A maintained absolute lymphocyte count predicts the overall survival benefit from eribulin therapy, including eribulin re-administration, in HER2-negative advanced breast cancer patients: a single-institutional experience.

PURPOSE: Eribulin methylate (eribulin) improved the overall survival (OS) of HER2-negative advanced breast cancer (HER2-ABC) patients; however, the mechanism underlying the OS improvement has not been clarified. Several reports suggest that eribulin promotes antitumor immunity via tumor micro-environment conditioning. Recently, a maintained baseline lymphocyte count was proposed as predictive marker for eribulin therapy in HER2-ABC patients; however, no associations with the OS have been noted. We retrospectively investigated the neutrophil-to-lymphocyte ratio and absolute lymphocyte count (ALC) in HER2-ABC patients receiving eribulin and assessed the utility of eribulin re-administration for further OS improvement. METHODS: HER2-ABC patients who received eribulin therapy at Shizuoka Cancer Center between November 2011 and December 2018 were retrospectively analyzed. RESULTS: A total of 144 HER2-ABC (108 estrogen receptor-positive [ER+], 36 ER-) patients were identified, and 32 patients (28 ER+ , 4 ER-) were re-administered with eribulin. In the ER+ subgroup, a multivariate analysis showed that an ALC ≥ 1000/µL and re-administration were significantly associated with the OS (hazard ratio [HR] 0.503; P = 0.034 and HR 0.366; P < 0.0001, respectively), and an ALC ≥ 1000/µL was also identified as the only predictive factor for re-administration (HR 0.329; P = 0.033). In contrast, a multivariate analysis in the ER- subgroup identified no predictive markers. CONCLUSION: In HER2-ER + ABC patients, ALC was identified as a predictive marker for eribulin therapy, and the re-administration of eribulin is considered a valid therapeutic option for further improvement of the OS.

Isolation of a thermotolerant bacterium producing medium-chain-length polyhydroxyalkanoate.

AIMS: The aim of this study was to isolate a thermotolerant micro-organism that produces polyhydroxyalkanoates (PHAs) composed of medium-chain-length (mcl) HA units from a biodiesel fuel (BDF) by-product as a carbon source. METHODS AND RESULTS: We successfully isolated a thermotolerant micro-organism, strain SG4502, capable to accumulate mcl-PHA from a BDF by-product as a carbon source at a cultivation temperature of 45°C. The strain could also produce mcl-PHA from acetate, octanoate and dodecanoate as sole carbon sources at cultivation temperatures up to 55°C. Taxonomic studies and 16S rRNA gene sequence analysis revealed that strain SG4502 was phylogenetically affiliated with species of the genus Pseudomonas. This study is the first report of PHA synthesis by a thermotolerant Pseudomonas. CONCLUSIONS: A novel thermotolerant bacterium capable to accumulate mcl-PHA from a BDF by-product was successfully isolated. SIGNIFICANCE AND IMPACT OF THE STUDY: A major issue regarding industrial production of microbial PHAs is their much higher production cost compared with conventional petrochemical-based plastic materials. Especially significant are the cost of a fermentative substrate and the running cost to maintain a temperature suitable for microbial growth. Thus, strain SG4502, isolated in this study, which assimilates BDF by-product and produces PHA at high temperature, would be very useful for practical application in industry.

[Application of the lower partial sternotomy approach to patients who may need tracheostomy in the early period after cardiac surgery].

Recent good results of cardiovascular surgery have led to expansion of its indication to elderly patients and patients with serious complications. Such patients may have serious respiratory complications after cardiac surgery and need to undergo tracheostomy relatively early in the postoperative period. Although the full sternotomy approach is the standard in almost all cardiac surgeries, superficial and deep sternal infections are rather common after early tracheostomy in full sternotomy patients. The lower partial sternotomy approach is a safer and more useful procedure in patients who will need tracheostomy in the early period after cardiac surgery. We report on 2 patients who were successfully tracheostomized within a week after cardiac surgery, with a review of the literature.

Quantification of hepatitis C virus in patients treated with peginterferon-alfa 2a plus ribavirin treatment by COBAS TaqMan HCV test.

