Influence of using history of immune checkpoint inhibitor therapy for neutropenia caused by combination therapy of ramucirumab and docetaxel.

Recently, pretreatment with immune checkpoint inhibitors (ICIs) has been shown to enhance the therapeutic effects of the combination therapy of ramucirumab (RAM) and docetaxel (DTX); however, its influence on the drug's side effects remains unclear. This study investigated the influence of pretreatment with ICIs on the incidence of neutropenia caused by RAM + DTX therapy in patients with non-small cell lung cancer (NSCLC). Patients with NSCLC who received RAM + DTX therapy at Gifu Prefectural General Medical Center between April 2016 and December 2020 were enrolled. Retrospective data regarding age, sex, performance status and detailed treatment history, among others, at treatment initiation were collected from the patients' electronic medical records. Additionally, data on the course number of RAM + DTX therapy, supportive therapy and blood biochemical parameters, including leukocyte and neutrocyte counts, during the treatment period were collected. We identified 41 patients receiving RAM + DTX therapy. Among the more than grade 3 adverse events caused by this therapy, neutropenia was the most common (78.1%). Despite the fact that all previous risk factors influencing this incidence rate had corresponded, the only factor influencing the incidence rate of neutropenia more than grade 3 was ICI treatment history. A difference in the incidence of neutropenia more than grade 3 in the Kaplan-Meier curve was observed between patients with and without ICI pretreatment history (p = 0.037). The pretreatment history of ICI therapy affects the incidence of neutropenia caused by RAM + DTX therapy in patients with NSCLC.

Waning of the specific interferon-gamma response after years of tuberculosis infection.

HYPOTHESIS: Memory T-cell responses to specific antigens wane over time in subjects with tuberculosis (TB) infection. SETTING: Accumulated evidence indicates that QuantiFERON-TB Gold (QFT-G), a specific whole-blood interferon-gamma (IFN-gamma) based assay, can detect recent TB infections with superior sensitivity and specificity. OBJECTIVE: We applied this technique to the adult population of a Japanese community to determine its epidemiological usefulness. METHOD: A total of 1559 subjects attending periodic health screening volunteered to participate in the study. RESULTS: The QFT-G positive rates were 3.1% for those aged 40-49 years, 5.9% for those aged 50-59 and 9.8% for those aged 60-69. The expected infection prevalence estimated by the authors from a series of studies was 11.1%, 29.6% and 53.1% for those aged 40-49, 50-59 and 60-69 years, respectively. This wide gap between the expected and observed positivity suggests that the IFN-gamma response waned substantially with time after infection. Those with X-rays suggestive of old TB lesions exhibited positivity rates well below 100%. CONCLUSION: The specific IFN-gamma response may wane considerably with time after infection. Longitudinal studies are required to investigate long-term dynamics of cell-mediated immunity in infected donors.

Binding of lithocholate and its glucuronide and sulfate by human serum albumin.

In the present study, the binding affinities of lithocholate sulfate and glucuronide by human serum albumin were compared to that of lithocholate by equilibrium dialysis, and the binding sites of these bile acids on those of various fluorescent probes and bilirubin were also studied. The dissociation constants for the primary binding sites for lithocholate sulfate and glucuronide on human serum albumin were 0.057 and 0.24 microM, respectively, which were lower than that for lithocholate (0.82 microM). Lithocholate sulfate and glucuronide, as well as lithocholate, did not simply inhibit the binding of the site II and III fluorescent probes or bilirubin to albumin. Inhibition by these bile acids of the site I fluorescent probe binding to albumin suggested that the secondary binding sites of these bile acids are equal to site I. The results of simultaneous equilibrium dialysis using [3H]lithocholate and [14C]lithocholate sulfate indicated that these compounds have the same primary binding site. In conclusion, sulfation and glucuronidation may increase the binding affinities of bile acids to human serum albumin without changing their binding site.

Evaluation of the therapeutic effect of radiotherapy on cervical cancer using magnetic resonance imaging.

PURPOSE: This study was performed to evaluate magnetic resonance imaging (MRI) in determining the therapeutic effect of radiotherapy (RT) on cervical cancer. METHODS AND MATERIALS: Serial MRI studies were performed in 42 patients with predominantly advanced cervical cancer before, during, and after radiotherapy. Patients underwent external irradiation combined with high-dose-rate intracavitary (HDR) brachytherapy. T-2 weighted spin-echo pulse sequences with long repetition and echo times were used at a field strength of 1.5 T. Multiple punch biopsies of the cervix were obtained from the high-signal intensity area in all patients at the same time as the MRI. RESULT: In biopsies performed immediately after RT, no residual tumors were found in 36 patients (86%); in 6 patients, residual tumors were observed. The simultaneous MRI study demonstrated no high-signal intensity on T2-weighted images in 28 patients. A high-signal area was observed in 14 patients, and this disappeared 3 months after RT in 8 patients with a negative histological study. The sensitivity, specificity, and accuracy of MRI studies at 3 months after RT were 100%. When the relationship between reduction of tumor volume at 30 Gy and local tumor control was analyzed, every patient with a reduction under 30% gained local control. Also, patients with no residual tumors 3 months after RT gained local control. CONCLUSION: MRI studies performed at 30 Gy of external irradiation and 3 months after RT were predictive factors of local control.

