Impact of twice-daily budesonide foam administration on early clinical response and endoscopic remission in patients with ulcerative colitis: a post hoc analysis.

BACKGROUND AND AIM: Early treatment response of ulcerative colitis (UC) symptom resolution is desirable. This post hoc analysis evaluated efficacy outcomes, including endoscopic remission, by responder status and the influence of once-daily (QD) versus twice-daily (BID) budesonide foam dosing in patients with UC. METHODS: Data were pooled from phase 2 and phase 3 clinical trials of budesonide rectal foam QD or BID or placebo for up to 12 weeks. Outcomes were evaluated by treatment and budesonide administration regimen and by responder group: early (rectal bleeding subscore [RBS] 0 from Week 2 through Week 6), delayed (RBS 0 at Week 6), and nonresponder (RBS > 0 at Week 6). RESULTS: The main analysis set included 55 (QD) and 120 (BID) budesonide-treated patients and 116 placebo-treated patients. At Week 6, the trend in early response rate was significant among treatment groups (BID, 45.3%; QD, 32.1%; placebo, 12.8%; P < 0.0001). Among BID recipients, trends for complete endoscopic remission rate (Mayo endoscopic score [MES] = 0) and endoscopic remission rate (MES = 0 or 1) were significant among responder status groups (early responder, 67.4% and 95.4%, respectively; delayed responder, 48.1% and 85.2%; nonresponder, 24.0% and 64.0%; P < 0.001 for both). Regardless of the administration regimen, most early responders achieved endoscopic remission at Week 6. Among responder status groups, early responders' cumulative non-relapse period was greatest (P = 0.07). CONCLUSION: A BID budesonide administration regimen is preferred to increase the probability of early response and, following endoscopic remission, a better prognosis after stopping treatment.

Upadacitinib Therapy Reduces Ulcerative Colitis Symptoms as Early as Day 1 of Induction Treatment.

BACKGROUND & AIMS: We evaluated the efficacy of once-daily (QD) upadacitinib 45 mg, an oral, reversible Janus kinase inhibitor, on early symptomatic improvement for ulcerative colitis (UC). Post hoc analyses were performed on pooled data from 2 replicate, phase 3, multicenter induction trials, U-ACHIEVE Induction and U-ACCOMPLISH, to determine the earliest time point of efficacy onset. METHODS: Diary entry data through 14 days from the first dose of placebo or upadacitinib 45 mg QD were analyzed for daily improvement in UC symptoms (stool frequency, rectal bleeding, abdominal pain, and bowel urgency). Changes in inflammatory markers, high-sensitivity C-reactive protein (hs-CRP), and fecal calprotectin (FCP) were assessed at week 2 and quality of life (QoL) at weeks 2 and 8. Regression analysis determined the association between changes in UC symptoms and the likelihood of achieving clinical remission/response per Adapted Mayo score at week 8. RESULTS: Overall, 988 patients (n = 328 placebo, n = 660 upadacitinib) were analyzed. Patients treated with upadacitinib demonstrated significant improvements vs placebo in all UC symptoms between days 1 and 3 and maintained through day 14. A >50% reduction from baseline in hs-CRP and FCP levels was achieved by 75.7% and 48.2% of patients, respectively (P < .001 vs placebo). Increased rates of clinical remission/response per Partial Mayo score from week 2 (26.9%/59.4% upadacitinib 45 mg QD vs 4.3%/22.3% placebo, P < .001) and significant improvements in QoL at weeks 2 and 8 were observed. Early improvement in stool frequency and bowel urgency by day 3 and reductions in hs-CRP and FCP by week 2 were significantly associated with clinical remission/response at week 8. CONCLUSIONS: Upadacitinib 45 mg QD provided rapid relief of UC symptoms from day 1. CLINICALTRIALS: gov: U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026).

Systemic innate immune response induces death of olfactory receptor neurons in Drosophila.

