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.

Novel integrative methodology for engineering large liver tissue equivalents based on three-dimensional scaffold fabrication and cellular aggregate assembly.

A novel engineering methodology for organizing a large liver tissue equivalent was established by intergrating both 'top down' and 'bottom up' approaches. A three-dimensional (3D) scaffold was engineered comprising 43 culture chambers (volume: 11.63 cm(3)) assembled in a symmetrical pattern on 3 layers, a design which enables further scaling up of the device to a clinically significant size (volume: 500 cm(3)). In addition, an inter-connected flow channel network was designed and proved to homogenously deliver culture medium to each chamber with the same pressure drop. After fabrication using nylon-12 and a selective laser sintering process, co-cultured cellular aggregates of human hepatoma Hep G2 and TMNK-1 cells were loosely packed into the culture chambers with biodegradable poly-L-lactic acid fibre pieces for 9 days of perfusion culture. The device enabled increased hepatic function and well-maintained cell viability, demonstrating the importance of an independent medium flow supply for cell growth and function provided by the current 3D scaffold. This integrative methodology from the macro- to the micro-scale provides an efficient way of arranging engineered liver tissue with improved mass transfer, making it possible to further scale up to a construct with clinically relevant size while maintaining high per-volume-based physiological function in the near future.

Low FOXA1 expression predicts good response to neo-adjuvant chemotherapy resulting in good outcomes for luminal HER2-negative breast cancer cases.

BACKGROUND: FOXA1 expression is a good prognostic marker for endocrine therapy in hormone-positive breast cancer. We retrospectively examined breast cancer patients with luminal human epidermal growth factor receptor 2 (HER2)-negative tumours, as defined by immunohistochemistry, who received neo-adjuvant chemotherapy (NAC) and investigated the relationship between treatment effects and FOXA1 expression. METHODS: Biopsy specimens from 103 luminal HER2-negative tumours were immunohistochemically examined. FOXA1 effects on chemo-sensitivity were also investigated employing in vitro experiments. RESULTS: FOXA1 and Ki67 expressions independently predicted a pathological complete response (pCR). Knockdown of FOXA1 by siRNA boosted the chemo-effect in oestrogen receptor-positive cells. The Cox hazards model revealed a pCR to be the strongest factor predicting a good patient outcome. CONCLUSIONS: Our present study showed low FOXA1 expression to be associated with a good response to NAC in luminal HER2-negative breast cancer. Improved outcomes of these patients suggest that NAC should be recommended to patients with low FOXA1 tumours.

An open-label study of lapatinib in women with HER-2-negative early breast cancer: the lapatinib pre-surgical study (LPS study).

BACKGROUND: This phase II, open-label, multicentre study aimed to evaluate changes in cell proliferation and biomarkers, as well as efficacy of lapatinib in treatment-naïve patients with HER-2-negative primary breast cancer. PATIENTS AND METHODS: Patients received 1500 mg lapatinib for 28-42 days before surgery with repeat biopsies and measurements. The primary end point was inhibition of cell proliferation measured by Ki67; the secondary end points included clinical response, adverse events and changes in FOXO3a, FOXM1, p-AKT and HER-3. RESULTS: Overall, there was no significant reduction in Ki67 with treatment (assessment carried out in 28 of 31 subjects enrolled). However, four patients (14%) showed a reduction in Ki67 ≥50%. Four of 25 patients (16%) had a partial response to treatment judged by sequential ultrasound measurements. Response, in terms of either Ki67 or ultrasound, did not relate to changes in any biomarker assessed at baseline, including the estrogen receptor (ER) and epidermal growth factor receptor (EGFR). However, all four clinical responders were HER-3 positive, as were three of four Ki67 responders. CONCLUSIONS: Overall, a pre-surgical course of lapatinib monotherapy had little effect on this group of patients; however, in subsets of patients, especially those with HER-3-positive tumors, we observed either reduction in proliferation (Ki67) or tumor size; EGFR/ER status had no impact.

