Dynamic changes in RAS gene status in circulating tumour DNA: a phase II trial of first-line FOLFOXIRI plus bevacizumab for RAS-mutant metastatic colorectal cancer (JACCRO CC-11).

BACKGROUND: Few prospective studies have used liquid biopsy testing in RAS-mutant metastatic colorectal cancer (mCRC), and its clinical significance remains unknown. Therefore, this study aimed to carry out a biomarker analysis by liquid biopsy using updated data of the phase II trial of FOLFOXIRI plus bevacizumab as first-line chemotherapy for RAS-mutant mCRC. MATERIALS AND METHODS: A total of 64 patients who received modified FOLFOXIRI regimen (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, levofolinate 200 mg/m2, and fluorouracil 2400 mg/m2) plus bevacizumab biweekly were enrolled. The primary endpoint was the objective response rate (ORR). Plasma samples were collected at pre-treatment, 8 weeks after treatment, and progression in participants included in the biomarker study. The levels of circulating tumour DNA (ctDNA) and specific KRAS and NRAS variants were evaluated using real-time PCR assays. RESULTS: There were 62 patients (median age: 62.5 years, 92% performance status 0, 27% right side) who were assessable for efficacy and 51 for biomarker analysis. ORR was 75.8% (95% confidence interval 65.1% to 86.5%). The median progression-free survival was 12.1 months, and the median overall survival (OS) was 30.2 months. In 78% of patients, RAS mutations disappeared in the ctDNA at 8 weeks after treatment; these patients tended to have better outcomes than those with RAS mutations. Interestingly, RAS mutations remained undetectable during progression in 62% of patients. Survival analysis indicated that the median OS from progression was significantly longer in patients with RAS mutation clearance than in those with RAS mutation in the ctDNA at disease progression (15.1 versus 7.3 months, hazard ratio: 0.21, P = 0.0046). CONCLUSIONS: Our biomarker study demonstrated no RAS mutations in ctDNA at disease progression in 62% of patients with RAS-mutant mCRC. Both OS and post-progression survival were better in patients with clearance of RAS mutations in ctDNA after triplet-based chemotherapy.

S-1 and oxaliplatin versus tegafur-uracil and leucovorin as post-operative adjuvant chemotherapy in patients with high-risk stage III colon cancer: updated 5-year survival of the phase III ACTS-CC 02 trial.

BACKGROUND: The ACTS-CC 02 trial demonstrated that S-1 plus oxaliplatin (SOX) was not superior to tegafur-uracil and leucovorin (UFT/LV) in terms of disease-free survival (DFS) as adjuvant chemotherapy for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). We now report the final overall survival (OS) and subgroup analysis according to the pathological stage (TNM 7th edition) for treatment efficacy. PATIENTS AND METHODS: Patients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, five cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80 mg/m2/day of S-1 on days 1-14, every 21 days, eight cycles). The primary endpoint was DFS and the patients' data were updated in February 2020. RESULTS: A total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the final analysis. With a median follow-up time of 74.3 months, the 5-year DFS rate was 55.2% in the UFT/LV group and 58.1% in the SOX group [stratified hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.76-1.11; P = 0.3973], and the 5-year OS rates were 78.3% and 79.1%, respectively (stratified HR 0.97; 95% CI 0.76-1.24; P = 0.8175). In the subgroup analysis, the 5-year OS rates in patients with T4N2b disease were 51.0% and 64.1% in the UFT/LV and SOX groups, respectively (HR 0.72; 95% CI 0.40-1.31). CONCLUSION: Our final analysis reconfirmed that SOX as adjuvant chemotherapy is not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer. The 5-year OS rate was similar in the UFT/LV and SOX groups.

Synaptotagmin XIII expression and peritoneal metastasis in gastric cancer.

BACKGROUND: Peritoneal metastasis is a frequent cause of death in patients with gastric cancer. The aim of this study was to identify molecules responsible for mediating peritoneal metastasis of gastric cancer. METHODS: Transcriptome and bioinformatics analyses were conducted to identify molecules associated with peritoneal metastasis. The therapeutic effects of intraperitoneally administered small interfering (si) RNA were evaluated using mouse xenograft models. Expression of mRNA and protein was determined in gastric tissues from patients with gastric cancer. RESULTS: Synaptotagmin XIII (SYT13) was expressed at significantly higher levels in patients with peritoneal recurrence, but not in those with hepatic or distant lymph node recurrence. Inhibition of SYT13 expression in a gastric cancer cell line transfected with SYT13-specific siRNA (siSYT13) was associated with decreased invasion and migration ability of the cells, but not with proliferation and apoptosis. Intraperitoneal administration of siSYT13 significantly inhibited the growth of peritoneal nodules and prolonged survival in mice. In an analysis of 200 patients with gastric cancer, SYT13 expression in primary gastric cancer tissues was significantly greater in patients with peritoneal recurrence or metastasis. A high level of SYT13 expression in primary gastric cancer tissues was an independent risk factor for peritoneal recurrence. CONCLUSION: SYT13 expression in gastric cancer is associated with perioneal metatases and is a potential target for treatment.

