Evaluation of pembrolizumab plus cisplatin and fluorouracil in radical treatment for patients with T4b esophageal squamous cell carcinoma.

BACKGROUND: Pembrolizumab plus cisplatin and 5-fluorouracil administered as first-line therapy for advanced esophageal cancer patients has shown a better objective response and survival than conventional chemotherapy with less severe hematological adverse events. The safety and efficacy of this regimen were evaluated in patients with T4b esophageal squamous cell carcinoma (ESCC). METHODS: Eight consecutive patients with T4b ESCC received this regimen according to KEYNOTE-590 as induction, and they were evaluated after 1-3 courses. The programmed death-ligand 1 (PD-L1) combined positive score (CPS) was also evaluated before chemotherapy. Efficacy for the primary lesion was evaluated by our original formula for the tumor reduction rate. RESULTS: The numbers of patients with partial response (PR), stable disease, and progressive disease (PD) were 5, 1, and 2, respectively. The tumor reduction rate ranged from 69 to 87% in PR patients, and all PR patients had relief from T4b. Two patients underwent conversion surgery with R0 resection. PD-L1 CPS was over 90 in 2 PR patients, but under 10 in 2 other PR patients. PD-L1 CPS was under 10 in PD patients. One patient had hyperprogression, resulting in an esophago-pulmonary fistula. Greater than grade 3 adverse events were bleeding gastric ulcer in one patient (12.5%), neutropenia without G-CSF in 3 patients (37.5%), and hypopotassemia in 1 patient (12.5%). No patient had febrile neutropenia. CONCLUSIONS: Marked tumor reduction was confirmed in 62.5% of patients with pembrolizumab plus cisplatin and 5-fluorouracil with less adverse events. This regimen could be administered as induction chemotherapy for patients with T4b ESCC.

PET/CT findings and dose distribution during radiotherapy in T1N0M0-T2N0M0 glottic cancer.

OBJECTIVE: To investigate the positron emission tomography/computed tomography (PET/CT) findings of T1/T2N0M0 glottic cancer (hereafter referred to as T1/T2) and dose distribution in radiotherapy. SUBJECTS AND METHODS: We retrospectively collected data from patients diagnosed with T1/T2N0M0 glottic cancer who received radiotherapy. The extent of fluorine-18-fluorodeoxyglucose (18F-FDG) accumulation in primary tumors, maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), tumor volume of primary tumors on PET/CT were compared. Furthermore, the tumor identified on PET/CT was incorporated into the radiotherapy plans. A dummy plan (radiation field 6x6cm, prescription point facing the vertebral body, maximum dose ≤107%, T1/T2 66Gy/33 fractions) was developed for three-dimensional conformal radiotherapy, and the dose distribution of primary tumors was calculated. RESULTS: Twenty-nine patients (27 men and two women) were included; their mean age was 67.2±15.0 years. Increased 18F-FDG accumulation in primary tumors was observed on PET/CT in 22/29 (78.5%; T1: 14/21 [67%], T2: 8/8 [100%]) patients. The median SUVmax, TLG, and primary tumor volume were significantly different between T1 and T2 (SUVmax, T1: 4.56 vs. T2: 8.43, P=0.035; TLG, T1: 1.01 vs. T2: 3.71 SUVxmL, P<0.01; primary tumor volume, T1: 0.38mL vs. T2: 0.80mL, P=0.01). At a TLG cut-off value of 3.470, the area under the curve was 0.875, sensitivity was 0.875, and specificity was 0.929 for T1-T2 differentiation. In 20 patients with 18F-FDG accumulation, the minimum radiation dose was significantly different between T1 and T2 (66Gy vs. 64Gy, P<0.01) at the same 66Gy prescription. The minimum radiation dose and primary tumor volume show the correlation value (r=-0.516, P=0.02). CONCLUSION: In glottic cancer, T1 and T2 can be differentiated by the extent of 18F-FDG accumulation in primary tumors on PET/CT. The minimum radiation dose rate decreases as volume increases.

Long-Term Prognosis and Related Factors in Patients with Cirrhosis Treated with Balloon-Occluded Retrograde Transvenous Obliteration.

