Totally laparoscopic resection of right-sided colon cancer using transvaginal specimen extraction with a 10-mm-long abdominal incision.

BACKGROUND: Natural orifice specimen extraction (NOSE) has been developed as a means of decreasing the incidence of surgical wound complications. We refined the procedure for totally laparoscopic colectomy with transvaginal specimen extraction using the reduced port surgery technique with the ultimate goal of attenuating damage to the abdominal wall. We herein report this innovative technique and its short- and long-term outcomes. METHODS: We prospectively collected data on seven patients who underwent totally laparoscopic colectomy using transvaginal specimen extraction with a 10-mm-long abdominal incision for right-sided colon cancer from January 2014 to December 2021. Two 5-mm ports were used in the procedure without laparotomy. Transverse transabdominal posterior colpotomy was then performed. We introduced a GelPOINT Mini advanced access platform (Applied Medical, Rancho Santa Margarita, CA, USA) into the transvaginal route for the insertion of a laparoscope, forceps, and stapling device. Lymph node dissection and transection of the ileum and distal colon were performed with transvaginal assistance. A specimen was then extracted transvaginally. Intracorporeal functional end-to-end anastomosis was conducted using a linear stapler through the vagina. After the removal of GelPOINT Mini, the vaginal incision was closed transvaginally. RESULTS: Seven patients successfully underwent this procedure. Median operative time was 219 min (range 174-255 min), median blood loss was 23 ml (range 10-37 ml), median number of harvested lymph nodes was 21 (range 17-35 lymph nodes) and median margins were 17.0 cm (range 9.0-25.0 cm) for the proximal margin and 9.5 cm (range 5.0-13.0 cm) for the distal margin. There were no complications more severe than Clavien-Dindo Grade II and there was no mortality. The median frequency of use intravenous analgesics from postoperative day 1 to discharge was once. Two patients did not require analgesics. A node-positive patient developed recurrence at the lung and paraaortic lymph nodes. CONCLUSIONS: This procedure appears to be feasible, safe, and oncologically acceptable for selected cases.

Large-scale prospective genome-wide association study of oxaliplatin in stage II/III colon cancer and neuropathy.

BACKGROUND: The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN. To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach. PATIENTS AND METHODS: A large prospective GWAS including 1379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial. Firstly, GWAS comparison of worst grade PSN (grade 0/1 versus 2/3) was carried out. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored. RESULTS: No SNPs exceeded the genome-wide significance (P < 5.0 × 10-8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. An association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs. CONCLUSION: Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice.

Treatment of twin-reversed arterial perfusion sequence using high-intensity focused ultrasound.

We describe our experience of high-intensity focused ultrasound (HIFU) for fetal therapy in twin-reversed arterial perfusion (TRAP) sequence. Six pregnant women underwent HIFU therapy, five before 16 weeks and one at 26 weeks. Two types of HIFU system were used: the first-generation system, which comprised a biaxial transducer and continuous exposure pattern, and the second-generation system, which comprised a coaxial transducer and sequential exposure pattern. The first-generation apparatus was used in four cases and the second-generation apparatus was used in two. In three cases, occlusion of the blood vessels mediating flow to the acardiac twin was achieved by HIFU. Two cases experienced intrauterine fetal death despite vessel occlusion. The total survival rate of pump fetuses 2 years after HIFU was 67% and the efficiency rate (the proportion of cases with occlusion or reduced blood flow on ultrasound after HIFU) was 83%. After more than 2 years of follow-up, the surviving infants had no severe clinical complications and no postnatal developmental problems. There was no significant difference in survival rate compared with TRAP cases managed expectantly. Given that complete occlusion of the blood vessels was not achieved in half of the cases, we could not show that HIFU therapy is superior to other treatments. However, HIFU can reduce the cardiac load of the pump fetus and, as it does not require uterine puncture for fetal therapy, there were no fatal complications, such as bleeding, rupture of membranes or infection. Thus, HIFU therapy may represent a less-invasive treatment for TRAP sequence in early pregnancy. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Large-scale prospective pharmacogenomics study of oxaliplatin-induced neuropathy in colon cancer patients enrolled in the JFMC41-1001-C2 (JOIN Trial).