Brainstem in Machado-Joseph disease: atrophy or small size?

Machado-Joseph disease (MJD), one of the most common types of hereditary spinocerebellar degeneration caused by abnormal expansion of the CAG repeat in the MJD1 gene, presents atrophy of the infratentorial structures neuropathologically and neuroradiologically. Although a significant positive correlation has been reported between infratentorial atrophy and the number of expanded CAG repeat units, the exact changing course of brainstem size in the individual case remains to be resolved. We investigated seven cases of genetically confirmed MJD longitudinally by magnetic resonance imaging with observation periods of 4.5-10.6 years. Measurement of the midsagittal areas of infratentorial structures disclosed progressive atrophy of the pontine base and cerebellum, which correlated significantly with age, whilst midbrain and pontine tegmentum showed atrophy with no significant progression, suggesting it was better identified as 'small size' and might have mostly been completed before the initial symptoms. Such differences between regions in atrophy progression must be caused by a difference in the neuropathological course.

Solid phase microextraction/gas chromatography of Salmonella-infected beef.

Eight strains of Salmonellae were incubated in TSB culture medium at 37 degrees C for 24 h. Volatile compounds derived from the bacteria were collected using solid-phase microextraction fibers and then applied to gas chromatography (GC). Similarity analysis of the GC patterns thus obtained could separate these strains on principal component similarity (PCS) scattergrams. Five major food-related pathogenic bacteria and 10 other bacteria (including one Salmonella strain) were also classified by growing in the same medium. It is then proposed to utilize this approach to improve the GC/PCS method of Nakai et al. [Nakai, S.; Wang, Z. H.; Dou, J.; Nakamura, S.; Ogawa, M.; Nakai, E.; Vangerstoep, J. J. Agric. Food Chem. 1999, 47, 576-583] that has been developed for screening safe foods by detecting bacteria contaminated foods. Inoculating food samples pre-enriched through preliminary incubation into a culture medium and then subjecting to the GC/PCS method after secondary incubation enhances the detectability of pathogenic bacteria.

Cerebral atrophy in multiple system atrophy by MRI.

Cranial magnetic resonance images (MRI) of the cerebral areas of 40 patients with multiple system atrophy (MSA) and of 61 age-matched controls were analyzed. The cerebral area of MSA patients was 131. 95+/-15.89 cm(2) (mean+/-S.D.), which was significantly smaller than that of normal controls at 149.01+/-10.93 cm(2) (P<0.0001). All 23 MSA cases subjected to the MRI study over a 1-year period showed progressive cerebral atrophy, and the atrophy rate was 2.46+/-1. 66%/year. There were no significant differences within the MSA subtypes or between gender. The progression of cerebral atrophy in MSA correlated more with duration (r=-0.634) than age (r=-0.421). We conclude that MRI findings throughout the course of MSA suggest progressive cerebral atrophy, which is common in all subtypes and reflects duration of the disease rather than age.

Raman spectroscopic study of changes in fish actomyosin during setting.

Actomyosins (AMs) isolated from tilapia, lemon sole, ling cod, and rock fish were heated at 40 degrees C, and structural changes in AMs were investigated using Raman spectroscopy to elucidate low-temperature gelling phenomenon, that is, "setting", of surimi. The following conformational transitions were observed in lemon sole, ling cod, and rock fish gels during setting: a slow unfolding of alpha-helix and exposure of hydrophobic amino acid residues occurring in long-time incubation at 40 degrees C, thereby forming hydrophobic interactions among AM molecules. In addition, the most frequent conformation in disulfide bonds was gauche-gauche-trans (g-g-t) form in the set gel. On the other hand, tilapia AM did not form a gel with heating at 40 degrees C, its alpha-helical structure in the myosin being far more stable than that of the other species. The heat resistance of the tight alpha-helix may prevent the gelation of tilapia AM. It is, therefore, likely that the unfolding of the alpha-helix of myosin is a prerequisite for gelation of AM during setting.

