Identifying prognostic biomarkers for palbociclib add-on therapy in fulvestrant-resistant breast cancer using cell-free DNA sequencing.

BACKGROUND: The FUTURE trial (UMIN000029294) demonstrated the safety and efficacy of adding palbociclib after fulvestrant resistance in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced and metastatic breast cancer (ABC/MBC). In this planned sub-study, cancer panel sequencing of cell-free DNA (cfDNA) was utilized to explore prognostic and predictive biomarkers for further palbociclib treatment following fulvestrant resistance. MATERIALS AND METHODS: Herein, 149 cfDNA samples from 65 patients with fulvestrant-resistant disease were analysed at the time of palbociclib addition after fulvestrant resistance (baseline), on day 15 of cycle 1, and at the end of treatment using the assay for identifying diverse mutations in 34 cancer-related genes. RESULTS: During the course of treatment, mutations in ESR1, PIK3CA, FOXA1, RUNX1, TBX3, and TP53 were the most common genomic alterations observed. Analysis of genomic mutations revealed that before fulvestrant introduction, baseline PIK3CA mutations were marginally lower in metastatic aromatase inhibitor (AI)-treated patients compared to adjuvant AI-treated patients (P = 0.063). Baseline PIK3CA mutations were associated with poorer progression-free survival [hazard ratio: 1.62, P = 0.04]. Comparative analysis between baseline and early-changing gene mutations identified poor prognostic factors including early-changing MAP3K1 mutations (hazard ratio: 4.66, P = 0.04), baseline AR mutations (hazard ratio: 3.53, P = 0.04), and baseline PIK3CA mutations (hazard ratio: 3.41, P = 0.02). Notably, the relationship between ESR1 mutations and mutations in PIK3CA, MAP3K1, and TP53 weakened as treatment progressed. Instead, PIK3CA mutations became correlated with TP53 and FOXA1 mutations. CONCLUSIONS: Cancer panel testing for cfDNA identified prognostic and predictive biomarkers for palbociclib add-on therapy after acquiring fulvestrant resistance in patients with HR+/HER2- ABC/MBC.

Ramucirumab plus FOLFIRI as second-line treatment for patients with RAS wild-type metastatic colorectal cancer previously treated with anti-EGFR antibody: JACCRO CC-16.

BACKGROUND: Chemotherapy in combination with anti-epidermal growth factor receptor (EGFR) antibody is considered a first-line treatment regimen for RAS wild-type and left-sided metastatic colorectal cancer (mCRC), whereas second-line treatment regimens have not yet been established. Few studies have prospectively evaluated second-line treatment with anti-vascular endothelial growth factor antibody after first-line anti-EGFR antibody therapy for RAS wild-type mCRC. PATIENTS AND METHODS: This non-randomized phase II trial investigated the clinical outcomes of second-line ramucirumab (RAM) plus fluorouracil, levofolinate, and irinotecan (FOLFIRI) after first-line anti-EGFR antibody in combination with doublet or triplet regimen in patients with RAS wild-type mCRC. The primary endpoint was the 6-month progression-free survival (PFS) rate. The secondary endpoints were PFS, overall survival (OS), objective response rate (ORR), rate of early tumor shrinkage (ETS), and safety. We hypothesized a threshold 6-month PFS rate of 30% and an expected 6-month PFS rate of 45%. Treatment was considered effective if the lower limit of the 90% confidence interval (CI) of the 6-month PFS rate was >0.30. RESULTS: Ninety-two patients were enrolled in the study. The primary tumor was located on the left side in 86 (95.6%) patients. Twenty (22.0%) patients had received triplet plus cetuximab as previous therapy. Six-month PFS rate was 58.2% (90% CI 49.3% to 66.2%) with a median PFS of 7.0 months (95% CI 5.7-7.6 months). Median OS was 23.6 months (95% CI 16.5-26.3 months). The ORR and ETS rate were 10.7% and 16.9%, respectively, in 83 patients with measurable lesions. The 6-month PFS rate was comparable between patients previously treated with doublet and triplet regimens; however, median PFS was longer for the doublet regimen (7.4 versus 6.4 months, P = 0.036). CONCLUSIONS: Our study demonstrated prospectively that RAM plus FOLFIRI is an effective second-line treatment after anti-EGFR antibody-containing first-line therapy in RAS wild-type and left-sided mCRC. Furthermore, the results were similar for patients who were previously treated with triplet regimen.

Recurrent Aphthous Stomatitis Caused by Cytomegalovirus, Herpes Simplex Virus, and Candida Species in a Kidney Transplant Recipient: A Case Report.