BACKGROUND: Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study. PATIENTS AND METHODS: Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN. RESULTS: Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences. CONCLUSIONS: Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.

A DFT and multi-configurational perturbation theory study on O2 binding to a model heme compound via the spin-change barrier.

Dioxygen binding to a model heme compound via intersystem crossing (ISC) was investigated with a multi-state multi-configurational self-consistent field method with second-order perturbation theory (MS-CASPT2) and density functional theory (DFT) calculations. In elongated Fe-O distances, the energy levels of the S0 and T1 states are separated, which decreases the probability of intersystem crossing in these structures. At the DFT(B97D) level of calculation, the Fe-O distances of the S0 and T1 states were 1.91 and 2.92 Å, respectively. The minimum energy intersystem crossing point (MEISCP) was located as a transition state at a Fe-O distance of 2.17 Å with an energy barrier of 1.0 kcal mol(-1) from the T1 minimum. The result was verified with MS-CASPT2 calculations including the spin-orbit interaction which also showed the intersystem crossing point at a Fe-O distance of 2.05 Å. An energy decomposition analysis on the reaction coordinate showed the important contribution of the ring-shrinking mode of the porphyrin ring, indicating that the reaction coordinates which control the relative energy level of the spin-states play a key role in intersystem crossing.

Genome-wide association study identifies a potent locus associated with human opioid sensitivity.

Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. Although opioid sensitivity is well known to vary widely among individual subjects, several candidate genetic polymorphisms reported so far are not sufficient for fully understanding the wide range of interindividual differences in human opioid sensitivity. By conducting a multistage genome-wide association study (GWAS) in healthy subjects, we found that genetic polymorphisms within a linkage disequilibrium block that spans 2q33.3-2q34 were strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery. The C allele of the best candidate single-nucleotide polymorphism (SNP), rs2952768, was associated with more analgesic requirements, and consistent results were obtained in patients who underwent abdominal surgery. In addition, carriers of the C allele in this SNP exhibited less vulnerability to severe drug dependence in patients with methamphetamine dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence' score on a personality questionnaire in healthy subjects. Furthermore, the C/C genotype of this SNP was significantly associated with the elevated expression of a neighboring gene, CREB1. These results show that SNPs in this locus are the most potent genetic factors associated with human opioid sensitivity known to date, affecting both the efficacy of opioid analgesics and liability to severe substance dependence. Our findings provide valuable information for the personalized treatment of pain and drug dependence.

Prediction of early- and late-onset pregnancy-induced hypertension using placental volume on three-dimensional ultrasound and uterine artery Doppler.

OBJECTIVES: To determine whether uterine artery (UtA) Doppler findings and three-dimensional (3D) ultrasound measurement of placental volume during the first trimester allowed prediction of early- and late-onset pregnancy-induced hypertension (early PIH and late PIH). METHODS: Subjects with singleton pregnancy who underwent an ultrasound scan at 11-13 weeks' gestation and delivered between 2011 and 2013 were enrolled prospectively into the study. The UtA Doppler indices and placental volume on 3D ultrasound at 11-13 weeks' gestation in cases that developed early PIH (< 34 weeks) or PIH later in pregnancy (≥ 34 weeks) were compared with values in unaffected pregnancies. RESULTS: Ten cases of early PIH, 67 cases of late PIH and 1285 unaffected pregnancies were analyzed. The UtA pulsatility index (PI) was higher in cases of early PIH than that in unaffected pregnancies (median, 2.35 vs. 1.79; P = 0.043) but did not differ between cases of late PIH and unaffected pregnancies. Placental volume was smaller in cases of early PIH than that in unaffected pregnancies (median, 43 cm3 vs. 62 cm(3) ; P = 0.003) but did not differ between cases of late PIH and unaffected pregnancies. The area under the receiver-operating characteristics curve for the prediction of early PIH, by combining UtA-PI and placental volume, was 0.832 (95% CI, 0.742-0.921), with this combination providing a detection rate for early PIH of 67.5% for a 5% false-positive rate. CONCLUSIONS: High UtA-PI and small placental volume were observed more often in cases of early PIH compared with unaffected pregnancies, but not in cases of late PIH. These results may indicate that there are differences in pathophysiology between early PIH and late PIH.