[Anesthetic management in a child with Drash syndrome].

Drash syndrome is characterized by nephropathy, Wilms tumor and male pseudohermaphroditism. We present a child with an incomplete form of this syndrome who underwent two operations. A full-term, 3070 g female was born after a normal transvaginal delivery. At the age of 1 year and 6 months, in order to confirm the diagnosis of the infantile nephrosis, a renal biopsy was performed with halothane anesthesia. Histological findings showed diffuse mesangium sclerosis. At the age of 3 years and 8 months, a chromosomal analysis revealed XY gonadal dysgenesis. Therefore, a diagnosis was made as the incomplete Drash syndrome. At the age of 5 years and 7 months, a gonadectomy and a CAPD catheter insertion for renal failure were performed under sevoflurane anesthesia. The main problems encountered by anesthetists were severe renal dysfunction, use of steroids, anticoagulants and immunodepressants, choice of anesthetic agent, and mental health care. This patient has been followed for the potential development of Wilms tumor.

[What do adolescents desire for the postoperative pain relief?--a speculation from an interview with a patient].

Three different methods of postoperative pain management were evaluated by a 16 year old girl within 1 month after the last surgery who had undergone intrathoracic surgery three times during the six months. The postoperative pain management was different after each surgery. The first bullectomy was performed under thoracoscopy and she did not complain of severe pain with nerve blocks and NSAID suppository. After the second and third intrathoracic surgery, postoperative pain relief was tried with iv PCA and epidural morphine respectively. Although she commented that epidural morphine had been more potent than i.v. PCA from the viewpoint of pain relief, she preferred i.v. PCA to bolus administered epidural morphine because she could always control her pain whenever pain relapsed. Bolus epidural morphine, however, was administered by physicians only, and she endured severe pain for more than two hours until the next dose at the midnight of the operation. That might be the reason why she was not satisfied with epidural morphine. It was concluded that we should try to offer not fluctuating analgesic level but readily available potent analgesics which could be hopefully administered by patients themselves in adolescent or adult population.

[Anesthetic problems in a very low birth weight infant with Kasabach-Merritt syndrome].

Kasabach-Merritt syndrome is characterized by thrombocytopenia and bleeding tendency leading to disseminated intravascular coagulation with giant hemangiomas. We present a very low birth weight infant with this syndrome who underwent four operations. A male baby (1179 g, 37 cm) was born at a gestational age of 28 weeks and 6 days by caesarean section. A large hemangioma, 7 x 8 cm in size, was recognized on the left thigh. As associated consumption coagulopathy (Kasabach-Merritt syndrome) was diagnosed with platelet count 5.1 +/- 10(4) mm-3 and fibrinogen 49 mg.dl-1. Despite treatment with liniac X-ray radiation, systemic steroid and component transfusion, coagulopathy became worse with extremely low platelet count of 1.1 x 10(4) mm-3. Infusion of dopamine and dobutamine was necessary for high output cardiac failure. On day 9, PDA ligation was performed. Cerebro-ventricular drainage, ventricuro-peritoneal shunt and shunt revision were required on day 15, 49 and 88, respectively, for hydrocephalus due to intraventricular hemorrhage. Main anesthetics used were fentanyl and sevoflurane. Major problems encountered by anesthetists were: bleeding tendency, water and electrolyte management, body temperature control, and immaturity and fragility of premature infant. Coagulopathy in Kasabach-Merritt syndrome must be a risk factor for intraventricular hemorrhage, which is a characteristic complication of a very low birth weight infant.

[Perioperative management for partial resection of a lymphangioma of the tongue].