INTRODUCTION: Balloon-occluded retrograde transvenous obliteration (BRTO) was developed as an effective treatment for gastric varices in patients with cirrhosis. Because liver fibrosis in these patients is assumed to be advanced, their prognosis is expected to be poor. In this study, we investigated the prognosis and characteristics of the patients. METHODS: We enrolled 55 consecutive patients with liver cirrhosis treated with BRTO between 2009 and 2021 at our department. To evaluate factors related to variceal recurrence and long-term prognosis, survival analysis was performed on 45 patients, excluding those who died within 1 month, had an unknown prognosis, or whose treatments were converted to other treatments. RESULTS: During a mean follow-up period of 2.3 years, esophageal varices recurred in 10 patients and could be treated endoscopically. Non-alcoholic steatohepatitis (NASH) was related to the variceal recurrence (hazard ratio [HR] = 4.27, 95% CI: 1.17-15.5, p = 0.028). The survival rate after the procedure at 1, 3, and 5 years was 94.2%, 74.0%, and 63.5%, respectively, and 10 patients died of hepatocellular carcinoma (n = 6), liver failure (n = 1), sepsis (n = 1), and unknown reasons (n = 2). The estimated glomerular filtration rate (eGFR) level was proved to be a significant poor prognostic factor (HR = 0.96, 95% CI: 0.93-0.99, p = 0.023). The comorbid hypertension (HTN) was the main cause of low eGFR, and HTN was also significantly related to survival (HR = 6.18, 95% CI: 1.57-24.3, p = 0.009). Most of the patients with HTN were treated with calcium channel blocker and/or angiotensin receptor blocker. CONCLUSION: The clinical course of patients with cirrhosis treated with BRTO was dependent on the metabolic factors including renal function, comorbid HTN, and NASH.

A good surgical field for para-aortic nodal dissection in gastric cancer by the Cattell-Braasch maneuver.

PURPOSE: Gastric cancer patients with para-aortic lymph node metastases may achieve long-term survival with radical gastrectomy and para-aortic lymph nodal dissection (PAND) following neoadjuvant therapy. We introduced the Cattell-Braasch maneuver to facilitate safe and complete PAND for advanced gastric cancer with extensive lymph node metastases. METHODS: Between January 2014 and March 2020, 7 patients with highly advanced gastric cancer received preoperative chemotherapy followed by radical gastrectomy and PAND using the Cattell-Braasch maneuver. This maneuver consists of mobilization of the right hemi-colon and the total small intestine. RESULTS: Five patients received preoperative chemotherapy for para-aortic lymph node metastases and 2 for bulky lymph node metastases around the supra-pancreatic area. All patients received S-1 + cisplatin therapy, and one was additionally treated with paclitaxel chemotherapy followed by nivolumab. After chemotherapy, 2 patients with para-aortic lymph node metastases achieved down-staging on imaging tests. Total gastrectomy with PAND by the Cattell-Braasch maneuver was performed on all patients and was accompanied by splenectomy (n = 5) and distal pancreatectomy (n = 1). Pathological assessments revealed that 3 patients had para-aortic lymph node metastases, and the median number of retrieved para-aortic lymph nodes was 16. Three patients without para-aortic lymph node metastasis survived for more than 5 years without recurrence. CONCLUSION: The Cattell-Braasch maneuver provides a good surgical field and is useful for complete PAND for gastric cancer.

Gain-of-function mutations in a member of the Src family kinases cause autoinflammatory bone disease in mice and humans.

Autoinflammatory syndromes are characterized by dysregulation of the innate immune response with subsequent episodes of acute spontaneous inflammation. Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder that presents with bone pain and localized swelling. Ali18 mice, isolated from a mutagenesis screen, exhibit a spontaneous inflammatory paw phenotype that includes sterile osteomyelitis and systemic reduced bone mineral density. To elucidate the molecular basis of the disease, positional cloning of the causative gene for Ali18 was attempted. Using a candidate gene approach, a missense mutation in the C-terminal region of Fgr, a member of Src family tyrosine kinases (SFKs), was identified. For functional confirmation, additional mutations at the N terminus of Fgr were introduced in Ali18 mice by CRISPR/Cas9-mediated genome editing. N-terminal deleterious mutations of Fgr abolished the inflammatory phenotype in Ali18 mice, but in-frame and missense mutations in the same region continue to exhibit the phenotype. The fact that Fgr null mutant mice are morphologically normal suggests that the inflammation in this model depends on Fgr products. Furthermore, the levels of C-terminal negative regulatory phosphorylation of Fgr Ali18 are distinctly reduced compared with that of wild-type Fgr. In addition, whole-exome sequencing of 99 CRMO patients including 88 trios (proband and parents) identified 13 patients with heterozygous coding sequence variants in FGR, including two missense mutant proteins that affect kinase activity. Our results strongly indicate that gain-of-function mutations in Fgr are involved in sterile osteomyelitis, and thus targeting SFKs using specific inhibitors may allow for efficient treatment of the disease.