Wearable near-infrared spectroscopy: reliability and sensitivity among different endurance cycling exercise intensities.

The present study investigated the reliability and sensitivity of a wearable near-infrared spectroscopy (wNIRS) device in moderate and heavy exercise intensity domains. On three separate days, eleven males performed an incremental test to exhaustion, and in the following visits, four submaximal constant-load bouts (i.e., test and retest) were performed in the moderate-intensity domain (100 and 130 W) and heavy-intensity domain (160 and 190 W). The local tissue oxygen saturation index (SmO2) and pulmonary oxygen uptake (V̇O2) were measured continuously. The absolute SmO2 and V̇O2 values and the change (Δ) from the 3rd to 6th min of exercise were calculated. There was good reliability for SmO2 measurements, as indicated by the high intraclass correlation coefficient analysis (ICC ≥0.84 for all) and low coefficient of variation between the two trials (CV ≤4.1% for all). Steady-state responses were observed for SmO2 and V̇O2 from the 3rd to the 6th min in the two moderate-intensity bouts (P>0.05), whereas SmO2 decreased and V̇O2 increased from the 3rd to the 6th min in the two heavy-intensity bouts (P<0.05). Together, these findings suggested that the SmO2 measured with a wNIRS device is reliable and sensitive to track local metabolic changes provoked by slight increments in exercise intensity.

First successful case of non-invasive in-utero treatment of twin reversed arterial perfusion sequence by high-intensity focused ultrasound.

High-intensity focused ultrasound (HIFU) has excellent potential as a non-invasive therapeutic tool in various fields of medicine. We present a case of twin reversed arterial perfusion sequence, in which non-invasive blood flow occlusion in the acardiac fetus was successfully achieved by means of HIFU exposure from outside the maternal abdomen. HIFU was applied to blood vessels of the acardiac fetus at the point at which the umbilical cord entered the body in a series of four procedures at 3-day intervals starting at 13 weeks' gestation, and in a final procedure with higher power at 17 weeks. The HIFU intensity was set at approximately 2300 W/cm(2) for the initial series of procedures and at 4600 W/cm(2) for the final procedure, with exposure periods of 10 s. As color Doppler examination revealed absence of blood flow to the acardiac fetus after the second round of HIFU exposure, we concluded that complete occlusion of target vessels had been achieved. Delivery was by Cesarean section at 37 weeks' gestation. A male neonate (the pump fetus) was born weighing 1903 g with Apgar scores of 8 and 9 at 1 and 5 min, respectively. At the time of writing, the baby was healthy and growing normally, with the exception of congenital pseudarthrosis.

Evaluation of chlorinated benz[a]anthracene on hepatic toxicity in rats and mutagenic activity in Salmonella typhimurium.

Chlorinated benz[a]anthracenes (Cl-BaA) are halogenated aromatic compounds (typified by dioxins) found in the environment at relatively high concentrations. Fischer 344 rats were intragastrically administered 0, 1, or 10 mg of Cl-BaA or its parent compound benz[a]anthracene (BaA) per kg of body weight for 14 consecutive days. Both chemicals at 10 mg/kg/day inhibited the gain in body weight, and consequent increase in relative liver weight. Hepatic gene expression of cytochrome P450 (CYP) 1A1, 1A2, and 1B1 was significantly stimulated by administration of BaA (10 mg/kg/day) compared with the control. After administration of Cl-BaA, only the CYP1A2 gene was significantly induced, even at the lower dosage; CYP1A1 and 1B1 mRNA levels remained unchanged in Cl-BaA-treated rats compared with controls. To elucidate the role of such Cl-BaA exposure and induced CYPs at toxicity onset, we investigated the mutagenicity of BaA and Cl-BaA using Salmonella typhimurium TA98 and TA100. BaA and Cl-BaA at 10 µg/plate produced positive results in both strains in the presence of rat S-9. Incubation of Cl-BaA with recombinant rat CYP1A2 produced a significantly higher number of revertant colonies in TA98 and TA100 than in controls, but no such change was observed for BaA. In conclusion, BaA changes its own physiological and toxicological actions by its chlorination; (1) daily exposure to Cl-BaA selectively induces hepatic CYP1A2 in rats and (2) Cl-BaA induces frameshift mutations in the presence of CYP1A2, although BaA does not exert mutagenicity. This indicates that CYP1A2 may metabolize Cl-BaA to active forms.