Extremely low levels of serum hepatitis C virus (HCV) RNA can be detected by COBAS TaqMan HCV test. To investigate whether the COBAS TaqMan HCV test is useful for measuring rapid virological response (RVR) and early virological response (EVR) to predict sustained virological response (SVR), we compared the virological response to PEG-IFN-alfa 2a plus RBV in 76 patients infected with HCV genotype 1 when undetectable HCV RNA by the COBAS TaqMan HCV test was used, with those when below 1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test was used, which corresponded to the use of traditional methods. Among the 76 patients, 28 (36.8%) had SVR, 13 (17.1%) relapsed, 19 (25.0%) did not respond, and 16 (21.0%) discontinued the treatment due to side effects. The positive predictive values for SVR based on undetectable HCV RNA by COBAS TaqMan HCV test at 24 weeks after the end of treatment [10/10 (100%) at week 4, 21/23 (91.3%) at week 8 and 26/33 (78.7%) at week 12] were superior to those based on <1.7 log IU/mL HCV RNA [17/19 (89.4%) at week 4, 27/38 (71.0%) at week 8, and 27/43 (62.7%) at week 12]. The negative predictive values for SVR based on <1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test [46/57 (80.7%) at week 4, 37/38 (97.3%) at week 8, and 32/33 (96.9%) at week 12] were superior to those based on undetectable HCV RNA [48/66 (72.7%) at week 4, 46/53 (86.7%) at week 8, and 41/43 (95.3%) at week 12]. The utilization of both undetectable RNA and <1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test is useful and could predict SVR and non-SVR patients with greater accuracy.

Hepatitis A virus (HAV) proteinase 3C inhibits HAV IRES-dependent translation and cleaves the polypyrimidine tract-binding protein.

Hepatitis A virus (HAV) infection is still an important issue worldwide. A distinct set of viruses encode proteins that enhance viral cap-independent translation initiation driven by an internal ribosome entry site (IRES) and suppress cap-dependent host translation. Unlike cytolytic picornaviruses, replication of HAV does not cause host cell shut off, and it has been questioned whether HAV proteins interfere with its own and/or host translation. HAV proteins were coexpressed in Huh-7 cells with reporter genes whose translation was initiated by either cap-dependent or cap-independent mechanisms. Among the proteins tested, HAV proteinase 3C suppressed viral IRES-dependent translation. Furthermore, 3C cleaved the polypyrimidine tract-binding protein (PTB) whose interaction with the HAV IRES had been demonstrated previously. The combined results suggest that 3C-mediated cleavage of PTB might be involved in down-regulation of viral translation to give way to subsequent viral genome replication.

Indications for the use of endoscopic mucosal resection for early gastric cancer in Japan: a comparative study with endoscopic submucosal dissection.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) has been reported to produce excellent treatment results for early gastric cancer. In terms of lesions that previously met the criteria for endoscopic mucosal resection (EMR), there is now controversy about which of the two methods is superior, and whether the two methods are comparable. PATIENTS AND METHODS: A total of 177 patients (202 lesions) with early gastric cancer who met the guidelines for EMR and who underwent either EMR or ESD were studied. The rates of en bloc resection, complete resection, local recurrence, and complications were compared between EMR and ESD. RESULTS: The overall en bloc and complete resection rates were lower in patients undergoing EMR than in those undergoing ESD (en bloc: 53.8 % vs. 94.3 %, P < 0.001; complete: 37.5 % vs. 92.6 %, P < 0.001). The overall 5-year recurrence-free rate was lower in the EMR group than in the ESD group (82.5 % vs. 100 %; P < 0.001). However, with regard to the tumor size, the two groups did not differ in en bloc ( P = 1.0) or complete resection rate ( P = 0.8) for tumors < or = 5 mm and in 5-year recurrence-free rate ( P = 0.19) for tumors < or = 10 mm. The mean time required for resection was longer for ESD than for EMR ( P < 0.001). Perforation and bleeding requiring blood transfusion occurred in a small percentage in the ESD group, but in none in the EMR group. CONCLUSION: In this study, EMR was comparable to ESD for the millimeter-sized lesions. We suggest that such small lesions might be well suited to treatment with EMR.