The multi-kinase inhibitor dasatinib suppresses autoinflammation and increases bone density in a mouse model for chronic recurrent multifocal osteomyelitis.

Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disease that presents with bone destruction and pain. Although genetic studies have identified signalling pathways involving CRMO, molecularly targeted drugs remain unavailable. We used an animal model of CRMO as an in vivo screening system for candidate therapeutic agents. A gain-of-function mutation in Fgr, a member of Src family kinases (SFKs), causes peripheral paw inflammation and reduced bone mineral density (BMD) in Ali18 mice. The SFK inhibitor dasatinib was selected for administration to Ali18 mice daily for 2 weeks. Local inflammation and BMD were assessed by clinical scoring and computed tomography, respectively. Pilot studies in a small number of animals showed that dasatinib administration effectively suppressed the early phase of autoinflammation in Ali18 mice. Serial oral gavage of dasatinib to a group of Ali18 mice confirmed significant suppression of paw swelling with no side effects. Histological analysis revealed that abnormal proliferative bone marrow cells and inflammatory infiltration into the skin in the affected area were clearly reduced in the animals with dasatinib administration. Further, trabecular BMD in Ali18 long bones was restored to levels similar to that found in wild type mice. Our results indicate that autoinflammation and related-bone phenotypes were completely suppressed by the dasatinib kinase inhibitor in CRMO model animals. Thus, it is strongly suggested that dasatinib can be used for clinical treatments of CRMO with the combination of molecular diagnosis of the FGR locus. SIGNIFICANCE OF THE STUDY: Autoinflammation and related-bone phenotypes were effectively suppressed by the kinase inhibitor dasatinib in CRMO model animals. In combination with molecular analysis of the FGR locus, dasatinib is a strong candidate for the clinical treatments of CRMO. We propose that the animal model employed in this study can be used to screen this and other potential drugs for CRMO.

Low prevalence of colonic mucosal injury and bleeding in patients taking direct oral anticoagulants for non-valvular atrial fibrillation.

OBJECTIVE: Direct oral anticoagulants are frequently used to prevent systemic embolism associated with atrial fibrillation. Gastrointestinal bleeding is a common adverse event of this pharmacotherapy, especially in the lower gastrointestinal tract. However, the prevalence of mucosal injury of the colon in patients taking direct oral anticoagulants has remained unknown. MATERIALS AND METHODS: This was a retrospective study using endoscopic records of the colon from patients taking oral anticoagulants. Records from colonoscopies for 120 patients with non-valvular atrial fibrillation who had been prescribed direct oral anticoagulants between April 2011 and June 2017 were reviewed to determine the prevalence of mucosal injury and other findings, compared with those of 140 patients on warfarin. RESULTS: The prevalence of mucosal injury was 1.6% in patients taking direct oral anticoagulants and 1.4% in those taking warfarin, lower than other findings such as diverticula, hemorrhoids, and polyps. Bleeding was more frequent with direct oral anticoagulants (18 patients; 15%) than with warfarin (9 patients; 6.4%). Colonic diverticulum was the most common cause of bleeding in patients on direct oral anticoagulants. The prevalence of mucosal injury and causes of bleeding did not differ among direct oral anticoagulants. CONCLUSION: Colonic mucosal injury was infrequent in patients on direct oral anticoagulants. Bleeding was more frequent with direct oral anticoagulants than with warfarin. Colonic diverticulum and vascular ectasia were common causes of bleeding in patients on direct oral anticoagulants. Little difference in cause of bleeding was evident among oral anticoagulants.