High-intensity focused ultrasound treatment for twin reversed arterial perfusion sequence.

Twin reversed arterial perfusion (TRAP) sequence is a serious complication of monochorionic twin pregnancies, in which arterioarterial anastomoses allow blood flow from a 'pump' fetus to an acardiac fetus via reversed flow in the latter's umbilical artery. Several trial treatments for TRAP sequence have been reported, but all of these have been invasive. We present a case of TRAP sequence in which high-intensity focused ultrasound (HIFU) was applied to the umbilical artery of the anomalous twin at 26 weeks as a non-invasive fetal therapy. The HIFU intensity was set at approximately 2300 W/cm(2) with exposure periods of 10 s. Color Doppler ultrasound showed a decrease in blood supply to the anomalous twin, although complete occlusion of the targeted vessel was not achieved. Delivery was by Cesarean section at 29 weeks' gestation and the pump twin survived, without severe clinical complications at 6 months.

Location of the placenta or the umbilical cord insertion site in the lowest uterine segment is associated with low maternal blood pressure.

OBJECTIVE: To evaluate whether placental abnormalities and umbilical cord insertion site affect the occurrence of pre-eclampsia and maternal blood pressure. DESIGN: Case-control study. SETTING: Showa University Hospital, Tokyo, Japan. POPULATION: A total of 5722 consecutive women who delivered singleton infants were included in the study. METHODS: The associations of placental abnormalities, the location of the placenta, the location of the cord insertion site, and maternal background with the occurrence of pre-eclampsia and maternal blood pressure at the term of pregnancy were analysed. MAIN OUTCOME MEASURE: Pre-eclampsia and maternal blood pressure at the term of pregnancy. RESULTS: Pre-eclampsia was observed in 236 women (4.1%). Pre-eclampsia was frequently observed in women with placental form abnormalities (odds ratio 3.0) and infarction of the placenta (odds ratio 5.3). Pre-eclampsia was observed in 0 and 4.1% of women with and without placenta praevia, respectively (P = 0.004), and in 0 and 2.5% of women with and without low cord insertion during the first trimester, respectively (P = 0.018). After adjustment for confounding variables, the multivariate regression analyses revealed reductions of 8.4 and 5.0 mmHg in systolic and diastolic blood pressure, respectively, in women with placenta praevia compared with women without placenta praevia, and reductions of 4.3 and 3.1 mmHg in systolic and diastolic blood pressure, respectively, in women with low cord insertion during the first trimester compared with women without low cord insertion. CONCLUSION: Not only placenta praevia but also low cord insertion are associated with low frequencies of pre-eclampsia and low maternal blood pressure.

Footwear designed to enhance energy return improves running economy compared to a minimalist footwear: does it matter for running performance?

The present study compared the effects of a footwear designed to enhance energy return (thermoplastic polyurethane, TPU) vs minimalist shoes on running economy (RE) and endurance performance. In this counterbalanced and crossover design study, 11 recreational male runners performed two submaximal constant-speed running tests and two 3-km time-trials with the two shoe models. Oxygen uptake was measured during submaximal constant-speed running tests in order to determine the RE at 12 km/h and oxygen cost of running (CTO2) at individual average speed sustained during the 3-km running time-trials wearing either of the two shoes. Our results revealed that RE was improved (2.4%) with TPU shoes compared with minimalist shoes (P=0.01). However, there was no significant difference for CTO2 (P=0.61) and running performance (P=0.52) comparing the TPU (710±60 s) and the minimalist (718±63 s) shoe models. These novel findings demonstrate that shoes with enhanced mechanical energy return (i.e. TPU) produced a lower energy cost of running at low (i.e., 12 km/h) but not at high speeds (i.e., average speed sustained during the 3-km running time-trial, ∼15 km/h), ultimately resulting in similar running performance compared to the minimalist shoe.

Detection of umbilical venous constriction by Doppler flow measurement at midgestation.