First Report of Leaf Rust of Blueberry Caused by Pucciniastrum vaccinii in Hawaii.

Blueberries (Vaccinium corymbosum L.) are a potential high-value, niche market crop for Hawaii. In May of 2007, rust-like symptoms were observed on multiple blueberry plants in a private nursery in Waimea, HI. In September of 2007, a similar leaf rust was observed on one bush of V. corymbosum cv. Sharpblue in the corner of a 36.6 × 9.1-m experimental plot at Mealani Research Station in Waimea. Within a month, rust was observed throughout the plot on 'Biloxi', 'Emerald', 'Jewel', 'Misty', 'Sapphire', and 'Sharpblue'. Preliminary field observations suggest that 'Sharpblue' and 'Sapphire' are highly susceptible to the rust and 'Biloxi' shows some tolerance. Leaf lesions began as approximately 1-mm2 chlorotic flecks that expanded and developed into reddish brown, necrotic spots with a chlorotic halo. New lesions and uredinia kept appearing over the course of 4 months. Defoliation occurred on plants where infection was severe. Yellowish orange pustules containing urediniospores first appeared on the abaxial side of older leaves and later appeared on new leaves. Urediniospores were elliptical to obovate (19.4 to 24.8 × 15.2 to 19.8 µm) with a thick, slightly roughened wall and a well-developed pore. Urediniospore morphology and dimensions were consistent with the description of Pucciniastrum vaccinii (G. Wint.) (1). A pathogenicity test was conducted with two 18-month-old 'Sharpblue' plants. Fully expanded leaves were sprayed with freshly collected urediniospores (3.8 × 105 spores per ml) suspended in a 0.05% solution of Tween 20 in water. The control plant was sprayed with sterile distilled water (SDW). Plants were covered with plastic bags for 48 h and held in a growth chamber at 20 to 22°C under continuous fluorescent lighting. The plastic bags were then removed and the plants were maintained in the growth chamber. Yellowish orange pustules that were identical to the original symptoms developed on 100% of inoculated leaves after 10 days. The plant inoculated with SDW remained symptomless. While leaf rust caused by P. vaccinii has been reported on Ohelo berry (V. reticulatum) (2), it has not been reported on V. corymbosum in Hawaii. To our knowledge, this is the first report of P. vaccinii on blueberry plants in Hawaii. This rust disease may pose a threat to the potential blueberry industry in Hawaii. References: (1) P. R. Bristow and A. W. Stretch. Page 20 in: Compendium of Blueberry and Cranberry Diseases. F. L. Caruso and D. C. Ramsdell, eds. The American Phytopathological Society, St. Paul, MN, 1995. (2) D. F. Farr et al. Fungal Databases. Systematic Botany and Mycology Laboratory. Online publication. ARS, USDA, 2008.

Major phenolic acids and total antioxidant activity in Mamaki leaves, Pipturus albidus.

Three phenolic acids, (+)catechins, chlorogenic acid, and rutin, were identified and quantified in Mamaki leaves using a liquid chromatograph-mass spectrometer technique. Concentrations of (+)catechins, chlorogenic acid, and rutin varied from 1.1 to 5.0 mg/g of Mamaki leaves as determined in the extract using 0.5% acetic acid in 90% aqueous methanol. This study also quantified total antioxidant capacity using the photochemiluminescence method, which was expressed in equivalents to ascorbic acid (AA). Mamaki teas brewed for 30 min contained total antioxidant activity (TAA) between 238 and 259 mg AA/g of tea. Mamaki teas brewed for 1 h and stored at 4 h, 1 d, and 3 d at 4 degrees C had available TAA 293, 271, 172, and 163 mg AA/g of tea leaves, respectively. The concentrations of (+)catechins and rutin in Mamaki leaves are compared to other types of popular teas. Mamaki teas contained relatively low amounts of TAA compared to green teas and Lipton teas.

Obstructed coarctation in a right aortic arch in an adult female.