Neural functions are known to decline during normal aging and neurodegenerative diseases. However, the mechanisms of functional impairment owing to the normal aging of the brain are poorly understood. Previously, we reported that caspase-3-like protease, the protease responsible for inducing apoptosis, is activated in a subset of olfactory receptor neurons (ORNs), especially in Drosophila Or42b neurons, during normal aging. Herein, we investigated the molecular mechanism underlying age-related caspase-3-like protease activation and cell death in Or42b neurons. Gene expression profiling of young and aged fly antenna showed that the expression of antimicrobial peptides was significantly upregulated, suggesting an activated innate immune response. Consistent with this observation, inhibition or activation of the innate immune pathway caused delayed or precocious cell death, respectively, in Or42b neurons. Accordingly, autonomous cell activation of the innate immune pathway in Or42b neurons is not likely required for their age-related death, whereas the systemic innate immune response induces caspase-3-like protease activation in Or42b neurons; this indicated that the death of these neurons is regulated non-cell autonomously. We propose a possible link between the innate immune response and the death of olfactory neurons during normal aging.

[A Case of Multiple Brain Metastases after Surgery for Lung Cancer Successfully Treated with Osimertinib].

Right upper lobectomy and lymph node dissection was performed on an 85-year-old male clinically diagnosed with primary lung cancer at the age of 78 years. His post-operative pathologic staging was adenocarcinoma pT1aN0M0, StageⅠ A1, and he was positive for the epidermal growth factor receptor(EGFR). Two years post-operation, a PET scan revealed cancer recurrence due to mediastinal lymph node metastasis. The patient received mediastinal radiation therapy followed by cytotoxic chemotherapy. Nine months later, a PET scan revealed bilateral intrapulmonary metastases and metastases to the ribs. He was subsequently treated with first-generation EGFR-TKIs and cytotoxic chemotherapy. However, his performance worsened 30 months later(6 years post-surgery)due to multiple brain metastases and tumor hemorrhage. Therefore, invasive biopsy was problematic, and liquid biopsy(LB)was performed instead. The results showed a T790M gene mutation, and osimertinib was administered to treat the metastases. The brain metastasis decreased, and PS improved. Thus, he was discharged from the hospital. Although the multiple brain metastases vanished, a CT scan showed liver metastasis 1 year and 6 months later. As a result, he died 9 years post-surgery. Conclusion: The prognosis for patients with multiple brain metastases after lung cancer surgery is poor. Long-term survival is expected with 3rd generation TKI treatment if LB is performed appropriately, even in post-operative multiple brain metastases of EGFR-positive lung adenocarcinoma with poor PS.

Significance of Conducting 2 Types of Fecal Tests in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: We compared the diagnostic accuracy of the fecal calprotectin (FCP) test vs the fecal immunochemical blood test (FIT) in determining the endoscopic severity and predicting outcomes of patients with ulcerative colitis (UC). METHODS: We performed a nationwide study of 879 patients with UC, enrolled at medical centers across Japan, from March 2015 to March 2017. We collected data on fecal biomarkers, endoscopic severities, and other clinical indices from Cohort 1 (n = 427) and assessed the diagnostic accuracy of FCP measurement and FIT results in determining clinical severity, based on Mayo score, and endoscopic remission, based on Mayo endoscopic sub-score (MES) or UC endoscopic index of severity. We also followed 452 patients in clinical remission from UC (Cohort 2) for 12 months and evaluated the associations of FCP levels and FIT results with clinical recurrence. RESULTS: The levels of FCP and FIT each correlated with the MES and UC endoscopic index of severity. There were no significant differences in the areas under the curve of FCP vs FIT in distinguishing patients with MES≤1 from those with MES≥2 (P = .394) or in distinguishing patients with MES=0 from those with MES≥1 (P = .178). Among 405 patients in clinical remission at baseline, 38 (9.4%) had UC recurrences within 3 months and 90 (22.2%) had recurrences within 12 months. FCP≥146 mg/kg (hazard ratio [HR], 4.83; 95% confidence interval [CI], 2.80-8.33) and FIT≥77 ng/mL (HR, 2.92; 95% CI, 1.76-4.83) were independently associated with clinical recurrence within 12 months. UC recurred within 12 months in 69% of patients with levels of FCP≥146 mg/kg and FIT ≥77 ng/mL; this value was significantly higher than the rate of recurrence in patients with levels of FCP≥146 mg/kg and FIT <77 ng/mL (31.5%, P < .001) or patients with levels of FCP<146 mg/kg and FIT ≥77 ng/mL (30.0%, P < .001). CONCLUSION: In a nationwide study of patients with UC in Japan, we found that the level of FCP and FIT could each identify patients with endoscopic markers of disease severity (MES≥2). The combination of FCP and FIT results can identify patients in remission who are at risk for disease recurrence. Clinical Trials Registry no: UMIN000017650 (http://www.umin.ac.jp/ctr/).