Anatomical change of SMV branches after the Cattell Braasch maneuver facilitates safe resection around the uncinated process in pancreatoduodenectomy.

BACKGROUND: The aims of the present study were to demonstrate the anatomical change of superior mesenteric vein (SMV) branches and to show how the Cattell Braasch maneuver facilitates a safer ligation of these venous branches during a pancreatoduodenectomy (PD). METHODS: Between January 2010 and December 2019, 97 patients with peripancreatic tumors underwent pancreatectomy. We retrospectively reviewed preoperative triple-phase enhanced computed tomography (CT) images and analyzed variations in SMV branches. Anatomical changes in SMV branches after the Cattell Braasch technique were observed using our operation video and illustrations. RESULTS: The first jejunal vein (J1v) in 75% of patients ran posterior to the superior mesenteric artery (SMA), while the remainder (25%) ran anterior to it. The inferior pancreatoduodenal vein (IPDV) was preoperatively detected in 91% of patients. The IPDV drained into the J1v in 74% of patients and into the SMV in 37%. After the Cattell Braasch maneuver, the J1v which ran posterior to the SMA now was found to lie to the right anterolateral side the SMA and the visualization of both the J1v and the IPDV were much more clearly visualized. CONCLUSIONS: The most frequent venous variation was the IPDV draining into the J1v posterior to the SMA. After the Cattell Braasch maneuver, the IPDV was now located to the right anterolateral anterior aspect of the SMA which facilitates its visualization and should allow a safer ligation.

[Second-line therapy with mycophenolate mofetil in patients with autoimmune hepatitis who were intolerant or failed to respond to standard treatment].

Although standard treatment for autoimmune hepatitis (AIH) comprises prednisolone (PSL) and azathioprine (AZA), some patients are intolerant to or do not respond to PSL and/or AZA. The clinical practice guidelines of AIH in Europe and North America recommend mycophenolate mofetil (MMF) as second-line treatment in these patients. We administered MMF as second-line therapy to 7 patients with AIH (male/female 1/6, age range 27-79 years) who were intolerant to or failed to respond to standard treatment. At the commencement of MMF, the median ALT value was 84U/L (28-254U/L), and the PSL dose was 15.0mg/day (0-45mg/day). In terms of adverse effects of PSL, diabetes mellitus was observed in 4 patients (insulin injection in 2) and femoral head necrolysis in 2. Adverse effects of AZA were present in 2, and 5 patients were not treated with AZA. At 24 weeks of MMF treatment, the median ALT and daily PSL dose were decreased to 16U/L (6-41U/L) and 7.0mg, respectively. Blood sugar control improved, and insulin injection was discontinued in both the patients. While intractable diarrhea developed in 1 patient with cirrhosis, no adverse effect was observed in other 6 patients. In conclusion, MMF appeared effective and safe in at least non-cirrhotic patients with AIH who were intolerant or failed to respond to standard treatment with PSL and AZA in Japanese clinical practice.

Functional links between SQSTM1 and ALS2 in the pathogenesis of ALS: cumulative impact on the protection against mutant SOD1-mediated motor dysfunction in mice.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by a selective loss of motor neurons in the brain and spinal cord. Multiple toxicity pathways, such as oxidative stress, misfolded protein accumulation, and dysfunctional autophagy, are implicated in the pathogenesis of ALS. However, the molecular basis of the interplay between such multiple factors in vivo remains unclear. Here, we report that two independent ALS-linked autophagy-associated gene products; SQSTM1/p62 and ALS2/alsin, but not antioxidant-related factor; NFE2L2/Nrf2, are implicated in the pathogenesis in mutant SOD1 transgenic ALS models. We generated SOD1H46R mice either on a Nfe2l2-null, Sqstm1-null, or Sqstm1/Als2-double null background. Loss of SQSTM1 but not NFE2L2 exacerbated disease symptoms. A simultaneous inactivation of SQSTM1 and ALS2 further accelerated the onset of disease. Biochemical analyses revealed that loss of SQSTM1 increased the level of insoluble SOD1 at the intermediate stage of the disease, whereas no further elevation occurred at the end-stage. Notably, absence of SQSTM1 rather suppressed the mutant SOD1-dependent accumulation of insoluble polyubiquitinated proteins, while ALS2 loss enhanced it. Histopathological examinations demonstrated that loss of SQSTM1 accelerated motor neuron degeneration with accompanying the preferential accumulation of ubiquitin-positive aggregates in spinal neurons. Since SQSTM1 loss is more detrimental to SOD1H46R mice than lack of ALS2, the selective accumulation of such aggregates in neurons might be more insulting than the biochemically-detectable insoluble proteins. Collectively, two ALS-linked factors, SQSTM1 and ALS2, have distinct but additive protective roles against mutant SOD1-mediated toxicity by modulating neuronal proteostasis possibly through the autophagy-endolysosomal system.

