPT-11, and T-2513 in BALB/cA Jcl nude mice bearing human gastric (H-81), colon (H-110), lung (Mqnu-1, H-74), esophageal (H-204), liver (H-181), and pancreatic (H-48) cancer lines, which had been serially transplanted s.c. and maintained in nude mice, and characterized the pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human gastric carcinoma St-4. RESULTS: MEN4901/T-0128 administered i.v. showed a marked antitumor activity in each of these tumor models, producing tumor shrinkage in the models of H-204 and H-181 carcinomas at its maximum tolerated dose of 80 mg/kg (expressed as T-2513) weekly for 4 weeks (q7d x 4) and tumor-shrinking or marked growth-inhibitory effects in the models of H-81, H-110, Mqnu-1, H-74, and H-48 carcinomas at 1/3 of its maximum tolerated dose (q7d x 4). Pharmacokinetic analysis showed that MEN4901/T-0128 had an extended plasma half-life with sustained tumor levels of T-2513, which may explain the superior activity of MEN4901/T-0128 in vivo. CONCLUSIONS: Because the efficacies of some drugs in this human cancer-nude mouse panel correlated well with their clinical outcomes in patients with the same type of cancers, the findings provide direct support that MEN4901/T-0128 is more efficacious than CPT-11 and is an excellent candidate for clinical trials for the treatment of solid tumors.

Dependence of chemotherapy response on p53 mutation status in a panel of human cancer lines maintained in nude mice.

In contrast to findings in vitro, the clinical response to anticancer chemotherapy is not simply associated with the p53 mutation status. To analyze the relationship between the actual response of solid tumors with p53 mutation and other biological characteristics, we used a human cancer-nude mouse panel of 21 lines derived from stomach, colorectal, breast, lung, and liver cancers for experimental chemotherapy. We examined the tumor growth rates of the cancer lines and the effects of nine drugs in clinical use, namely, mitomycin C (MMC), cisplatin (CDDP), nimustine hydrochloride (ACNU), irinotecan (CPT-11), cyclophosphamide (CPA), 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207), a 4:1 mixture of uracil and FT-207 (UFT), 5'-deoxy-5-fluorouridine (5'-DFUR), and adriamycin (ADM), on these tumors. The chemotherapy response was expressed as the tumor growth inhibition rate (IR). The genomic DNA sequences of the p53 gene in exons 5 through 8 were analyzed in these cancer tissues, and p53 mutations were detected in 10 of the 21 cancer lines (48%). Resistance to MMC was observed in p53 mutant tumors with smaller IRs than those for wild-type tumors (57.7% vs. 79.9%, P < 0.03). No significant differences were noted with the other eight drugs. To explore the role of the p53 function in the chemotherapy response, we calculated the correlation coefficients between chemosensitivity and tumor growth rate separately in p53 mutant and wild-type groups. In the p53 wild-type group, we found a positive correlation for the following drugs: ADM (P < 0.02), ACNU (P < 0.007), CPA (P < 0.011), UFT (P < 0.012), and FT-207 (P < 0.02). In the p53 mutant group, only CPA (P < 0.003) showed a positive correlation. The kinetics suggests that in the wild-type tumors, DNA damage caused by anticancer drugs occurs proportionally to the rate of DNA synthesis, and p53-mediated apoptosis is subsequently induced. The low frequency of positive correlation in the p53 mutant tumors is compatible with the loss of function or malfunction of mutant p53. The present results provide kinetic evidence that p53 function affects the response to anticancer drugs. Preserved p53 function tended to confer good chemosensitivity on rapidly growing tumors. However, the p53 mutation status did not seem to be suitable for use as an exclusive indicator to predict the chemotherapy response of human cancer xenografts.

[Antitumor activity of combination treatment combining gemcitabine with topotecin against human lung cancer xenografted in nude mice].

Gemcitabine is a new deoxycytidine derivative that shows a distinguishing, potent antitumor activity against various human tumor lines transplanted to nude mice. We have investigated the antitumor activity of gemcitabine combined with cisplatin (CDDP) or vindesine (VDS) using a lung cancer line, H-74, that was insensitive to almost all antitumor drugs and relatively insensitive to gemcitabine. We found that the antitumor effects of gemcitabine combined with CDDP or VDS were more potent and lasted longer than that of each drug alone, without an increase in side effects such as body weight loss. In this study, the antitumor activity of combined gemcitabine with topotecin (CPT-11) was evaluated using a similar method for 8 weeks, including a 4-week treatment period and a subsequent 4-week drug-free period, with reference to tumor growth inhibition rate, histological changes, and side effects. The treatment combining gemcitabine with CPT-11 administered at each 1/2 MTD showed an additive effect at 4 and 8 weeks after start of administration. Furthermore, no remarkable side effects were observed. Since these study results demonstrated that gemcitabine combined with CPT-11 increased and prolonged the antitumor activity without increasing side effects such as body weight loss, it is expected that CPT-11 could be one of the useful drugs used in combination with gemcitabine for lung cancer therapy.

Anti-tumor effect of intraperitoneal administration of cisplatin-loaded microspheres to human tumor xenografted nude mice.

This study evaluates the anti-tumor effect of cisplatin-loaded microspheres (CDDP-MS) against peritoneal carcinomatosis using human tumor xenografts. The incorporated CDDP was released from CDDP-MS for 3 weeks in vivo as well as in vitro. CDDP-MS at a dose of 35 mg/kg (at maximal tolerable dose (MTD)) showed effective anti-tumor activity (tumor growth inhibition rate (IR)=70.3%) against Li-7 (human liver cancer) xenografts transplanted into the peritoneal cavity. This procedure also resulted in increased life span (ILS (%)=47.2%), whereas CDDP dissolved in saline solution (CDDP-SOL) at a dose of 8 mg/kg (at MTD) was ineffective (IR=15.7%, ILS=2.6%). Likewise, CDDP-MS (35 mg/kg) significantly prolonged the mean survival time (ILS=50.8%) compared with a CDDP-SOL group (8 mg/kg) (ILS=13.1%) in the mice with Li-7 xenografts transplanted into the spleen. Furthermore, CDDP-MS showed markedly effective anti-tumor activity (IR=82.2%) against H-154 (human stomach cancer) xenografts, in which CDDP-SOL was effective (IR=69.5%) at the MTDs. The suppressive effect of CDDP-MS on accumulation of malignant ascites was intimately related to unchanged CDDP concentration in ascites. These results demonstrated that the administration of CDDP-MS resulted in an unchanged CDDP concentration in ascites, and induced a sustained tumor growth inhibition along with a prolonged survival time.