[Müllerian Cyst of the Posterior Mediastinum].

Müllerian cyst is rarely reported in the literature. Here, we reported a rare case of Müllerian cyst of the posterior mediastinum. The patient was a 46-year-old woman who was found to have an abnormal shadow on chest X-ray film at medical examination and was followed up as suspected of bronchogenic cyst. One year later, the lesion increased and she was referred to our hospital for surgery. Chest computed tomography demonstrated a 36 mm diameter cystic tumor in front of the right 4~5 thoracic vertebra level. We performed thoracoscopic surgery for diagnosis and treatment. Histopathological examination revealed that the cyst wall was covered with a layer of columnar epithelium. In addition, the estrogen receptor was found to be positive in the epithelia by immnunohistology and the pathological diagnosis was a Müllerian cyst. Müllerian cyst have been reported in the literature to be associated with gynecological disorders or obesity. The present case was found to have ovarian enlargement, which has been carefully followed up.

Comparison of Safety and Efficacy of Tacrolimus versus Infliximab for Active Ulcerative Colitis.

BACKGROUND: This narrative review was to determine which medication, tacrolimus (TAC) or infliximab (IFX), is safer and more effective in the management of active UC. Our literature search identified 5 studies directly comparing the outcomes of TAC versus IFX for active UC. A review of the 5 studies was undertaken. SUMMARY: The incidence of serious adverse events was not significantly different between the TAC and IFX groups. The short-term clinical remission and response rates and the colectomy-free rates were similar between the groups. TAC was usually withdrawn at week 12 and, therefore, the long-term efficacy of TAC could not be properly evaluated. The majority of patients in the IFX group maintained clinical remission in the long-term. The efficacy of IFX as second-line salvage therapy after failure of TAC appeared to be favourable, but the efficacy of TAC after failure of IFX was questionable. Key Messages: Both TAC and IFX appeared to be equally safe and effective in the short-term for patients with active UC. For the moment, treatment choice, TAC or IFX, should be guided by physician and centre experience. Randomised controlled trials are urgently warranted to rigorously compare the efficacy of TAC versus IFX for active UC.

Long-term Outcome of Pulmonary Resection for Nontuberculous Mycobacterial Pulmonary Disease.

BACKGROUND: Pulmonary resection along with multiple antimicrobial therapy has produced favorable outcomes at a few centers. However, little is known regarding the risk factors for long-term survival and microbiological recurrence after pulmonary resection for nontuberculous mycobacterial pulmonary disease (NTMPD). We evaluated the long-term outcomes of pulmonary resection, including microbiological recurrence and survival. METHODS: This retrospective cohort study included 125 patients (median age, 60 years) with NTMPD treated by pulmonary resection at two referral centers between January 1994 and August 2015. RESULTS: Postoperative complications occurred in 27 patients (22%). The complication rate after pneumonectomy was significantly higher than those after other types of pulmonary resection (odds ratio, 4.1; 95% confidence interval [CI], 1.6-10.3; P = .005). The median follow-up period was 7.1 years. While 19 patients experienced microbiological recurrence, 26 died. Multivariate analysis revealed pneumonectomy (adjusted hazard ratio [aHR], 0.12; 95% CI, .007-.66; P = .0098) and cavitary lesions after surgery (aHR, 6.73; 95% CI, 1.68-22.7; P = .0095) to be predictors of microbiological recurrence and old age (aHR, 1.06; 95% CI, 1.01-1.13; P = .016), low body mass index (BMI; aHR for every 1-kg/m2 increase, 0.72; 95% CI, .60-.85; P < .0001), pneumonectomy (aHR, 4.38; 95% CI, 1.78-11.3; P = .014), and remnant cavitary lesions (aHR, 3.53; 95% CI, 1.35-9.57; P = .011) to be predictors of poor prognosis. CONCLUSIONS: Patients who could benefit from pulmonary resection should be carefully selected considering age, BMI, remnant lesions after surgery, and type of pulmonary resection.