Evaluation of renal cell carcinoma histological subtype and fuhrman grade using 18F-fluorodeoxyglucose-positron emission tomography/computed tomography.

OBJECTIVES: We evaluated 18F-fluorodeoxyglucose (FDG) uptake by renal cell carcinomas (RCCs) to determine whether different histological subtypes and Fuhrman grades can be distinguished. METHODS: We retrospectively reviewed the records and maximum standardised uptake value (SUVmax) of 147 patients with 154 RCCs who underwent FDG-positron emission tomography (PET)/computed tomography (CT) prior to tumour resection. RESULTS: The SUVmax was significantly lower in chromophobe RCC (chRCC) tumours than in clear cell RCC (ccRCC; p = 0.003) and papillary RCC (pRCC; p = 0.034) tumours. The mean tumour SUVmax was 4.58 ± 4.1 (range, 1.29-30.4) for ccRCC, 3.98 ± 1.9 (range, 0.49-6.72) for pRCC, and 1.93 ± 0.9 (range, 0.89-3.41) for chRCC. The SUVmax was not significantly different between the ccRCC and pRCC groups. In ccRCC and pRCC tumours, high-grade tumours had a significantly greater SUVmax (p < 0.001 and p < 0.05) than low-grade tumours by analysis of variance (ANOVA) and the Mann-Whitney U test. In ccRCC, multivariate regression analysis indicated that the SUVmax was a significant indicator of Fuhrman grade. No significant differences in uptake were observed between high- and low-grade chRCC tumours. CONCLUSIONS: The SUVmax obtained using FDG-PET/CT may be an important indicator for predicting tumour grade in ccRCC and pRCC. KEY POINTS: • FDG accumulation reflects tumour aggressiveness and correlates with Fuhrman grade. • FDG-PET/CT enables the differentiation of high- and low-grade ccRCC and pRCCs. • FDG-PET/CT may valuable in the identification of some high-grade RCCs.

Impact of lubiprostone on gastric-emptying profile and the possible effect of concomitant domperidone in healthy adults
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BACKGROUND: Lubiprostone is effective for patients with chronic constipation. This agent sometimes causes upper gastrointestinal symptoms, such as nausea, which is one of the chief reasons for discontinuation. However, the etiology of and strategy against bothersome gastrointestinal symptoms of lubiprostone remain unclear. AIMS: The goal of this study was to investigate the influence of lubiprostone on the gastric-emptying profile of healthy adults. The effect of domperidone on gastric emptying and gastrointestinal symptoms after lubiprostone administration were also assessed. MATERIALS AND METHODS: 80 healthy male participants underwent 13C acetate breath testing to evaluate gastric emptying. The test meal comprised 200 kcal of a standard liquid nutrient. Each participant underwent 3 random breath tests with: 1) no premedication; 2) 24 µg of lubiprostone 30 minutes prior to the study; and 3) 24 µg of lubiprostone plus 10 mg of domperidone 30 minutes prior to the study. Gastrointestinal symptoms (heartburn, regurgitation, epigastric pain, fullness, distress feeling) during testing were evaluated using a 7-point scoring system. RESULTS: Gastric emptying was significantly delayed by the administration of lubiprostone. Among all 8 subjects, 4 reported heartburn after taking lubiprostone, whereas this symptom was not found when subjects received concomitant domperidone. However, gastric emptying showed little change between lubiprostone alone and lubiprostone plus domperidone. CONCLUSION: Lubiprostone delayed gastric emptying of liquid in healthy adults, which could be associated with the gastrointestinal symptoms caused by the agent. Domperidone seemed effective against such gastrointestinal symptoms after administration of lubiprostone. This effect seemed unrelated to gastric motility.
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Extensive gastric mucosal atrophy is a possible predictor of clinical effectiveness of acotiamide in patients with functional dyspepsia
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BACKGROUND: Acotiamide is known as an effective agent for functional dyspepsia. However, clinical factors related to its effectiveness have not been fully elucidated, so it is difficult to predict the drug's effectiveness prior to its administration in patients. AIMS: The present retrospective study was conducted to examine the relationship between clinical factors and the effectiveness of acotiamide for functional dyspepsia. MATERIALS AND METHODS: The study subjects were 149 patients with functional dyspepsia who were prescribed acotiamide. Based on medical records and clinical factors, including endoscopic findings, the effectiveness of acotiamide was investigated. RESULTS: Significant clinical factors associated with acotiamide's effectiveness were identified. These included postprandial syndrome, concomitant mental disorder, and extensive gastric mucosal atrophy. On multiple regression analysis, extensive gastric mucosal atrophy showed the strongest relationship with the clinical effectiveness of acotiamide; the other significant factor was concomitant mental disorder. CONCLUSION: Although the pathophysiology of the relationship between mucosal atrophy and acotiamide remains uncertain, a decrease in hormonal secretion, such as that of ghrelin, may be a possible mechanism.
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Conditional knockout of Foxc2 gene in kidney: efficient generation of conditional alleles of single-exon gene by double-selection system.