Coarctation of a right aortic arch is rare congenital anomaly. We report a rare case of a 24-year-old female with coarctation of the right aortic arch with aberrant left subclavian artery between the right common carotid and right subclavian arteries. The coarctation progressed into complete obstruction as the interruption of the aorta in adulthood. To prevent cerebral complications and progression to heart failure, surgical procedure was selected. Extraanatomical bypass grafting between the ascending and descending aorta was successfully performed using cardiopulmonary bypass. Some patients diagnosed with interruption of the aortic arch in adulthood might be displaying progression of undiagnosed coarctation, as our in case. Three-dimensional computed tomography was useful to detect the obstructive lesion and to determine the surgical approach and methods.

Williams syndrome associated with complete atrioventricular septal defect.

Williams syndrome is a genetic disorder associated with characteristic facies, supravalvar aortic stenosis, peripheral pulmonary stenosis, mental retardation, hypertension, premature aging of skin, and congenital cardiac defects. Many cardiac defects such as bicuspid aortic valve, mitral valve regurgitation, coarctation of the aorta, and ventricular or atrial septal defects are linked to the syndrome. Complete atrioventricular septal defect has rarely been associated with Williams syndrome and only one necropsy case has been reported in the literature. The long term follow up of Williams syndrome associated with complete atrioventricular septal defect is reported. During a 10 year follow up period, the pressure gradient in the ascending aorta did not increase despite narrowing of the ascending aorta as identified on an aortogram.

A new generic column switching system for quantitation in cassette dosing using LC/MS/MS.

Cassette dosing is a method in which multiple drugs are administered to a single animal at the same time, and the plasma concentrations of the individual compounds are simultaneously determined. This method enables high-throughput rapid screening for pharmacokinetic assessment of new drug candidates. An available gradient method was modified for cassette dosing analysis to attain the advantages of high sensitivity and applicability to a wide range of compounds. However, two problems arose; (1). the time-consuming optimization of mobile phases for each compound group, which limited applicability and (2). the remarkable suppression of ionization by polyethyleneglycol, which is commonly used in intravenous administration. To resolve these problems, a new column switching method was established to attain wider applicability and avoid the ionization suppression. This column switching system is very simple because the trap column and the analytical column are specified and the mobile phase is selected from only two species. Method optimization requires only the selection of the mobile phase and takes only a few hours. About 200 compounds, which were administered as about 50 cassettes, were analyzed using this column switching system. Assay validation of one cassette was carried out, and good accuracy and precision were obtained. About 90% of the compounds could be determined within 20% bias. These results showed that this new column switching system for cassette dosing is accurate enough for the screening of drug candidates and offers wide applicability for various compounds. This system was shown to be very useful for the determination of cassette dosing samples, containing multiple compounds.

hTR repressor-related gene on human chromosome 10p15.1.

Somatic cells express genes that suppress telomerase activity and these genes may be inactivated in tumour cells. We postulated that cancer cells acquire immortality by activation of telomerase by the loss of such a gene. We have reported recently that a telomerase repressor gene may be located on 10p15.1 by deletion mapping using microcell-mediated chromosome transfer (MMCT), radiated microcell fusion (RMF), fluorescent in situ hybridization (FISH) and STS analysis. To independently confirm this result, we correlated expression of RNA component of telomerase (hTR) as a marker of telomerase expression by in situ hybridization with allelic loss in pulmonary carcinoid tumours. Unlike most malignant tumours, pulmonary carcinoids (which are low-grade malignant tumours) are heterogeneous for telomerase expression. Loss of 5 closely spaced polymorphic markers on 10p15.1, especially D10S1728, were highly correlated with hTR expression. In an additional experiment, 10p15.1 showed higher and more significant correlation than any region of 3p where it has been predicted as another chromosomal location of telomerase repressor with allelic loss of the region. Our findings strongly suggest that 10p15.1 harbours a gene involved in repression of telomerase RNA component in human somatic cells and each putative repressor (on 3p and 10p) may act independently.

Surgical treatment of pacemaker induced left innominate vein occlusion using a spiral vein graft.