Geographic distribution and environmental control of vertebral count in Ammodytes spp. along the northern Pacific coast of Japan.

To examine species composition and population structures in sand lance (Ammodytidae) along the northern Pacific coast of Japan, genetic analysis were carried out for specimens collected in 2014 from Otsuchi Bay, Iwate, Ishinomaki Bay, Miyagi, off Soma, Fukushima and Ise-Mikawa Bays, Aichi. The samples consisted of Ammodytes japonicus and Ammodytes heian, of which the latter is a recently described species. Neither species exhibited significant genetic differences among localities. Only A. japonicus was found in the most southern locality at Aichi, but it decreased northward to <90% in Miyagi and Fukushima and the two species occurred almost evenly in Iwate suggesting a latitudinal cline in their species composition along the northern Pacific coast of Japan, off Tohoku. The vertebral counts differed between A. japonicus and A. heian with modes of 65 and 63, respectively, but this characteristic did not differ significantly within a locality (Iwate). This suggests that the vertebral counts of Ammodytes spp. in Japanese waters are probably strongly determined by the environment than by a species-specific genetic trait.

Children with nocturnal enuresis have posture and balance disorders.

INTRODUCTION: Integration of the neuromuscular system is required for maintaining balance and adequate voiding function. Children with enuresis have delayed maturation of the motor cortex, with changes in the sensory and motor systems. Along with various alterations, including the genetic, hormonal, behavioral, and sleep disturbances, and neuromotor and sensory deficits associated with nocturnal enuresis (NE) in children and adults, a consistent alteration in the posture of children with NE has been observed in the current practice. Because posture and the balance control system are strongly connected, this study aimed to investigate posture and balance in children and teenagers with NE. MATERIAL AND METHODS: A total of 111 children with enuresis were recruited to the enuretic group (EG) and 60 asymptomatic children made up the control group (CG). The participants were divided into two age subgroups: (A) 7-11 years old, N = 77 for EG/A, N = 38 for CG/A; and (B) 12-16 years old, N = 34 for EG/B, N = 22 for CG/B. Balance was assessed using an electronic force plate (100 Hz) to calculate the area of the center of pressure (COP) displacement. The COP is the point that results from the action of vertical forces projected onto the force plate. Sensory integration was analyzed using a 60-s trial with the subject standing under four conditions: (1) eyes open, stable surface; (2) eyes closed, stable surface; (3) eyes open, unstable surface; (4) eyes closed, unstable surface. Posture was assessed by placing reflective anatomical landmarks on the anterior superior iliac spine, the posterior superior iliac spine, the greater trochanter, and lateral malleolus. A photograph was taken while the subject stood quietly. The angles were obtained from landmark connections using software to assess the following posture variables: pelvic ante/retroversion and pelvic ante/retropulsion. RESULTS: The EG showed a greater area of COP displacement compared with the CG under all four sensory conditions and both subgroups, except for EG/B in condition 3. Regarding posture, EG showed higher pelvic anteversion angles than CG. CONCLUSIONS: Enuretic children showed forward inclination of the pelvis and had worse balance compared with control children.

Salvage pharyngolaryngectomy with total esophagectomy following definitive chemoradiotherapy.

Historically, total pharyngolaryngectomy with total esophagectomy has been the standard radical surgical treatment for synchronous cancer of the thoracoabdominal esophagus and pharyngolaryngeal region, and for cancer of the cervical esophagus that has invaded as far as the thoracic esophagus. Although definitive chemoradiotherapy that enables preservation of the larynx has often been the first choice of treatment for cancers involving the cervical esophagus, total pharyngolaryngectomy with total esophagectomy is required as a salvage therapy for cases involving failure of complete remission or locoregional recurrence after chemoradiotherapy. However, salvage esophageal surgery after definitive high-dose chemoradiotherapy is generally associated with high morbidity and mortality. The aim of this study was to examine the short-term outcome of salvage total pharyngolaryngectomy with total esophagectomy. From 2001 to 2014, nine patients underwent salvage total pharyngolaryngectomy with total esophagectomy at the Department of Gastroenterological Surgery, Nagoya University. The mortality and morbidity rates were high at 22% and 89%, respectively. Four patients (44%) developed tracheal necrosis, which in two patients eventually led to lethal hemorrhage. Salvage total pharyngolaryngectomy with total esophagectomy is an uncommon and highly demanding surgical procedure that should be carefully planned and conducted in selected centers of excellence. Measures must be taken to preserve the tracheal blood supply, thus avoiding fatal complications.