Recipients of organ transplants are immunosuppressed and at high risk of oral infection. Oral diseases are often neglected compared with infections of other organs that typically confer higher morbidity. However, severe local symptoms hinder oral intake, decrease quality of life, and are sometimes lethal. Here we describe a case of a 57-year-old woman who developed recurrent aphthous stomatitis after kidney transplantation; the cause of the infection was complex and included cytomegalovirus, herpes simplex virus, and Candida species. Since misdiagnosis of oral diseases impairs patient quality of life and increases morbidity, clinicians should be aware of possible etiologies of oral infections in renal transplant recipients.

Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).

BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.

Blue-light hazard from CO2 arc welding of mild steel.

OBJECTIVES: The objective was to quantify the blue-light hazard from CO(2) arc welding of mild steel. METHODS: The spectral radiance of arcs in CO(2) arc welding of mild steel was measured for solid and flux-cored wires at welding currents of 120-480 A. Effective blue-light radiance and the maximum acceptable exposure duration were calculated from the spectral radiance using their definitions in American Conference of Governmental Industrial Hygienists guidelines. RESULTS: The effective blue-light radiance ranged from 22.9 to 213.1 Wcm(-2)sr(-1). The corresponding maximum acceptable exposure duration was only 0.47-4.36 s, meaning that the total daily exposure to the welding arc without eye protection should not exceed this duration. CONCLUSIONS: It is very hazardous to view the arcs in CO(2) arc welding of mild steel. Welders and their helpers should use appropriate eye protectors in these arc-welding operations. Also, they should avoid direct light exposure when starting an arc-welding operation.

Canine oocyte maturation in culture: significance of estrogen and EGF receptor gene expression in cumulus cells.

We examined the role of cumulus cells regarding in vitro maturation of canine oocytes, and investigated estrogen and epidermal growth factor (EGF) receptor gene expression and action on nuclear maturation. Canine cumulus-oocyte complexes (COC) were collected from anestrous and diestrous bitches; only COC with vitelline diameter >100 microm were used. In Experiment 1, expression of estrogen receptor (ER) alpha, ERbeta and EGF-receptor (EGF-R) were determined by reverse transcription-polymerase chain reaction (RT-PCR), using mRNA from the oocyte or cumulus cell. Transcripts for the ERbeta and EGF-R were detected in oocytes and cumulus cells, but no message was detected for ERalpha. In Experiment 2, intact COC and the denuded oocytes were cultured in TCM199 medium supplemented with various concentrations of estradiol-17beta (E(2); 0-10 microg/mL) or EGF (0-100 ng/mL) for 72 h; nuclear maturation was then evaluated. In oocytes cultured within intact COC, the rate of germinal vesicle breakdown (GVBD) was higher in the 1 microg/mL E(2) supplemented group (P<0.05), and the rate of metaphase I (MI) was higher in the 10 ng/mL EGF supplemented group, than in the non-supplemented group (P<0.05). However, supplementation of E(2) or EGF to denuded oocytes failed to promote nuclear maturation. In Experiment 3, intact COC were cultured in TCM199 supplemented with 1 microg/mL E(2), 10 ng/mL EGF, and 10% fetal bovine serum (FBS) for 72 h, and nuclear maturation was evaluated. There was no significant difference in the rate of metaphase II (MII) between the medium only, E(2)+EGF, and FBS supplement groups. When E(2) and EGF in combination with FBS were supplemented, the rate of MII was higher than in other groups (P<0.05). We inferred that cumulus cells were involved in mediating the stimulatory effects of E(2) and EGF on nuclear maturation of canine oocytes, and that E(2) and EGF in combination with FBS promoted the completion of oocyte meiotic maturation.

Compact Er:Yb:glass-laser-based supercontinuum source for high-resolution optical coherence tomography.

We present a low coherence light source by direct super-continuum generation from a diode-pumped, passively modelocked Er:Yb:glass-laser, which generates 198 fs transform-limited pulses with an average power of 100 mW at a repetition rate of 75 MHz. The pulse train is launched into a dispersion optimized highly nonlinear fiber for spectral broadening. The optical bandwidth spans from 1150 nm to 2400 nm, which is more than one octave. The potential for ultrahigh-resolution optical coherence tomography (OCT) is demonstrated by coherence measurements supporting an axial resolution of 3.5 microm in air.

Phosphorylation and interaction of the movement and coat proteins of brome mosaic virus in infected barley protoplasts.

The 3a movement protein (B3a) of brome mosaic virus (BMV) plays essential roles in the cell-to-cell movement of BMV. B3a is known to bind nucleic acids, to transport RNA to neighbouring cells, and to form tubular structures. Here, we tested the assumption that phosphorylation may be a mechanism that regulates B3a functions and showed that not only B3a but also the coat protein, BCP, was phosphorylated in BMV-infected barley protoplasts. Both BCP and B3a were detected in a complex immunoprecipitated from BMV-infected protoplasts with anti-B3a antiserum, implying an interaction between BCP and B3a.