Foxc2 is a single-exon gene and a key regulator in development of multiple organs, including kidney. To avoid embryonic lethality of conventional Foxc2 knockout mice, we conditionally deleted Foxc2 in kidneys. Conditional targeting of a single-exon gene involves the large floxed gene segment spanning from promoter region to coding region to avoid functional disruption of the gene by the insertion of a loxP site. Therefore, in ES cell clones surviving a conventional single-selection, e.g., neomycin-resistant gene (neo) alone, homologous recombination between the long floxed segment and target genome results in a high incidence of having only one loxP site adjacent to the selection marker. To avoid this limitation, we employed a double-selection system. We generated a Foxc2 targeting construct in which a floxed segment contained 4.6 kb mouse genome and two different selection marker genes, zeocin-resistant gene and neo, that were placed adjacent to each loxP site. After double-selection by zeocin and neomycin, 72 surviving clones were screened that yielded three correctly targeted clones. After floxed Foxc2 mice were generated by tetraploid complementation, we removed the two selection marker genes by a simultaneous-single microinjection of expression vectors for Dre and Flp recombinases into in vitro-fertilized eggs. To delete Foxc2 in mouse kidneys, floxed Foxc2 mice were mated with Pax2-Cre mice. Newborn Pax2-Cre; Foxc2(loxP/loxP) mice showed kidney hypoplasia and glomerular cysts. These results indicate the feasibility of generating floxed Foxc2 mice by double-selection system and simultaneous removal of selection markers with a single microinjection.

Disappearance of centroacinar cells in the Notch ligand-deficient pancreas.

Notch signaling has been shown to contribute to murine pancreatic development at various stages. Delta-like 1 (Dll1) or Jagged1 (Jag1) are the Notch ligands that solely function to trigger this signaling during the pancreatic bud stage (~e9.5) or after birth, respectively. However, it has not been elucidated whether these Notch ligands are required at the later stage (e10.5-18.5) when the particular pancreas structures form. Here, we detected the dual expression of Dll1 and Jag1 in the epithelium after e10.5, which was restricted to the ductal cell lineage, including centroacinar cells expressing Sox9, CD133 and Hes1 but not the ductal cell markers Hnf1ß and DBA, at e18.5. To evaluate the significance of the Notch ligands during this period, we established double-floxed mice of Dll1 and Jag1 genes with Ptf1a-Cre knock-in allele and examined the effects on development. The abrogation of both ligands but not a single one led to the loss of centroacinar cells, which was due to the decrease in cell proliferation and the increase in cell death, as well as to the reduction of Sox9. These results suggested that Dll1 and Jag1 function redundantly and are necessary to maintain the centroacinar cells as an environmental niche in the developing pancreas.