Maloclusión pseudoclase III en la dentición decidua resolución con aparato progénico / Pseudo Class III malocclusion treatment in primary dentition with progenic appliance

La maloclusión pseudoclase III es caracterizada par un desequilibrio funcional que, por lo general, resulta de contactos oclusales prematuros que causan un desplazamiento funcional anterior de la mandíbula. Estos casos, si no son tratados en una etapa inicial de desarrollo, pueden generar interferencias en el crecimiento normal de las bases óseas y resultar en una deformidad facial. Este papel conlleva a la selecci6n de un aparato apropiado, tomando cuenta opciones actuales, para una intervenci6n temprana en el desarrollo de maloclusiones de clase III. El uso del aparato progenico en este tipo de maloclusión, permite la correcci6n dental en pocos meses y una estabilidad terapéutica de la mandíbula mesio-posicionada fomentando un crecimiento esquelético favorable en una niña de 5,6 años de edad que acude a la clínica de postgrado del Instituto Latino Americano de Investigaci6n y Enseñanza Odontológica (ILAPEO) en Curitiba, Brasil...

Pseudo Class III malocclusion is a functional imbalance that generally results from premature occlusal contacts that causes a functional anterior displacement of the mandible. These cases, if not treated at an early stage of development, may interfere in normal growth of bone bases, resulting in facial deformity. This paper suggests the selection of an adequate appliance considering the available possibilities for early intervention of Class III malocclusion. The use of the progenic appliance in such dental malocclusion allows correction in a few months and therapeutic stability mesio-positioned mandible encouraging favorable skeletal growth in a child of 5.6 years of age who came to the Postgraduate Clinic of the Latin American Institute of Dental Research and Education (ILAPEO) in Curitiba, Brazil...

An internally and externally validated nomogram for predicting the risk of irinotecan-induced severe neutropenia in advanced colorectal cancer patients.

BACKGROUND: In Asians, the risk of irinotecan-induced severe toxicities is related in part to UGT1A1*6 (UGT, UDP glucuronosyltransferase) and UGT1A1*28, variant alleles that reduce the elimination of SN-38, the active metabolite of irinotecan. We prospectively studied the relation between the UGT1A1 genotype and the safety of irinotecan-based regimens in Japanese patients with advanced colorectal cancer, and then constructed a nomogram for predicting the risk of severe neutropenia in the first treatment cycle. METHODS: Safety data were obtained from 1312 patients monitored during the first 3 cycles of irinotecan-based regimen in a prospective observational study. In development of the nomogram, multivariable logistic regression analysis was used to test the associations of candidate factors to severe neutropenia in the first cycle. The final nomogram based on the results of multivariable analysis was constructed and validated internally using a bootstrapping technique and externally in an independent data set (n=350). RESULTS: The UGT1A1 genotype was confirmed to be associated with increased risks of irinotecan-induced grade 3 or 4 neutropenia and diarrhoea. The final nomogram included type of regimen, administered dose of irinotecan, gender, age, UGT1A1 genotype, Eastern Cooperative Oncology Group performance status, pre-treatment absolute neutrophil count, and total bilirubin level. The model was validated both internally (bootstrap-adjusted concordance index, 0.69) and externally (concordance index, 0.70). CONCLUSIONS: Our nomogram can be used before treatment to accurately predict the probability of irinotecan-induced severe neutropenia in the first cycle of therapy. Additional studies should evaluate the effect of nomogram-guided dosing on efficacy in patients receiving irinotecan.

Longitudinal changes in objectively measured sedentary behaviour and their relationship with adiposity in children and adolescents: systematic review and evidence appraisal.