An unusual renal vascular anomaly: common origin of arteries to the lower poles demonstrated by a computed tomography angiography using 16-slice multidetector computed tomography.

Arterial connection between the left and right kidneys is extremely rare. Only eight cases of such anomalous conditions have been reported in the world literature and all were confirmed by invasive angiography or dissection. We report a patient with this vascular anomaly clearly demonstrated by 16-slice multidetector computed tomography.

Ocular blood flow changes after dynamic exercise in humans.

PURPOSE: To investigate control mechanisms for ocular blood flow changes after dynamic exercise using two different methods. METHODS: Changes over time in the tissue blood flow in the retina and choroid-retina of healthy volunteers were determined after dynamic exercise (Master's double two-step test), using scanning laser Doppler flowmetry (SLDF) and laser speckle flowgraphy (LSFG). Changes in intraocular pressure (IOP), blood pressure, plasma CO(2) gas concentration (pCO(2)), and levels of nitric oxide (NO) metabolites were examined. RESULTS: Retinal blood flow measured by SLDF increased significantly only at 15 min after exercise. In contrast, normalized blur (NB) values in the choroid-retina, obtained by LSFG, increased significantly up to 60 min after exercise. Ocular perfusion pressure (OPP), calculated from IOP and blood pressure, increased significantly immediately and 15 min after exercise. The plasma NO metabolite levels increased significantly, although pCO(2) levels were unchanged. CONCLUSIONS: Dynamic exercise changes OPP and produces increased tissue blood flow in the retina in the immediate postexercise period, while blood flow increases more persistently in the choroid-retina. Difference in control of blood flow in these two regions may be related to stronger autoregulatory mechanism of blood flow in the retina. Nitric oxide may play a role in the regulation of blood flow.

Coat protein-independent cell-to-cell movement of bromoviruses expressing brome mosaic virus movement protein with an adaptation-related amino acid change in the central region.

The movement protein (MP) of Brome mosaic virus (BMV) depends on the coat protein (CP) to mediate the cell-to-cell movement of BMV and CCMV(B3a), a recombinant Cowpea chlorotic mottle virus (CCMV) expressing BMV MP. Previous studies identified gain-of-function mutations in the central region of BMV MP that enable CCMV(B3a) to adapt to a resistant host. This study demonstrates that all adaptation-related MPs can partially or almost fully mediate the cell-to-cell movement of CCMV(B3a) and BMV without CP. Based on these results, we discuss adaptation mechanisms of CCMV(B3a) and the role of the central region of MP in the determination of virus movement mode.

Synthesis of infectious in vitro transcripts from Cassia yellow blotch bromovirus cDNA clones and a reassortment analysis with other bromoviruses in protoplasts.

Cassia yellow blotch virus (CYBV), genus Bromovirus, was isolated from the Australian native legume, Cassia pleurocarpa, in western Queensland, and its host range was found to be distinct from other bromoviruses. In this study, CYBV was shown to infect systemically and efficiently a model plant species, Arabidopsis thaliana, as we recently reported for another bromovirus, Spring beauty latent virus (SBLV). We constructed full-length cDNA clones of CYBV genomic RNAs from which infectious in vitro transcripts can be transcribed, and determined their complete nucleotide sequences. CYBV RNA3 contains the box B motif in the intercistronic region, but lacks the subgenomic promoter-like sequence in the 5' noncoding region, as does Brome mosaic virus (BMV). To understand relationships among bromoviruses, we generated reassortants between CYBV and three other bromoviruses, BMV, SBLV and Cowpea chlorotic mottle virus. We found that all reassortants between BMV and CYBV accumulated viral RNAs to detectable levels in protoplasts of Nicotiana benthamiana, even when RNAs 1 and 2, which encode the replication proteins 1a and 2a, respectively, were heterologous. Sequence comparison and reassortment experiments of CYBV and other bromoviruses demonstrated that CYBV is closely related to BMV.

Chromoendoscopy using indigo carmine dye spraying with magnifying observation is the most reliable method for differential diagnosis between non-neoplastic and neoplastic colorectal lesions: a prospective study.