Level of Fecal Calprotectin Correlates With Severity of Small Bowel Crohn's Disease, Measured by Balloon-assisted Enteroscopy and Computed Tomography Enterography.

BACKGROUND & AIMS: Previous studies have not found a correlation between fecal level of calprotectin and small bowel Crohn's disease (CD). However, these studies evaluated patients mainly by ileocolonoscopy, which views up to only the terminal ileum rather than entire small intestine. We investigated whether level of fecal calprotectin (FC) is a marker of active CD of the small bowel, identified by balloon-assisted enteroscopy and computed tomography enterography (CTE). METHODS: We performed a prospective study of 123 patients with CD (35 with ileitis, 72 with ileocolitis, and 16 with colitis) evaluated by balloon-assisted enteroscopy from May 2012 through July 2015 at Toho University Sakura Medical Centre in Japan. Patients with strictures detected by balloon-assisted enteroscopy were evaluated by CTE (n = 17). Fecal samples were collected from each patient, and levels of calprotectin were measured; patient demographic variables and medical history were also collected. We developed a CTE scoring system for disease severity that was based on bowel wall thickness, mural hyperenhancement, and engorged vasa recta. The association between level of FC and simple endoscopic index for CD score or CTE was evaluated by using Spearman rank correlation coefficient. RESULTS: Level of FC correlated with the simple endoscopic index for CD score (r = 0.6362, P < .0001), even in patients with only active disease of the small intestine (r = 0.6594, P = .0005). In the 17 patients with strictures that could not be passed with the enteroscope, CTE detected all lesions beyond the strictures as well as areas in the distal side of the strictures. Level of FC correlated with CTE score in these patients (r = 0.4018, P = .0011, n = 63). In receiver operating characteristic analyses, the FC cutoff value for mucosal healing was 215 µg/g; this cutoff value identified patients with healing with 82.8% sensitivity, 71.4% specificity, positive predictive value of 74.3%, negative predictive value of 80.6%, odds ratio of 12.0, and area under the receiver operating characteristic curve value of 0.81. CONCLUSIONS: A combination of measurement of level of FC and CTE appears to be effective for monitoring CD activity in patients with small intestinal CD, including patients with strictures that cannot be passed by conventional endoscopy.

Accuracy of CT Colonography for Detection of Polypoid and Nonpolypoid Neoplasia by Gastroenterologists and Radiologists: A Nationwide Multicenter Study in Japan.

