Does embryo categorization by existing artificial intelligence, morphokinetic or morphological embryo selection models correlate with blastocyst euploidy rates?

RESEARCH QUESTION: Does embryo categorization by existing artificial intelligence (AI), morphokinetic or morphological embryo selection models correlate with blastocyst euploidy? DESIGN: A total of 834 patients (mean maternal age 40.5 ± 3.4 years) who underwent preimplantation genetic testing for aneuploidies (PGT-A) on a total of 3573 tested blastocysts were included in this retrospective study. The cycles were stratified into five maternal age groups according to the Society for Assisted Reproductive Technology age groups (<35, 35-37, 38-40, 41-42 and >42 years). The main outcome of this study was the correlation of euploidy rates in stratified maternal age groups and an automated AI model (iDAScore® v1.0), a morphokinetic embryo selection model (KIDScore Day 5 ver 3, KS-D5) and a traditional morphological grading model (Gardner criteria), respectively. RESULTS: Euploidy rates were significantly correlated with iDAScore (P = 0.0035 to <0.001) in all age groups, and expect for the youngest age group, with KS-D5 and Gardner criteria (all P < 0.0001). Additionally, multivariate logistic regression analysis showed that for all models, higher scores were significantly correlated with euploidy (all P < 0.0001). CONCLUSION: These results show that existing blastocyst scoring models correlate with ploidy status. However, as these models were developed to indicate implantation potential, they cannot accurately diagnose if an embryo is euploid or aneuploid. Instead, they may be used to support the decision of how many and which blastocysts to biopsy, thus potentially reducing patient costs.

Correlation between an annotation-free embryo scoring system based on deep learning and live birth/neonatal outcomes after single vitrified-warmed blastocyst transfer: a single-centre, large-cohort retrospective study.

PROPOSE: Does an annotation-free embryo scoring system based on deep learning and time-lapse sequence images correlate with live birth (LB) and neonatal outcomes? METHODS: Patients who underwent SVBT cycles (3010 cycles, mean age: 39.3 ± 4.0). Scores were calculated using the iDAScore software module in the Vitrolife Technology Hub (Vitrolife, Gothenburg, Sweden). The correlation between iDAScore, LB rates, and total miscarriage (TM), including 1st- and 2nd-trimester miscarriage, was analysed using a trend test and multivariable logistic regression analysis. Furthermore, the correlation between the iDAScore and neonatal outcomes was analysed. RESULTS: LB rates decreased as iDAScore decreased (P < 0.05), and a similar inverse trend was observed for the TM rates. Additionally, multivariate logistic regression analysis showed that iDAScore significantly correlated with increased LB (adjusted odds ratio: 1.811, 95% CI: 1.666-1.976, P < 0.05) and decreased TM (adjusted odds ratio: 0.799, 95% CI: 0.706-0.905, P < 0.05). There was no significant correlation between iDAScore and neonatal outcomes, including congenital malformations, sex, gestational age, and birth weight. Multivariate logistic regression analysis, which included maternal and paternal age, maternal body mass index, parity, smoking, and presence or absence of caesarean section as confounding factors, revealed no significant difference in any neonatal characteristics. CONCLUSION: Automatic embryo scoring using iDAScore correlates with decreased miscarriage and increased LB and has no correlation with neonatal outcomes.

Discovery of a Potent Anticancer Agent PVHD303 with in Vivo Activity.

As a part of our continuous structure-activity relationship (SAR) studies on 1-(quinazolin-4-yl)-1-(4-methoxyphenyl)ethan-1-ols, the synthesis of derivatives and their cytotoxicity against the human lung cancer cell line A549 were explored. This led to the discovery of 1-(2-(furan-3-yl)quinazolin-4-yl)-1-(4-methoxyphenyl)ethan-1-ol (PVHD303) with potent antiproliferative activity. PVHD303 disturbed microtubule formation at the centrosomes and inhibited the growth of tumors dose-dependently in the HCT116 human colon cancer xenograft model in vivo.

Up-regulation of POMC and CART mRNAs by intermittent hypoxia via GATA transcription factors in human neuronal cells.