OBJECTIVES: To investigate whether umbilical venous velocity and venous velocity pulsation are associated with umbilical vein diameter, umbilical ring diameter and umbilical cord coiling index at midgestation. METHODS: Two hundred and eighty pregnant women were enrolled in the study at between 18 and 24 weeks of gestation. The diameter of the umbilical cord and internal diameter of the umbilical vein in a free loop and at the ring, and the umbilical coiling index, were measured using ultrasonography. Umbilical venous velocities were measured by Doppler ultrasonography at the umbilical ring and a free loop of the cord. RESULTS: All variables were successfully measured in 92% of the patients. There were negative correlations between the diameters of the umbilical ring and of the umbilical vein at the ring and the venous velocity at the umbilical ring. The venous velocity at the umbilical ring was significantly higher and the umbilical ring diameter was significantly lower in fetuses with umbilical venous pulsation at the free loop. Significant correlations were observed between the venous velocity and amplitude of pulsation. Venous pulsations at the free loop were frequently observed in fetuses with a hypercoiled cord. CONCLUSION: High venous velocity and increased venous pulsation at the umbilical ring may be associated with umbilical cord constriction.

A detailed analysis of the spin-crossover reaction of H2S binding to heme and the six-coordinated FeP(Im)-HS- porphyrin complex.

The potential energy surfaces of the H2S binding to iron-porphyrin (FeP) with the imidazole (Im) ligand via intersystem crossings are investigated by using density functional theory. The minimum energy intersystem crossing point (MEISCP) between the quintet and triplet states (MEISCPTQ) for the Fe(II)P(Im)-H2S complex is located at a Fe-S distance of 3.39 Šwith only 1.1 kcal/mol above the quintet state minimum. The second spin-crossover point, where a change from the triplet to the singlet state occurs, comes at a much shorter Fe-S distance of 2.79 Å, and the MEISCPST is located at 3.7 kcal/mol above the triplet state minimum. The nature of the chemical bonding along the Fe-S reaction coordinate from the ground state singlet to the quintet state along the path to the separated species is analyzed. An inspection of the vibrational modes reveals that the largest contribution to the triplet-quintet transition around the quintet and triplet state minimum comes from the symmetric shrinking of the pyrrole units of the porphyrin ring, indicating that the related reaction coordinate plays a main role in the intersystem crossing. The fully optimized structures of the Fe(II)P(Im)-HS- complex corresponding to three different spin multiplicities (M = 1, 3, 5) are characterized by a bent Fe-H-S conformation. The binding of the hydrosulfide anion to Fe(II)P(Im) in the quintet state induces a 0.2 Šdisplacement of the Fe atom out of the nitrogen porphyrin (Npyr) plane. The fully optimized structure of the ground state of Fe(II)P(Im)-HS- agrees well with experimental data for the corresponding heme models.

Predisposing factors for massive hemorrhage during Cesarean section in patients with placenta previa.

OBJECTIVES: To investigate whether maternal history and ultrasound findings can be predictors for massive hemorrhage during Cesarean section in patients with placenta previa and adherence of the placenta. METHODS: We reviewed 127 singleton pregnancies with placenta previa. Maternal history, antenatal ultrasound findings of the placenta, including location, presence of placental lacunae, lack of a clear zone, presence of sponge-like findings of the cervix and presence of a marginal sinus in cases of placenta previa were reviewed retrospectively, and their association with amount of bleeding during Cesarean section was analyzed. RESULTS: Logistic regression analysis revealed that advanced maternal age (odds ratio (OR), 5.4; 95% CI, 1.8-16.4), previous Cesarean section (OR, 20.4; 95% CI, 4.0-105.2) and sponge-like findings in the cervix (OR, 5.6; 95% CI, 1.8-17.0) were associated with massive bleeding (> 2500 mL). Placental adherence occurred in five cases and was more frequent in cases where the placenta was located at the site of the scar of a previous Cesarean section (OR, 123.1; 95% CI, 4.5-3395.2) and where there was lack of a clear zone (OR, 48.0; 95% CI, 3.8-604.7). CONCLUSIONS: Advanced maternal age, previous Cesarean section and presence of sponge-like findings in the cervix are risk factors for massive bleeding during Cesarean section in cases of placenta previa, regardless of whether placental adherence is present. Placental location on the scar of a previous Cesarean section and lack of a clear zone are risk factors for placental adherence. When these findings are identified preoperatively, management should be tailored accordingly.