OBJECTIVES: The objective of this study was to assess prospectively the diagnostic accuracy of computer-assisted computed tomographic colonography (CTC) in the detection of polypoid (pedunculated or sessile) and nonpolypoid neoplasms and compare the accuracy between gastroenterologists and radiologists. METHODS: This nationwide multicenter prospective controlled trial recruited 1,257 participants with average or high risk of colorectal cancer at 14 Japanese institutions. Participants had CTC and colonoscopy on the same day. CTC images were interpreted independently by trained gastroenterologists and radiologists. The main outcome was the accuracy of CTC in the detection of neoplasms ≥6 mm in diameter, with colonoscopy results as the reference standard. Detection sensitivities of polypoid vs. nonpolypoid lesions were also evaluated. RESULTS: Of the 1,257 participants, 1,177 were included in the final analysis: 42 (3.6%) were at average risk of colorectal cancer, 456 (38.7%) were at elevated risk, and 679 (57.7%) had recent positive immunochemical fecal occult blood tests. The overall per-participant sensitivity, specificity, and positive and negative predictive values for neoplasms ≥6 mm in diameter were 0.90, 0.93, 0.83, and 0.96, respectively, among gastroenterologists and 0.86, 0.90, 0.76, and 0.95 among radiologists (P<0.05 for gastroenterologists vs. radiologists). The sensitivity and specificity for neoplasms ≥10 mm in diameter were 0.93 and 0.99 among gastroenterologists and 0.91 and 0.98 among radiologists (not significant for gastroenterologists vs. radiologists). The CTC interpretation time by radiologists was shorter than that by gastroenterologists (9.97 vs. 15.8 min, P<0.05). Sensitivities for pedunculated and sessile lesions exceeded those for flat elevated lesions ≥10 mm in diameter in both groups (gastroenterologists 0.95, 0.92, and 0.68; radiologists: 0.94, 0.87, and 0.61; P<0.05 for polypoid vs. nonpolypoid), although not significant (P>0.05) for gastroenterologists vs. radiologists. CONCLUSIONS: CTC interpretation by gastroenterologists and radiologists was accurate for detection of polypoid neoplasms, but less so for nonpolypoid neoplasms. Gastroenterologists had a higher accuracy in the detection of neoplasms ≥6 mm than did radiologists, although their interpretation time was longer than that of radiologists.

Caspase inhibition in select olfactory neurons restores innate attraction behavior in aged Drosophila.

Sensory and cognitive performance decline with age. Neural dysfunction caused by nerve death in senile dementia and neurodegenerative disease has been intensively studied; however, functional changes in neural circuits during the normal aging process are not well understood. Caspases are key regulators of cell death, a hallmark of age-related neurodegeneration. Using a genetic probe for caspase-3-like activity (DEVDase activity), we have mapped age-dependent neuronal changes in the adult brain throughout the lifespan of Drosophila. Spatio-temporally restricted caspase activation was observed in the antennal lobe and ellipsoid body, brain structures required for olfaction and visual place memory, respectively. We also found that caspase was activated in an age-dependent manner in specific subsets of Drosophila olfactory receptor neurons (ORNs), Or42b and Or92a neurons. These neurons are essential for mediating innate attraction to food-related odors. Furthermore, age-induced impairments of neural transmission and attraction behavior could be reversed by specific inhibition of caspase in these ORNs, indicating that caspase activation in Or42b and Or92a neurons is responsible for altering animal behavior during normal aging.

[Lung Cancer with Multiple Cavitation and Ground Glass Opacity;Report of a Case].

A 81-year-old man was referred to our hospital because of cough and fever. Chest computed tomography(CT) showed multiple cavitation and ground glass opacity in the right lower lobe. Antibiotic treatment was effective in the improvement of the infiltrative shadow and the inflammatory reaction. After 1 year, bronchoscopy was performed because the shadow remained on the following chest CT, and the adenocarcinoma of the lung was found. A lower lobectomy of the right lung was performed.

[Early VATS(Video-Assisted Thoracoscopic Surgery)Was Effective for a Case of Chylothorax after Lung Cancer Excision].

A 66-year-old man underwent a right upper lobectomy and lymph node dissection for lung cancer. We confirmed a milky white pleural effusion after diet initiation on the first postoperative day, and a chylothorax was diagnosed. The patient began a f at-restricted diet; however, the pleural effusion did not decrease. Therefore, we performed VATS(video-assisted thoracoscopic surgery)1 week after surgery with good results. Early VATS for a postoperative chylothorax was useful.

[A Case of Long-Term Survival after Resection of Metachronous Metastases to the Liver and Lungs from Primary Rectal Cancer].