Sleep apnea syndrome (SAS) is characterized by intermittent hypoxia (IH) during sleep. SAS and obesity are strongly related to each other. Here, we investigated the effect of IH on the expression of major appetite regulatory genes in human neuronal cells. We exposed NB-1, SH-SY5Y, and SK-N-SH human neuronal cells to IH (64 cycles of 5 min hypoxia and 10 min normoxia), normoxia, or sustained hypoxia for 24 h and measured the mRNA levels of proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), galanin, galanin-like peptide, ghrelin, pyroglutamylated RFamide peptide, agouti-related peptide, neuropeptide Y, and melanocortin 4 receptor by real-time RT-PCR. IH significantly increased the mRNA levels of POMC and CART in all the neuronal cells. Deletion analysis revealed that the -705 to -686 promoter region of POMC and the -950 to -929 region of CART were essential for the IH-induced promoter activity. As possible GATA factor binding sequences were found in the two regions, we performed real-time RT-PCR to determine which GATA family members were expressed and found that GATA2 and GATA3 mRNAs were predominantly expressed. Therefore, we introduced siRNAs against GATA2 and GATA3 into NB-1 cells and found that GATA2 and GATA3 siRNAs abolished the IH-induced up-regulation of both POMC and CART mRNAs. These results indicate that IH stress up-regulates the mRNA levels of anorexigenic peptides, POMC and CART, in human neuronal cells via GATA2 and GATA3. IH can have an anorexigenic effect on SAS patients through the transcriptional activation of POMC and CART in the central nervous system.

A giant uterine tumor in a woman with myotonic dystrophy.

Patients with myotonic dystrophy are at particularly high risk for cancer arising in the endometrium, brain, colon, or ovary. Giant leiomyoma can occur in patients with myotonic muscular dystrophy, a disease accompanied by muscle wasting.

Early progression of brain atrophy in patients with anti-N-methyl-D-aspartate receptor encephalitis: Case reports.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis responds to immunnotherapy, and approximately 80% of patients with this disorder fully recover or have only minor sequelae. Brain magnetic resonance imaging (MRI) does not show a specific abnormality, but some patients have progressive cerebral atrophy. The cerebral atrophy can become reversible after clinical improvement. METHODS: We describe 3 patients with diffuse cerebral atrophy (DCA) on serial brain MRI. RESULTS: Two women had the typical spectrum of this disorder, and one man had mainly psychiatric symptoms. In a woman with an ovarian tumor, DCA was reversible and DCA developed within about a half month. In another woman without a tumor, DCA was evident within 19 days and had progressed over the course of 4 years. The titers of anti-NMDAR antibodies in serum and cerebrospinal fluid (CSF) initially decreased, and low titers of the antibodies persisted. In a man without a tumor, DCA progressed within 14 days, and during this short period, he did not receive prolonged treatment with corticosteroids, various antiepileptic agents, or propofol, and he was free of seizures and ventilatory support. CONCLUSION: Not only a woman but also a man with anti-NMDAR encephalitis can have DCA in the early phase of this disorder. However, DCA can be reversible after clinical improvements. The early progression of DCA is not necessarily a poor prognostic factor.

Development of RNA-FISH Assay for Detection of Oncogenic FGFR3-TACC3 Fusion Genes in FFPE Samples.

INTRODUCTION AND OBJECTIVES: Oncogenic FGFR3-TACC3 fusions and FGFR3 mutations are target candidates for small molecule inhibitors in bladder cancer (BC). Because FGFR3 and TACC3 genes are located very closely on chromosome 4p16.3, detection of the fusion by DNA-FISH (fluorescent in situ hybridization) is not a feasible option. In this study, we developed a novel RNA-FISH assay using branched DNA probe to detect FGFR3-TACC3 fusions in formaldehyde-fixed paraffin-embedded (FFPE) human BC samples. MATERIALS AND METHODS: The RNA-FISH assay was developed and validated using a mouse xenograft model with human BC cell lines. Next, we assessed the consistency of the RNA-FISH assay using 104 human BC samples. In this study, primary BC tissues were stored as frozen and FFPE tissues. FGFR3-TACC3 fusions were independently detected in FFPE sections by the RNA-FISH assay and in frozen tissues by RT-PCR. We also analyzed the presence of FGFR3 mutations by targeted sequencing of genomic DNA extracted from deparaffinized FFPE sections. RESULTS: FGFR3-TACC3 fusion transcripts were identified by RNA-FISH and RT-PCR in mouse xenograft FFPE tissues using the human BC cell lines RT112 and RT4. These cell lines have been reported to be fusion-positive. Signals for FGFR3-TACC3 fusions by RNA-FISH were positive in 2/60 (3%) of non-muscle-invasive BC (NMIBC) and 2/44 (5%) muscle-invasive BC (MIBC) patients. The results of RT-PCR of all 104 patients were identical to those of RNA-FISH. FGFR3 mutations were detected in 27/60 (45%) NMIBC and 8/44 (18%) MIBC patients. Except for one NMIBC patient, FGFR3 mutation and FGFR3-TACC3 fusion were mutually exclusive. CONCLUSIONS: We developed an RNA-FISH assay for detection of the FGFR3-TACC3 fusion in FFPE samples of human BC tissues. Screening for not only FGFR3 mutations, but also for FGFR3-TACC3 fusion transcripts has the potential to identify additional patients that can be treated with FGFR inhibitors.