Harmonic superposition for tailored optical frequency comb generation by a Mach-Zehnder modulator.

This Letter demonstrates tailored optical frequency comb (OFC) generation using a LiNbO3 Mach-Zehnder modulator driven by a combination of first- and second-order harmonics of the RF signal. A quasi-rectangular-shaped OFC with less than 1 dB flatness among 11 lines was experimentally obtained when a slight second-order harmonic of the RF signal (0.1 times the half-wavelength voltage) was introduced. Good agreement was obtained between the measured and calculation results for OFCs. We discuss conditions to obtain flat OFCs using this method along with details concerning OFC conversion efficiency and bandwidth.

Characterization of Kidney and Skeleton Phenotypes of Mice Double Heterozygous for Foxc1 and Foxc2.

Foxc1 and Foxc2 play key roles in mouse development. Foxc1 mutant mice develop duplex kidneys with double ureters, and lack calvarial and sternal bones. Foxc2 null mice have been reported to have glomerular abnormalities in the kidney and axial skeletal anomalies. Expression patterns of Foxc1 and Foxc2 overlap extensively and are believed to have interactive roles. However, cooperative roles of these factors in glomerular and skeletal development are unknown. Therefore, we examined the kidneys and skeleton of mice that were double heterozygous for Foxc1 and Foxc2. Double heterozygotes were generated by mating single heterozygotes for Foxc1 and Foxc2. Newborn double heterozygous mice showed many anomalies in the kidney and urinary tract resembling Foxc1 phenotypes, including duplex kidneys, double ureters, hydronephrosis and mega-ureter. Some mice had hydronephrosis alone. In addition to these macroscopic anomalies, some mice had abnormal glomeruli and disorganized glomerular capillaries observed in Foxc2 phenotypes. Interestingly, these mice also showed glomerular cysts not observed in the single-gene knockout of either Foxc1 or Foxc2 but observed in conditional knockout of Foxc2 in the kidney. Serial section analysis revealed that all cystic glomeruli were connected to proximal tubules, precluding the possibility of atubular glomeruli resulting in cyst formation. Dorsally opened vertebral arches and malformations of sternal bones in the double heterozygotes were phenotypes similar to Foxc1 null mice. Absent or split vertebral bodies in the double heterozygotes were phenotypes similar to Foxc2 null mice, whilst hydrocephalus noted in the Foxc1 phenotype was not observed. Thus, Foxc1 and Foxc2 have a role in kidney and axial skeleton development. These transcription factors might interact in the regulation of the embryogenesis of these organs.

Clinical role of early dynamic FDG-PET/CT for the evaluation of renal cell carcinoma.

OBJECTIVES: We studied the usefulness of early dynamic (ED) and whole-body (WB) FDG-PET/CT for the evaluation of renal cell carcinoma (RCC). METHODS: One hundred patients with 107 tumours underwent kidney ED and WB FDG-PET/CT. We visually and semiquantitatively evaluated the FDG accumulation in RCCs in the ED and WB phases, and compared the accumulation values with regard to histological type (clear cell carcinoma [CCC] vs. non-clear cell carcinoma [N-CCC]), the TNM stage (high stage [3-4] vs. low stage [1-2]), the Fuhrman grade (high grade [3-4] vs. low grade [1-2]) and presence versus absence of venous (V) and lymphatic (Ly) invasion. RESULTS: In the ED phase, visual evaluation revealed no significant differences in FDG accumulation in terms of each item. However, the maximum standardized uptake value and tumour-to-normal tissue ratios were significantly higher in the CCCs compared to the N-CCCs (p < 0.001). In the WB phase, in contrast, significantly higher FDG accumulation (p < 0.001) was found in RCCs with a higher TNM stage, higher Furman grade, and the presence of V and Ly invasion in both the visual and the semiquantitative evaluations. CONCLUSIONS: ED and WB FDG-PET/CT is a useful tool for the evaluation of RCCs. KEY POINTS: • ED and WB FDG-PET/ CT helps to assess patients with RCC • ED FDG-PET/CT enabled differentiation between CCC and N-CCC • FDG accumulation in the WB phase reflects tumour aggressiveness • Management of RCC is improved by ED and WB FDG-PET/CT.