A 81-year-old man had undergone high anterior resection for rectalcancer in 20XX. Abdominalcomputed tomography (CT)showed an isolated shadow of 2 cm in size in the liver, 9 years after surgery for colorectal cancer. We performed liver S4 segmental resection and cholecystectomy. Histopathological examination confirmed liver metastases of rectal cancer. On examination of the liver metastasis 5 years after surgery, chest CT showed a shadow of 10mm in size in S6 of the left lung. We performed partialresection via video-assisted thoracic surgery(VATS)in 20XX+14. Histopathological examination revealed lung metastases of rectal cancer. We believe that metachronous metastases from rectal cancer should be removed surgically if radicalcure is possible.

Blue light-induced dimerization of monomeric aureochrome-1 enhances its affinity for the target sequence.

Aureochrome-1 (AUREO1) is a blue light (BL) receptor that mediates the branching response in stramenopile alga, Vaucheria frigida. AUREO1 contains a basic leucine zipper (bZIP) domain in the central region and a light-oxygen-voltage sensing (LOV) domain at the C terminus, and has been suggested to function as a light-regulated transcription factor. We have previously reported that preparations of recombinant AUREO1 contained the complete coding sequence (full-length, FL) and N-terminal truncated protein (ZL) containing bZIP and LOV domains, and suggested that wild-type ZL (ZLwt2) was in a dimer form with intermolecular disulfide linkages at Cys(162) and Cys(182) (Hisatomi, O., Takeuchi, K., Zikihara, K., Ookubo, Y., Nakatani, Y., Takahashi, F., Tokutomi, S., and Kataoka, H. (2013) Plant Cell Physiol. 54, 93-106). In the present study, we report the photoreactions, oligomeric structures, and DNA binding of monomeric cysteine to serine-mutated ZL (ZLC2S), DTT-treated ZL (DTT-ZL), and FL (DTT-FL). Recombinant AUREO1 showed similar spectral properties and dark regeneration kinetics to those of dimeric ZLwt2. Dynamic light scattering and size exclusion chromatography revealed that ZLC2S and DTT-ZL were monomeric in the dark state. Dissociation of intermolecular disulfide bonds of ZLwt2 was in equilibrium with a midpoint oxidation-redox potential of approximately -245 ± 15 mV. BL induced the dimerization of monomeric ZL, which subsequently increased its affinity for the target sequence. Also, DTT-FL was monomeric in the dark state and underwent BL-induced dimerization, which led to formation of the FL2·DNA complex. Taken together, our results suggest that monomeric AUREO1 is present in vivo, with dimerization playing a key role in its role as a BL-regulated transcription factor.

C-reactive protein level at 2 weeks following initiation of infliximab induction therapy predicts outcomes in patients with ulcerative colitis: a 3 year follow-up study.

BACKGROUND: Poor response to anti-tumour necrosis factor biologicals like infliximab (IFX) is observed in patients with ulcerative colitis (UC), which may lead to prolonged morbidity and waste of medical resources. We aimed to look for potential biomarkers of response to IFX in patients with UC who were to undergo IFX induction therapy. METHODS: Seventy-two IFX naïve UC patients with partial Mayo (pMayo) score of 4-9 received IFX infusion at weeks 0, 2 and 6 as induction therapy. The pMayo score, trough IFX and C-reactive protein (CRP) concentrations were measured. At week 14, patients who achieved a pMayo score of ≤ 2 with no individual subscore exceeding 1 were judged as responders, while patients who responded, but did not achieve a pMayo score of ≤ 2 were judged as partial responders. Likewise, patients who showed unchanged pMayo score or worsened were judged as non-responders. Patients were followed for up to 3.3 years. RESULTS: Response, partial response and no response rates were 40.3, 33.3, and 26.4%, respectively. CRP level at week 2 in responders was significantly lower vs partial-responders (P = 0.0135) or non-responders (P = 0.0084) in spite of similar trough IFX level. Further, the median CRP (week 2/week 0) ratio was significantly lower in patients who responded vs partial-responders or non-responders, 0.06, 0.39 and 1.00, respectively. When the cut-off value was set at 0.19 for the CRP (week 2/week 0) ratio, this ratio could predict partial-responders with 79.1% sensitivity and 75.9% specificity. Patients with the CRP (week 2/week 0) ratio greater than 0.19 were likely to be partial-responder, with odds ratio 10.371 (P < 0.0001; 95% confidence interval 3.596-33.440). CONCLUSIONS: In this study, CRP level at week 2 following initiation of IFX induction therapy appeared to be a clinically relevant biomarker of response to IFX in UC patients.