Early onset of cardiomyopathy and intellectual disability in a girl with Danon disease associated with a de novo novel mutation of the LAMP2 gene.

Danon disease, primary lysosome-associated membrane protein-2 (LAMP-2) deficiency, is characterized clinically by cardiomyopathy, myopathy and intellectual disability in boys. Because Danon disease is inherited in an X-linked dominant fashion, males are more severely affected than females, who usually have only cardiomyopathy without myopathy or intellectual disability; moreover, the onset of symptoms in females is usually in adulthood. We describe a girl with Danon disease who presented with hypertrophic cardiomyopathy and Wolff-Parkinson-White (WPW) syndrome at 12 years of age. Subsequently, she showed signs of mild learning disability and intellectual disability on psychological examinations. She had a de novo novel mutation in the LAMP-2 gene and harbored an identical c.749C > A (p.Ser250X) variant, resulting in a stop codon in exon 6. She showed decreased, but not completely absent LAMP-2 expression on immunohistochemical and Western blot analyses of a skeletal muscle biopsy specimen, which has been suggested to be caused by a 50% reduction in LAMP-2 expression (LAMP-2 haploinsufficiency) in female patients with Danon disease caused by a heterozygous null mutation. To our knowledge, our patient is one of the youngest female patients to have been given a diagnosis of Danon disease. In addition, this is the first documented case in a girl that was clearly associated with intellectual disability, which is very rare in females with Danon disease. Our findings suggest that studies of female patients with Danon disease can extend our understanding of the clinical features of this rare disease.

Hypertrophic Pachymeningitis as a Delayed Complication of Granulomatosis with Polyangiitis.

A 69-year-old man presented with upper airway symptoms, multiple lung nodules and masses, proteinuria and hematuria, and an increased level of proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA). Granulomatosis with polyangiitis (GPA) was diagnosed by a transbronchial lung biopsy. All of these symptoms were ameliorated and the level of PR3-ANCA declined following treatment with prednisolone and cyclophosphamide. The patient developed a headache 16 months after the onset of symptoms, and contrast-enhanced magnetic resonance imaging showed the thickening of the dura mater, which suggested that hypertrophic pachymeningitis (HP) had developed as a complication of GPA. HP can be a unique complication of GPA at recurrence, and can occur without the relapse of other lesions or an increase in PR3-ANCA level.

Effects of postoperative administration of celecoxib on pain management in patients after total knee arthroplasty: study protocol for an open-label randomized controlled trial.

BACKGROUND: Multimodal analgesia is achieved by combining different analgesics and different methods of analgesic administration, synergistically providing superior pain relief when compared with conventional analgesia. Multimodal analgesia can also result in reductions in the side effects and complications of analgesia, thereby improving patient safety. Preventive analgesia, treatment before initiation of the surgical procedure, has a potential to be more effective in reducing pain sensitization than treatment initiated after surgery. Multimodal analgesia that includes prophylactic administration of selective cyclooxygenase-2 (COX-2) inhibitors can improve postoperative pain and reduce opioid analgesic consumption after total knee arthroplasty (TKA). However COX-2 inhibitors are not approved for use as preventive analgesia in Japan. Thus, assessing the effectiveness of COX-2 inhibitors during the early postoperative period is important to establish clinical practice guidelines in Japan. This study was designed to examine the effects of celecoxib administration immediately after surgery, in addition to multimodal analgesia, on postoperative pain management after TKA. METHODS/DESIGN: This randomized, prospective, open-label controlled study will include 120 patients undergoing unilateral TKA. All patients will routinely receive single injections of femoral and sciatic nerve blocks, along with postoperative patient-controlled analgesia (PCA) with fentanyl. Patients will be randomly assigned to receive or not receive immediate postoperative administration of celecoxib. The primary outcome is a visual analog scale (VAS) pain score the second day after surgery. Secondary outcomes include opioid consumption, VAS pain score for 7 days after surgery, range of knee motion, evaluation of sleep quality, overall evaluations by patients and physicians, rates of postoperative nausea and vomiting, and consumption of rescue analgesics. DISCUSSION: The objective of this study is to evaluate the effects of celecoxib administration immediately after surgery on pain after TKA surgery. A randomized controlled trial design will address the hypothesis that administration of oral celecoxib immediately after surgery, along with multimodal analgesia that includes peripheral nerve block and PCA, could reduce VAS pain score after TKA surgery. TRIAL REGISTRATION: UMIN-CTR 000014624 (23 July 2014).