Superior vena cava syndrome due to transvenous pacing leads is an uncommon but potentially life-threatening complication. This case involves a 54-year-old man who developed left innominate vein occlusion due to a pacemaker lead. This complication induced a progressive swelling on the left side of his face, neck, arm, and upper chest. The left innominate vein occlusion was surgically treated using a composite spiral saphenous vein graft. Postoperatively, the patient has received anticoagulation therapy with warfarin to prevent thrombosis and, thereby, the long-term patency of the graft. He has undergone follow-up on a regular outpatient basis without showing any recurrence of clinical symptoms.

Pyrrolidine inhibitors of human cytosolic phospholipase A2. Part 2: synthesis of potent and crystallized 4-triphenylmethylthio derivative 'pyrrophenone'.

We synthesized a potent and crystallized human cytosolic phospholipase A2alpha inhibitor, pyrrophenone (6) which inhibits the isolated enzyme with an IC50 value of 4.2 nM. Pyrrophenone shows potent inhibition of arachidonic acid release, prostaglandin E2, thromboxane B2, and leukotriene B4 formation in human whole blood. The magnitudes of prostaglandin E2 and thromboxane B2 inhibition are the same as those of indomethacin.

A case of Standford type B aortic dissection involving a right-sided aortic arch with mirror-image branching and right-sided descending aorta.

Isolated right aortic arch with mirror-image branching is a rare congenital anomaly. To date, no case has been reported for aortic dissection involving a right aortic arch with mirror-image branching. We report here on a case involving a 58-year-old man in whom expanding type B aortic dissection was demonstrated in the right aortic arch with mirror-image branching and a right descending aorta. The patient was successfully treated by interposition of a prosthetic graft via a right posterolateral thoracotomy approach. We also reviewed the literature.

Disseminated cholesterol embolism after coronary artery bypass grafting.

Blue toe syndrome caused by cholesterol emboli is a relatively benign disease. However, disseminated cholesterol embolism is a life-threatening condition. We describe here the case of a 71-year-old female admitted because of anterior chest pain and intermittent claudication. Following cardiac catheterization, warfarin potassium was administered. However, the patient's toes soon darkened bilaterally, and BUN and creatinine levels increased from the normal value. Skin discoloration and renal failure were improved after stopping warfarin potassium administration. The patient underwent coronary artery bypass grafting and left femoropopliteal bypass. Cerebral infarction and renal failure occurred postoperatively due to disseminated cholesterol embolism. The patient died from renal failure on the 16th postoperative day without regaining consciousness following surgery. For high risk patients, interventional procedures to the ascending aorta must be avoided. When CABG cannot be avoided for coronary revascularization, off-pump bypass and use of arterial grafts are recommended.

Solid-pseudopapillary tumor of the pancreas: immunohistochemical localization of neuroendocrine markers and CD10.

To clarify the neuroendocrine differentiation and CD10 expression in solid-pseudopapillary tumors (SPTs) of the pancreas, we performed immunohistochemical analysis in 19 such tumors, including one solid-pseudopapillary carcinoma (SPC), along with 20 pancreatic neuroendocrine tumors (PNTs), six acinar cell carcinomas (ACCs), and one pancreatoblastoma (PB). We used antisera directed against CD56, synaptophysin, protein gene product 9.5, the alpha-subunit of Go protein, chromogranin A, CD10, trypsin, chymotrypsin, various cytokeratins (CKs), CA19-9, vimentin, and alpha-1-antitrypsin (AAT). All SPTs exhibited immunoreactivity for CD56 and CD10, and 15 expressed other neuroendocrine markers focally with the exception of chromogranin A. Frequent clustering of synaptophysin-positive cells was noted. Two cases contained a peculiar nodule that cytomorphologically and immunohistochemically resembled PNT. CD10-positive cells were scarce in one SPC. PNTs were CD56-positive, but often with faint intensity, and staining for other neuroendocrine markers, including chromogranin A, was diffusely positive. CD10 was detected, mostly in a focal pattern, in five PNTs. Pan-CK, CK8, CK18, and CK19 were more frequently demonstrated in PNT than SPT. Vimentin and AAT were often identified in PNT as well and were not specific for SPT. ACCs were CD56-negative, with the exception of one case designated as a mixed acinar-endocrine carcinoma. PB was focally positive for CD56 at the periphery of the tumor nests. Four ACCs and one PB exhibited focal CD10 reactivity. This study demonstrated the unique immunohistochemical features of SPT. Our results also suggest that SPT exhibits, at least focally, neuroendocrine differentiation, and that these neuroendocrine markers and CD10 are diagnostically useful.