Blue light-induced conformational changes in a light-regulated transcription factor, aureochrome-1.

Aureochrome-1 (AUREO1) is a blue light (BL) receptor that mediates the branching response in the stramenopile alga, Vaucheria frigida. AUREO1 harbors a basic leucine zipper (bZIP) domain at the N-terminus and a light-oxygen-voltage-sensing (LOV) domain within the C-terminal region, and has been suggested to function as a light-regulated transcription factor. To understand the molecular mechanism of AUREO1, we have prepared three recombinant proteins: a full-length AUREO1 (FL), an N-terminal truncated construct containing bZIP and LOV (ZL) and a LOV-only (LOV) construct. The constructs showed the same absorption and fluorescent spectra in the dark state and underwent the characteristic cyclic reaction as previously observed in LOV domains upon BL excitation. FL and ZL bound to DNA in a sequence-specific manner. BL appeared to induce a shift of the α-helical structure of the LOV domain to a ß-sheet structure, but did not alter the hydrodynamic radius (R(H)) of this domain. ZL formed a dimer possibly through disulfide linkages in the bZIP and the linker region between bZIP and LOV. BL induced an approximately 5% increase in the R(H) of ZL, although its secondary structure was unchanged. These results support a schema where BL-induced changes in the LOV domain may cause conformational changes in the bZIP and/or the linker of a dimeric ZL molecule. Since a 5% increase of the R(H) was also observed with the FL construct, BL may induce global conformational changes similar to those observed for ZL, and formation of the FL dimer may facilitate DNA binding.

[A case of mediastinum malignant teratoma which recurred as bone metastases seven years after a resection, and survived for a long-duration].

We performed median sternotomy, anterior mediastinum tumor resection+cardiac sac, and right pleural+superior vena cava partial excision in the anterior mediastinum, for which tumor markers were abnormal, after preoperative chemotherapy (PEB therapy)for a mediastinal malignant teratoma of 8×6 cm in a malignant germ cell tumor. The tumor markers became normal. We postoperatively performed a course of the same chemotherapy. In spite of the normal tumor markers, bone metastases recurred seven years later, and he underwent the ninth thoracic vertebra resection+spinal fusion. Five years have passed since surgery and he has survived without a recurrence. This seemed to be a rare case in which a part of the mediastinum malignant teratoma which did not produce a tumor marker had a recurrence.

[A case of lung cancer resistant to pemetrexed responding to S-1 monotherapy].

Pemetrexed(PEM)and S-1 are both cytotoxic anti-tumor drugs that target thymidylate synthase(TS). Here, we report a case of lung cancer resistant to PEM, but responsive to S-1 monotherapy. A 50-year-old male with lung cancer(adenocarcinoma, EGFR mutation negative)at Stage III B(T4N2M0)received PEM as third-line chemotherapy. However, metastatic mediastinal lymph nodes were increased in size. A switch to gemcitabine(GEM)resulted in further enlargement of the nodes and elevation of the serum CEA level. Introduction of S-1 monotherapy(120mg/body/day divided into two doses, 4-week administration every 6 weeks, 6 courses)reduced the size of the nodes and serum CEA was normalized. Although S-1 as well as PEM, target TS, the mechanisms in these two drugs that lead to resistance are not the same. Furthermore, S-1 induces dysfunction of RNA through the generation of fluoro-uridine monophosphate(FUMP). We conclude that S-1 can be a drug of choice, even in cases that show resistance to PEM.