Prevalence of spontaneous coronary artery dissection in patients with acute coronary syndrome.

AIMS: Spontaneous coronary artery dissection (SCAD) found typically in young females without classical coronary risk factors is thought to be a very rare cause of acute coronary syndrome (ACS). The prevalence of SCAD in ACS subjects has been unclear, probably due to the nature of coronary angiography. The aim of this study was to use optical coherence tomography (OCT) to investigate the prevalence of SCAD in ACS. METHODS AND RESULTS: This study consisted of 326 patients with ACS (with or without ST-segment elevation) who underwent OCT to explore the entire culprit artery. According to OCT findings, patients were divided into a SCAD, a plaque rupture (PR), and a non-SCAD/non-PR group. OCT revealed 13 (4.0%) SCADs and 160 (49.1%) plaque ruptures in ACS subjects. The percentage of females versus males was greater in the SCAD group (SCAD: 53.8% vs. PR: 20.0% vs. non-SCAD/non-PR: 23.5%, p=0.02) while no difference was observed in age (SCAD: 67.3±13.3 vs. PR: 66.5±11.1 vs. non-SCAD/non-PR: 67.0±10.5, p=0.90). The prevalence of dyslipidemia (SCAD: 30.8% vs. PR: 63.8% vs. non-SCAD/non-PR: 67.5%, p=0.03) and current smoking (SCAD: 7.7% vs. PR: 57.9% vs. non-SCAD/non-PR: 59.7%, p<0.01) were significantly lower in the SCAD group. CONCLUSIONS: SCAD is not a rare cause for ACS, especially in females without classical coronary risk factors.

Establishment of a Novel In Vitro Model for Predicting Incidence and Severity of Microtubule-targeting Agent-induced Peripheral Neuropathy.

Peripheral neuropathy (PN) is a major dose-limiting side-effect of microtubule-targeting agents (MTAs), considered to be induced by inhibition of axonal microtubules. Therefore, it was thought that a useful method for predicting the frequencies of severe sensory-PN (FPN) would be to evaluate the neurite-disrupting effects of MTAs. Using neurite outgrowth from neuron-like cell lines, we comprehensively evaluated the neurite-disrupting effects of several anti-cancer drugs including MTAs, and the reversibility of the effects of MTAs. MTAs that induce PN showed neurite-disrupting effects more strongly than MTAs and anticancer drugs that do not induce PN, but the effects were not related to the FPN. On the other hand, MTAs with high FPN exhibited lower reversibility than those with low FPN. These findings suggest that neurite-disrupting effects are associated with the incidence of PN, and the reversibility of the effects is associated with FPN.

Characteristic MRI Findings of upper Limb Muscle Involvement in Myotonic Dystrophy Type 1.

The objective of our study was to evaluate the relation between muscle MRI findings and upper limb weakness with grip myotonia in patients with myotonic dystrophy type 1 (DM1). Seventeen patients with DM1 were evaluated by manual muscle strength testing and muscle MRI of the upper limbs. Many DM1 patients presenting with decreased grasping power frequently showed high intensity signals in the flexor digitorum profundus (FDP) muscles on T1-weighted imaging. Patients presenting with upper limb weakness frequently also showed high intensity signals in the flexor pollicis longus, abductor pollicis longus, and extensor pollicis muscles. Disturbances of the distal muscles of the upper limbs were predominant in all DM1 patients. Some DM1 patients with a prolonged disease duration showed involvement of not only distal muscles but also proximal muscles in the upper limbs. Muscle involvement of the upper limbs on MRI strongly correlated positively with the disease duration or the numbers of CTG repeats. To our knowledge, this is the first study to provide a detailed description of the distribution and severity of affected muscles of the upper limbs on MRI in patients with DM1. We conclude that muscle MRI findings are very useful for identifying affected muscles and predicting the risk of muscle weakness in the upper limbs of DM1 patients.