This review aimed to determine longitudinal changes in objectively measured overall sedentary behaviour, and to examine their associations with adiposity in children and adolescents. A search for longitudinal studies was performed using several electronic databases. Of 161 potentially eligible papers, 10 for change in sedentary behaviour and 3 for longitudinal associations with change in adiposity were included. Weighted mean increase in daily sedentary behaviour per year was 5.7% for boys and 5.8% for girls. Only one paper included preschool children, and it showed a decrease in sedentary behaviour. Nine studies were from Western countries. Null associations were reported between sedentary behaviour and adiposity in two studies, the other found that increases in sedentary behaviour were associated with increases in adiposity, but only in those with body mass index above the 50th percentile. There was consistent evidence that sedentary behaviour increases with age in school-age children and adolescents, by approximately 30 min extra daily sedentary behaviour per year. There was little evidence on the influence of changes in sedentary behaviour on changes in adiposity. There is a need for more longitudinal research, for more evidence from outside the Western world, and for more studies that examine 'dose-response' associations between changes in sedentary behaviour and changes in adiposity.

Proteins differentially expressed by Shiga toxin-producing Escherichia coli strain M03 due to the biliar salt sodium deoxycholate.

Shiga toxin-producing Escherichia coli (STEC) can cause conditions ranging from diarrhea to potentially fatal hemolytic uremic syndrome. Enteropathogen adaptation to the intestinal environment is necessary for the development of infection, and response to bile is an essential characteristic. We evaluated the response of STEC strain M03 to the bile salt sodium deoxycholate through proteomic analysis. Cell extracts of strain M03 grown with and without sodium deoxycholate were analyzed by two-dimensional electrophoresis; the differentially expressed proteins were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Three proteins were found to be differentially expressed due to sodium deoxycholate. Glycerol dehydrogenase and phosphate acetyltransferase, which are involved in carbon metabolism and have been associated with virulence in some bacteria, were downregulated. The elongation factor Tu (TufA) was upregulated. This protein participates in the translation process and also has chaperone activities. These findings help us understand strategies for bacterial survival under these conditions.

The effects of repetitive haemarthrosis on postural balance in children with haemophilia.

Sensory information from visual, vestibular and proprioceptive systems is necessary to control posture and balance. Impairment in proprioception due to repetitive joints bleeding may lead to a deficit in postural balance which, in turn, leads to high joint stress and risk of bleeding recurrence. Despite the increase in attention in this field during the past few years, the data concerning to how bleeds can affect postural control in children with haemophilia (CWH) remain scarce. This study aimed to evaluate the postural balance in CWH. Twenty CWH Haemophilia Group (HG) and 20 age-matched children Control Group (CG) were recruited to this study. A force plate was used to record centre of pressure (COP) displacement under four different postural conditions during quiet standing: eyes open on firm surface, eyes open on foam surface, eyes closed on firm surface and eyes closed on a foam surface. Variables of COP as sway area and mean velocity and in anterior-posterior (y) medio-lateral (x) direction were processed and for each variable sensory, quotients were calculated and compared between groups. No differences were found in visual and vestibular quotients variables between groups. A higher value was found in sway area variable on proprioception quotient in the HG when compared with CG (P = 0.042). CWH with repetitive joint bleed on lower limbs showed differences in postural balance when compared with non-haemophiliac children. The identification of early balance impairments in CWH can help us understand better the effects of bleeds inside joints on postural control and plan a more effective preventive and rehabilitative treatment.

Postural adjustment after an unexpected perturbation in children with haemophilia.

Children with haemophilia often bleed inside joints and muscles, which may impair postural adjustments. These postural adjustments are necessary to control postural balance during daily activities. The inability to quickly recover postural balance could elevate the risk of bleeding. To determine whether children with haemophilia have impaired postural adjustment after an unexpected perturbation compared with healthy children. Twenty children with haemophilia comprised the haemophilic group (HG), and 20 healthy, age-paired children comprised the control group (CG). Subjects stood on a force plate, and 4% of the subjects' body weight was applied via a pulley system to a belt around the subjects' trunks. The centre of pressure (COP) displacement was measured after the weight was unexpectedly released to produce a controlled postural perturbation followed by postural adjustment to recover balance. The subjects' postural adjustments in eight subsequent intervals of 1 s (t1-t8), beginning with the moment of weight removal, were compared among intervals and between groups. The applied perturbation magnitudes were the same for both groups, and no difference was observed between the groups in t1. However, the COP displacement in t2 in the HG was significantly higher than in the CG. No differences were observed between the groups in the other intervals. Within-group analysis showed that the COP was higher in t2 than in t4 (P = 0.016), t5 (P = 0.001) and t8 (P = 0.050) in the HG. No differences were observed among intervals in the CG. Children with haemophilia demonstrated differences in postural adjustment while undergoing unexpected balance perturbations when compared with healthily children.