Intraoperative radiotherapy and bypass surgery for unresectable pancreatic cancer.

BACKGROUND/AIMS: Conflicting results have been reported concerning the usefulness of radiotherapy for unresectable pancreatic cancer. We evaluated the clinical efficacy of intraoperative radiotherapy and/or external beam radiotherapy in combination with bypass surgery. METHODOLOGY: Twenty-six patients with unresectable pancreatic cancer (16 in Stage II-III and 10 in Stage IV) were treated with intraoperative radiotherapy plus external beam radiotherapy (16 patients) or intraoperative radiotherapy alone (10 patients). The dose of intraoperative radiotherapy was either 25 or 30 Gy and the external beam radiotherapy dose was 31-60 Gy. The feasibility and clinical outcome were analyzed. RESULTS: The median survival time for Stage II-III and Stage IV were 11.5 and 6.5 months, respectively. The difference between Stage II-III and Stage IV in survival patterns was statistically significant (P < 0.05). For Stage II-III patients, the survival curves between the groups of intraoperative radiotherapy plus external beam radiotherapy and intraoperative radiotherapy alone were not significantly different, and only performance status was a significant factor in the prognosis (P < 0.05). Gastrointestinal bleeding was noted in 8%, but did not occur in the patients treated with an external beam radiotherapy dose less than 50 Gy. Palliative radiation was successfully performed to relieve pain, jaundice and appetite-loss and to shorten the hospital stay. CONCLUSIONS: The combination therapy with intraoperative radiotherapy and bypass surgery is considered to be tolerable and effective for unresectable pancreatic cancer, and also may improve the quality of life of the patients.

Assembly of chloroplast cytochromes b and c.

The synthesis of holocytochromes in plastids is a catalyzed process. Several proteins, including plastid CcsA, Ccs1, possibly CcdA and a thioredoxin, plus at least two additional Ccs factors, are required in sub-stoichiometric amounts for the conversion of apocytochromes f and c(6) to their respective holoforms. CcsA, proposed to be a heme delivery factor, and Ccs1, an apoprotein chaperone, are speculated to interact physically in vivo. The formation of holocytochrome b(6) is a multi-step pathway in which at least four, as yet unidentified, Ccb factors are required for association of the b(H) heme. The specific requirement of reduced heme for in vitro synthesis of a cytochrome b(559)-derived holo-beta(2) suggests that cytochrome b synthesis in PSII might also be catalyzed in vivo.

Age of onset, not type of onset, affects the positivity and evanescence of IA-2 antibody.

Autoantibody against IA-2 (IA-2A) was found to be discordant with autoantibody against glutamic acid decarboxylase (GADA) with respect to both positivity and titer in Japanese, the same as in Caucasians. In this study, 247 type 1 diabetic patients were tested in order to clarify how the type of onset, age of onset, and duration of diabetes affect the frequency and evanescence of IA-2A. Among the young onset patients, the frequency of IA-2A was higher (52.2%), but evanescent (54.5, 66.7 and 36.7% in the insulin therapy duration < or =1, 2-5 years, and > or =6 years groups, respectively), whereas among adult onset patients, the frequency was lower (19.3%) but persistent (19.6, 13.3 and 23.5%, respectively). In addition, in the follow-up study, two of three IA-2A-positive young onset patients converted to negative in only three years, while all five adult onset patients remained positive for over 5 years. Among the adult onset patients, IA-2A frequency was similar in the slowly progressive type and the abrupt onset type. In view of the above findings, IA-2A positivity and evanescence in type 1 diabetic patients appear to be affected by age of onset, not type of onset.