Effect of atorvastatin therapy on fibrous cap thickness in coronary atherosclerotic plaque as assessed by optical coherence tomography: the EASY-FIT study.

BACKGROUND: The detailed mechanism of plaque stabilization by statin therapy is not fully understood. OBJECTIVES: The aim of this study was to assess the effect of lipid-lowering therapy with 20 mg/day of atorvastatin versus 5 mg/day of atorvastatin on fibrous cap thickness in coronary atherosclerotic plaques by using optical coherence tomography (OCT). METHODS: Seventy patients with unstable angina pectoris and untreated dyslipidemia were randomized to either 20 mg/day or 5 mg/day of atorvastatin therapy. OCT was performed to assess intermediate nonculprit lesions at baseline and 12-month follow-up. RESULTS: Serum low-density lipoprotein cholesterol level was significantly lower during therapy with 20 mg/day compared with 5 mg/day of atorvastatin (69 mg/dl vs. 78 mg/dl; p = 0.039). The increase in fibrous cap thickness was significantly greater with 20 mg/day compared with 5 mg/day of atorvastatin (69% vs. 17%; p < 0.001). The increase in fibrous cap thickness correlated with the decrease in serum levels of low-density lipoprotein cholesterol (R = -0.450; p < 0.001), malondialdehyde-modified low-density lipoprotein (R = -0.283; p = 0.029), high-sensitivity C-reactive protein (R = -0.276; p = 0.033), and matrix metalloproteinase-9 (R = -0.502; p < 0.001), and the decrease in grade of OCT-derived macrophages (R = -0.415; p = 0.003). CONCLUSIONS: Atorvastatin therapy at 20 mg/day provided a greater increase in fibrous cap thickness in coronary plaques compared with 5 mg/day of atorvastatin. The increase of fibrous cap was associated with the decrease in serum atherogenic lipoproteins and inflammatory biomarkers during atorvastatin therapy. (Effect of Atorvastatin Therapy on Fibrous Cap Thickness in Coronary Atherosclerotic Plaque as Assessed by Optical Coherence Tomography: The EASY-FIT Study; NCT00700037).

Preoperative low-dose steroid can prevent respiratory insufficiency after thymectomy in generalized myasthenia gravis.

BACKGROUND: Postoperative respiratory insufficiency (PRI) in myasthenia gravis (MG) often occurs within several days after thymectomy and remains problematic. In limited studies reporting that preoperative steroids prevented PRI in patients with MG, high doses of steroids were used and detailed information on the use of steroids is limited. Because high-dose steroids significantly increase the risk of adverse effects, we studied 37 patients with generalized MG to investigate whether low-dose steroids might prevent PRI. METHODS: The low-dose steroids were started orally, and the dose was gradually increased to the maximum level (30 mg/day). Immediately before thymectomy, patients received the maximum dose of oral steroids daily. PRI was defined as the development of restrictive dysfunction requiring mechanical ventilation within 3 days after thymectomy and total postoperative mechanical ventilation support time of >24 h. RESULTS: The rate of PRI in the low-dose steroid use group was significantly lower than that in the no-steroid use group. The postoperative stay in the intensive care unit was shorter in the steroid use group. CONCLUSIONS: Extended thymectomy is a well-accepted surgical treatment for selected patients with MG. However, PRI remains problematic. Our results suggest that not only preoperative high-dose steroid treatment, but also low-dose steroid treatment can prevent PRI.

Antitumor effect of a novel phenanthroindolizidine alkaloid derivative through inhibition of protein synthesis.

AIM: The present study aimed to determine the antitumor efficacy of a new Phenanthroindolizidine alkaloid (PA) derivative, YPC-10157, and to elucidate its mechanism of action. MATERIALS AND METHODS: The in vitro and in vivo antitumor activity of YPC-10157 was evaluated against several human cancer cell lines and mouse xenograft models, respectively. Cell apoptosis was determined by measuring caspase-3/7 activity. The effect on protein synthesis was assessed using an in vitro cell-free translation assay system. RESULTS: In vitro, YPC-10157 exhibited marked cell growth inhibition and induced apoptosis. In vivo, YPC-10157 had a strong antitumor effect on xenograft models of human colon cancer and leukemia. Moreover, YPC-10157 and its derivatives inhibited protein synthesis and their inhibitory activity on protein synthesis significantly correlated regarding cell growth. CONCLUSION: YPC-10157 has promising antitumor effects and suggest that its cytotoxic mechanism might involve the inhibition of protein synthesis.