Twelve month old boy had been suffering from a neck lymphangioma. Partial resection was carried out in his newborn period at another hospital, and he was obliged to be tracheostomied because of severe airway obstruction due to postoperative edema. He was scheduled for partial glossectomy since his tongue had increased in mass, which could easily be injured by teeth, and he had difficulties in swallowing recently. His airway was not obstructive even during sleep and preoperative MRI showed adequate space around the larynx. We induced anesthesia by a mask and he was subseqently intubated with a fiberscope via his nose because his huge and less mobile tongue could not allow the insertion of a laryngoscope and this might cause bleeding. We did not extubate the endotracheal tube for fear of airway obstruction attributable to postoperative edema. Marked edema around the neck persisted longer than we expected. We tried to evaluate the degree of diminution of edema with MRI twice to decide when extubation could be attempted. However, examination with MRI could not give us useful informations. Consequently we evaluated the timing of extubation by examining whether he could close his mouth or not, whether his tongue could move freely and the degree of edema. We realized lymphangioma caused marked and extensive edema after the operation and we should keep in mind that lymphangioma of the tongue might cause various anesthetic problems especially on airways.

Suppression of interleukin-2 receptor expression on mouse CD4+ T cells by bovine kappa-caseinoglycopeptide.

Bovine kappa-caseinoglycopeptide (residues 106-169, CGP) completely inhibited the PHA-induced proliferation of mouse splenocytes when CGP was added simultaneously with PHA. The inhibitory effect, however, was reduced to about one-half when CGP was added after 24 h of cultivating the splenocytes with PHA or when anti-IL-1ra antibody was added simultaneously with PHA and CGP. On the other hand, CGP bound to mouse CD4+ T cells but not to CD8+ T cells. CGP suppressed IL-2 receptor expression of the PHA-stimulated mouse CD4+ T cells.

[Anesthetic problems in a 480 g infant for ventriculo-peritoneal shunt surgery].

A 480 g, 38-day-old female infant underwent ventriculo-peritoneal shunt surgery for hydrocephalus after intra-ventricular hemorrhage. The patient was born at a gestational age of 25 weeks and 5 days, weighing 600 g, as one of twins by a cesarean section. Although respiratory distress syndrome developed, it was relieved with surfactant. The esophagus was easily perforated by a gastric tube. At the age of 7 days, PDA was closed conservatively with indomethacin. Anesthesia was induced and maintained with fentanyl (induction dose 4 micrograms.kg-1, total dose 6 micrograms.kg-1) and vecuronium. Ventilation was controlled with oxygen and air (FIO2 0.21-0.25). The main problems encountered by anesthetists in the perioperative period were; fluid management (hyperkalemia, hyponatremia, infusion volume), bradycardia due to increased intracranial pressure, body temperature control (hypothermia), and transport to the operating room. In anesthesia for extremely low birth weight (extremely premature) infants, utmost care and proficient procedure are required because of their immaturity, fragility and smallness.

[Unexpected intraoperative respiratory distress; an infant who developed tracheomalacia and fatal aortoesophageal fistula due to unrecognized vascular ring].

Vascular rings cause respiratory distress and dysphasia by tracheoesophageal compression. We present a case of tracheomalasia and fatal aortoesophageal fistula due to unrecognized vascular ring. A 3-month-old (7.3 kg) boy underwent V-P shunt operation under sevoflurane anesthesia. The trachea was intubated easily using vecuronium with a relatively large-size tube with a diameter of 4.5 mm, because of leakage. Gastric intubation was difficult. During scrubbing of the head, an asthma-like respiratory distress suddenly occurred. The condition responded poorly to ventilatory support and pharmacological interventions. Although intraoperative fiberscopy through the tracheal tube and chest X-ray showed no tracheobroncheal abnormality, postoperative fiberscopy revealed a tracheomalacia. Adequate ventilation was possible only when the tip of the tracheal tube was located between the stenotic part and the tracheal carina. On the 9th postoperative day, during respiratory management with a tracheal tube, fatal esophageal hemorrhage broke out. Postmortern examination revealed a double aortic arch with tracheal stenosis and aortoesophageal fistula. The nasogastric tube may have led to fistula formation by compression of the esophageal wall against an anomalous vessel. When anesthetists encounter an infantile respiratory distress, even in perioperative period, vascular rings should be taken into consideration.