Mass balance, excretion and metabolism of [¹4C] ASA404 in cancer patients in a phase I trial.

PURPOSE: To determine the mass balance, excretion and metabolism of the small molecule flavonoid tumour vascular disrupting agent ASA404 in patients with advanced cancer. METHODS: Seven cancer patients were given a single dose of 3,000 mg [(14)C] ASA404 by intravenous infusion over 20 min prior to collection of samples of plasma, urine and faeces. Pharmacokinetic samples were analysed by HPLC, liquid scintillation counting, mass spectrometry, glusulase treatment and comparison to authentic standards. Descriptive pharmacokinetic parameters were generated by noncompartmental analysis. RESULTS: Mass balance was achieved (mean recovery of radioactivity in excreta = 86.9% of the dose) with balanced excretion between urine (mean recovery of radioactivity in urine = 53.9% of dose) and faeces (mean recovery of radioactivity in faeces = 33.3% of dose). ASA404 was eliminated as parent drug, three known metabolites (6-methylhydroxy-ASA404, ASA404 acyl glucuronide and 6-methylhydroxy-ASA404 acyl glucuronide) and two novel metabolites (an ASA404 dimer and an ASA404 dimer glucuronide conjugate). Unchanged ASA404 was the major radioactivity component detected in plasma within the first 24 h after dosing. At later time points, irreversibly protein bound ASA404 and all of the metabolites that had been detected in excreta contributed to total plasma radioactivity. CONCLUSION: This study defined the substantial excretion of ASA404, mainly as metabolites, in both urine (over half of the dose) and faeces (about one-third of the dose) after intravenous administration. Two novel metabolites were identified that were not reported by previous studies using nonradioactive techniques.

Understanding contradictory data in contraction stress tests.

The literature shows contradictory results regarding the role of composite shrinkage and elastic modulus as determinants of polymerization stress. The present study aimed at a better understanding of the test mechanics that could explain such divergences among studies. The hypothesis was that the effects of composite shrinkage and elastic modulus on stress depend upon the compliance of the testing system. A commonly used test apparatus was simulated by finite element analysis, with different compliance levels defined by the bonding substrate (steel, glass, composite, or acrylic). Composites with moduli between 1 and 12 GPa and shrinkage values between 0.5% and 6% were modeled. Shrinkage was simulated by thermal analogy. The hypothesis was confirmed. When shrinkage and modulus increased simultaneously, stress increased regardless of the substrate. However, if shrinkage and modulus were inversely related, their magnitudes and interaction with rod material determined the stress response.

Can fiber posts increase root stresses and reduce fracture?

The clinical success of fiber posts has been attributed to their lower elastic modulus. The tested hypothesis was that fiber posts could lead to lower risk of post debonding and lower risk of root fracture, despite an increase in root stresses. Stress analyses were carried out with a 3D finite element model of a premolar restored with a metallic or a fiber post. Bonded and non-bonded post/cement interface conditions were simulated. We calculated risk-of-fracture indices by determining the highest principal stress values divided by the tensile strength. Shear stresses along the post/cement interface were analyzed for the bonded models. Compared with the premolar restored with a metallic post, the fiber post generated lower stresses along the interface and higher stresses in the root. However, with the fiber post, fracture was less likely to occur in the root, since its core and post fracture indices were higher.

Clinical pharmacokinetics of the BCR-ABL tyrosine kinase inhibitor nilotinib.

This article describes studies that investigated the pharmacokinetics of nilotinib, a highly specific, oral, second-generation BCR-ABL tyrosine kinase inhibitor. After a once- or twice-daily regimen at doses ranging from 50 to 1,200 mg/day in 119 patients with chronic myeloid leukemia (CML), the area under the serum concentration-time curve (AUC) and peak serum concentration (C(max)) of nilotinib were found to be nearly dose proportional up to a dose of 400 mg once daily. Solubility-limited absorption at higher doses was observed, but this was partially overcome by dividing the daily dose into two. For instance, the administration of 400 mg nilotinib twice daily resulted in a 35% increase in AUC as compared to a once-daily dose of 800 mg. Exploratory pharmacodynamic assessment showed a general trend of greater reduction in white blood cell (WBC) levels with increase in nilotinib concentrations. This finding was consistent with the observation of an 82% reduction in WBC levels in patients after a regimen of 400 mg nilotinib twice daily for 15 days. The type and quantity of food intake variably affected nilotinib absorption. When administered after a high-fat meal, the AUC of nilotinib increased by 50% in CML patients (n = 10) and by 82% in healthy volunteers (n = 44).