BACKGROUND AND AIMS: Differential diagnosis between non-neoplastic and neoplastic lesions is very important at colonoscopy, since removal or biopsy of non-neoplastic polyps wastes time and resources. We therefore conducted a prospective study to examine whether indigo carmine dye spraying with and without magnification is more reliable than the conventional method for differential diagnosis. PATIENTS AND METHODS: 122 patients with 206 lesions of 10 mm or smaller were recruited into this study. All lesions detected on colonoscopy were first diagnosed using the conventional view, then at chromoendoscopy using 0.2 % indigo carmine, and finally at chromoendoscopy with magnification. The diagnosis at each step were recorded consecutively. All lesions were finally categorized as neoplastic or non-neoplastic according to pit pattern; non-neoplastic lesions were biopsied for histological evaluation, and all the neoplastic ones were removed endoscopically. The accuracy rate of each type of endoscopic diagnosis was evaluated, using histological findings as reference. RESULTS: Histologically, 46 lesions (22 %) were non-neoplastic and 160 (78 %) were neoplastic. The overall diagnostic accuracies by conventional view, chromoendoscopy, and chromoendoscopy with magnification were 84.0 % (173/206), 89.3 % (184/206) and 95.6 % (197/206), respectively. CONCLUSION: Chromoendoscopy with magnification is the most reliable method for determining whether a colorectal lesion is non-neoplastic or neoplastic.

Diurnal variation in microcirculation of ocular fundus and visual field change in normal-tension glaucoma.

PURPOSE: Diurnal variations in microcirculation of the ocular fundus in normal-tension glaucoma (NTG) were examined to compare with the normal control eyes. The correlation between progression of visual field impairment and diurnal variations in ocular circulation was also studied. METHODS: The subjects were 12 patients with NTG and 12 normal controls. Blood pressure (BP), intraocular pressure (IOP), ocular perfusion pressure (OPP), and square blur rate (SBR), an index of microcirculation acquired by the laser speckle method, were measured at 9 a.m. (morning), 3 p.m. (afternoon), and 9 p.m. (night). Diurnal variations in SBR were tested using the Friedman test and Wilcoxon signed ranks test. On the other hand, diurnal variations in BP, IOP, and OPP were tested by the analysis of variance. The visual field was evaluated at the same time as determining diurnal variation and again about 9 months later to calculate the change. The correlation between variation ratio in SBR and the change in visual field was examined by simple regression. RESULTS: A significant decrease (P=0.04) was found in SBR at night, as compared with the morning value, in the optic nerve head (ONH) of NTG, although no significant diurnal variations were found in SBR either in the choroid-retina or in normal control eyes. Other parameters showed no significant diurnal variations. The larger diurnal variation was in SBR of the ONH, and the more exacerbated visual field impairment was (r=0.59, P=0.04). CONCLUSION: These findings suggest that diurnal variations in the microcirculation of the ONH may play a role in the progression of NTG.

A neonatal form of glycogen storage disease type IV.

We report of an infant with neonatal glycogen storage disease type IV (GSD IV) who was examined for severe hypotonia and cardiomyopathy. On the muscle biopsy there were many fibers with diastase-resistant polyglucosan bodies. Glycogen branching enzyme (GBE1) activity in the muscle was markedly reduced. The infant had a homozygous single nucleotide deletion in the open reading frame of GBE1 gene.

[Surgically treated mucoepidermoid carcinoma in a 6-year-old boy; report of a case].

A 6-year-old boy was admitted to our hospital with a history of recurrent obstructive pneumonia and hemoptysis. A chest computed tomography (CT) showed atelectasis in the left lower lobe. Angiograpy, which was performed for the suspicion of pulmonary sequestration, showed no feeding artery and revealed bleeding from the bronchial artery in the left lower lobe. As hemoptysis would not stop, an emergency left lower lobectomy was performed. Macroscopic examination of the resected specimen revealed a mass measuring 20 x 15 x 17 mm in the S8 proximal lung parenchyma, bronchiectasis, and an abscess in the distal lung parenchyma. Histopathologic examination determined the tumor was a mucoepidermoid carcinoma. Immunohistochemical staining revealed some tumor cells were positive for CA 19-9. The child has not had a recurrence 3 years postoperatively.

Malignant transformation in a mature testicular teratoma left untreated for more than 50 years since childhood.

Although testicular teratoma in childhood is regarded as a benign tumor, little is known about the consequences of pediatric teratoma being left untreated. We report herein a case of malignant transformation observed in a mature testicular teratoma that was presumed to have remained benign for >50 years.

The movement protein gene is involved in the virus-specific requirement of the coat protein in cell-to-cell movement of bromoviruses.

Brome mosaic virus (BMV) requires the coat protein (CP) for cell-to-cell movement whereas Cowpea chlorotic mottle virus (CCMV), from the same genus, does not. Chimeric viruses created by exchanging the movement protein (MP) gene between the viruses can move from cell to cell. We show that interference in CP expression impaired the movement of the chimeric CCMV with the BMV MP gene but not of the chimeric BMV with the CCMV MP gene. We thus conclude that the MP gene plays a crucial role in determination of the virus-specific CP requirement in bromovirus cell-to-cell movement.