Supercritical fluid chromatographic determination of cholesterol and cholesteryl esters in serum on ODS-silica gel column.

Cholesterol and cholesteryl esters in human serum were determined by supercritical fluid chromatography on an inert ODS-silica gel column using supercritical carbon dioxide as a mobile phase without a modifier. Chromatograms were obtained by monitoring the eluent simultaneously with an FID and UV detector at the wavelength of 190 nm. The retention behavior of cholesterol and cholesteryl esters was investigated in terms of the density of CO2 mobile phase. The separation mode was found to be reversed phase, as in liquid chromatography. The amounts of cholesterol and cholesteryl esters extracted from human serum reference material (NIST SRM 909) were determined individually using cholesteryl laurate as an internal standard to give good agreement of total cholesterol with the value certified by NIST.

[Anesthetic management of palliative surgery for hypoplastic left heart syndrome--a case report].

The first patient with hypoplastic left heart syndrome who was treated successfully by palliative surgery at our hospital is reported. Soon after birth, the female infant showed tachypnea and cyanosis, and was transferred to our institution under a presumptive diagnosis of HLHS. Although cardiologists confirmed the diagnosis by two-dimensional echocardiography, the surgery was postponed for one month because it was possible to keep the ductus arteriosus open without PGE1, and the patient showed no deterioration. Fortunately, an abnormal vessel connecting the left atrium with the superior vena cava relieved severe pulmonary venous congestion by diverting the blood flow. During the pre-CPB period, frequent adjustment of the oxygen concentration and ventilator setting was required in order to keep the blood gas values optimal compared with the values before surgery. After CPB, adequate blood pressure using catecholamines and hyperventilation with 100% oxygen was necessary to increase the pulmonary blood flow and to decrease the pulmonary vascular resistance. It is concluded that preservation of the balance between PVR and SVR during the perioperative period, and adequate systemic arterial pressure after CPB are crucial. Furthermore, constant and intense observation is mandatory to facilitate immediate treatment even after surgery in case of systemic hypoperfusion due to excessive pulmonary blood flow.

Scopolamine patch reduces postoperative emesis in paediatric patients following strabismus surgery.

Scopolamine patch was evaluated for the prevention of postoperative emesis in 50 children undergoing strabismus surgery. All subjects were premedicated, with none receiving narcotic premedicants. Anaesthesia included controlled ventilation with the use of muscle relaxants, atropine, and halothane. Before operation, the subjects were randomly assigned to one of two groups: a treatment group received a scopolamine patch at a dose of either 0.75 mg or 0.375 mg, and a control group received no patch. Both the incidence and frequency of vomiting in the scopolamine-treated group were significantly (P less than 0.05) lower than in the control group.

Accidental extubations during respiratory management in a children's hospital.

An investigation was conducted on the frequency of accidental extubations at Shizuoka Children's Hospital during the past 12 years. The study was performed on 150 randomly selected patients who received respiratory support for more than 24 hr. Fifteen accidental extubations occurred in 9 patients. Most of them (87%) occurred in the neonatal intensive care unit (NICU), and the rate was 1 per 54 days of intubation. The time at which these accidents happened varied, although they were more common during the day-time. The reasons of accidental extubation could not be specified in two-thirds of the cases. It became clear that more immature babies were more likely to suffer accidental extubation, perhaps reflecting the fact that most of the immature babies in the NICU were intubated orally, and that a larger proportion of them required a longer period of respiratory support. Therefore, early weaning from respiratory support is recommended if it is possible. In conclusion, increased surveillance and more secure methods of taping of endotracheal tubes are crucial for preventing life-threatening accidental extubations during respiratory support.