Maternal age and initial ß-hCG levels predict pregnancy outcome after single vitrified-warmed blastocyst transfer.

PURPOSE: We retrospectively examined a large cohort of females who underwent single blastocyst transfer to determine if initial ß-human chorionic gonadotrophin (ß-hCG) levels on day 7 after single vitrified-warmed blastocyst transfer (SVBT) could be used to predict pregnancy outcome. METHODS: The treatment cycles that gave rise to the early pregnancies included in this study were performed from 2004 to 2011 in a private infertility center. In SVBT cycles, embryos were transferred during a natural cycle or after endometrial preparation with exogenous estrogen and progesterone. A total of 11,458 cycles with ß-hCG levels ≥1.0 UI/ml on day 7 after SVBT were evaluated. The proportion of live births per positive ß-hCG cycle was established for 10 ß-hCG ranges in 3 different age groups (Group A: 21-34 years old; Group B: 35-39 years old; Group C: 40-44 years old). RESULTS: The proportion of live births gradually increased from 1.5 to 93.7%, 0.8 to 87.9%, and 0.6 to 76.2% in Groups A, B, and C, respectively. For each range of ß-hCG levels, the proportion of live births was higher for the younger age group, which reflected the increased risk of early pregnancy loss with advancing female age. CONCLUSIONS: ß-hCG levels on day 7 after SVBT, in conjunction with maternal age, may be used to predict pregnancy outcomes.

Favorable outcome after withdrawal of immunosuppressant therapy in progressive multifocal leukoencephalopathy after renal transplantation: case report and literature review.

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by the JC polyomavirus (JCV). Most patients with PML after renal transplantation have had poor outcomes. We describe a patient with PML after renal transplantation who had a good response to the withdrawal of immunosuppressant therapy. We performed quantitative real-time PCR testing for JCV DNA in cerebrospinal fluid (CSF), and assessed mutation of the JC virus genome detected in the CSF. At the same time, we checked cranial magnetic resonance imaging (MRI). Immunosuppressant therapy was discontinued immediately. The MRI scan that followed showed markedly decreased numbers of high intensity signals, and the results of real-time PCR for JCV DNA in CSF became negative. The patient had no other neurological deficits. Withdrawal of immunosuppressant treatment has a beneficial effect on the course of PML after renal transplantation, and quantitative PCR may facilitate the immediate withdrawal of immunosuppressant agents.

ABCG2 inhibitor YHO-13351 sensitizes cancer stem/initiating-like side population cells to irinotecan.

BACKGROUND/AIM: The aim of this study was to determine the efficacy of the combination of irinotecan and newly-synthesized ABCG2 (breast cancer-resistant protein) inhibitor YHO-13351 in cancer chemotherapy. MATERIALS AND METHODS: Side population (SP) and non-SP cells from the human cervical carcinoma cell line HeLa were isolated by fluorescence-activated cell sorting. The antitumor activity of combination therapy with irinotecan and YHO-13351 was evaluated in xenograft studies in athymic BALB/c nude mice. RESULTS: While SP cells exhibited cancer stem/initiating cell-like properties and low sensitivity to irinotecan-alone, YHO-13351 sensitized them to irinotecan in both in vitro and in vivo studies. YHO-13351 in conjunction with irinotecan reduced the increase of the SP cell ratio in the tumors compared to those observed with treatment with irinotecan-alone. CONCLUSION: Combination therapy with irinotecan and YHO-13351 would not only accelerate the antitumor effect of this regimen, but also play a crucial role in preventing resistance or relapse.

Dropped head with positive intravenous edrophonium, progressing to myasthenia gravis.

'Dropped head syndrome' (DHS) may be associated with a variety of neurological diseases. The absence of neurological clues to the underlying cause of DHS can make management particularly challenging. We review six patients who presented with only DHS, responded to intravenous edrophonium and turned out to have myasthenia gravis (MG) including similar patients who were previously documented. Six patients presented with neck weakness and three had bulbar symptoms. Acetylcholine receptor (AchR) was positive in four patients. One patient had thymoma. The interval from the onset of DH to the presentation of typical MG features was shorter in patients who tested positive for anti-Ach antibody (1-2 months) than in patients who tested negative for anti-AchR antibody (13 months, 4 years). Our results suggest that patients with DHS responding to intravenous edrophonium might turn out to have MG and such patients might respond to a combination of anticholinesterase agents and steroids.