Preservation of photic blink reflex in Leber's hereditary optic neuropathy.

PURPOSE: To examine whether the early response of photic blink reflex (PBR) is spared in patients with Leber's hereditary optic neuropathy (LHON). METHODS: Twenty-six patients with bilateral optic neuropathy (visual acuity < or = 0.1) and central scotomata were divided into LHON group with one of three mitochondrial DNA mutations at nucleotide position of 3460, 11778, or 14484 and non-LHON group without them. Latencies of the PBR early response and those of the electrically evoked blink reflex (EBR) response were compared among the 26 patients and 20 healthy volunteers. RESULTS: In controls, average latency of the PBR response was 50.3 +/- 2.4 msec and was in accordance with previous reports. Ten of eleven patients with LHON had normal PBR responses, whereas 12 of 15 controls without LHON had abnormal responses (P = 0.0005). Latencies of EBR responses were normal in all but one patient with LHON. CONCLUSIONS: The afferent fibers of the PBR early response, as well as those of the light reaction, are reported to terminate presumably in the pretectum. Together with the reported evidence of the preserved light reaction in patients with LHON, we presume that W retinal ganglion cells may project common afferent fibers of these two neuronal pathways and may be preferentially spared in patients with LHON.

Retinal control on the axial length mediated by transforming growth factor-beta in chick eye.

PURPOSE: To clarify retinal control on scleral growth in form-deprivation myopia (FDM) in the chick, the authors studied change in transforming growth factor-beta (TGF-beta) in the form-deprived eye and the effect of this growth factor on scleral cell proliferation and axial length. METHODS: Change in TGF-beta in FDM in the chick was measured by reverse transcriptase polymerase chain reaction (RT-PCR), immunoblot, and immunohistochemistry. The effect of TGF-beta on [3H]thymidine uptake of scleral chondrocytes was determined by organ culture. Urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) were administered to determine the effect of TGF-beta activation on the axial length in normal and FDM eyes. RESULTS: The content of TGF-beta messenger RNA (mRNA) and the active form of TGF-beta protein were reduced in FDM eyes compared with the control specimen. Reduced immunoreactivity of TGF-beta in FDM eyes was found in the photoreceptor layer. The TGF-beta inhibited [3H]thymidine uptake into scleral chondrocytes. In the nondeprived eyes, the vitreous chamber depth and axial length were reduced after uPA treatment, whereas PAI-1 increased them. In the form-deprived eyes, uPA inhibited vitreous depth and axial length elongation, but PAI-1 had no effect. CONCLUSIONS: The authors' results suggest that TGF-beta mediates retinal control of ocular growth. Axial elongation in FDM probably is correlated with the reduction of TGF-beta in the retina, retinal pigment epithelium, and choroid. The uPA and PAI-1 treatment controls the activation of TGF-beta and affects axial length.

Differential expression of neuroendocrine-specific protein in form-deprived chick eyes.

PURPOSE: To identify genes that are highly expressed in form-deprived retina-retinal pigment epithelium-choroid tissues. Neuroendocrine-specific proteins were found to be highly expressed. METHODS: mRNAs enriched in retina-retinal pigment epithelium-choroid tissues from 3-, 7-, and 14-day form-deprived chick eyes were isolated by differential display technique with cDNA library screening. Neuroendocrine-specific protein A and C were cloned in control and form-deprived eyes. mRNA and protein levels, with respective regional localizations, were examined by Northern blot, Western blot, and immunohistochemical analyses, respectively. RESULTS: The isolated clone included an insert with a sequence homologous to both chick neuroendocrine-specific proteins A and C. The increases in mRNA and protein levels were confirmed by Northern and Western blot analyses, respectively. Immunohistochemical localization of neuroendocrine-specific proteins A and C was detected in the layer of photoreceptor inner segments, presumably in the cone cells. Northern blot analysis using negative lenses showed that levels of neuroendocrine-specific protein A and C mRNAs were not altered using negative lenses. CONCLUSIONS: The expression of both neuroendocrine-specific proteins A and C mRNAs in cone photoreceptor cells was upregulated within 14 days of form deprivation, but not in response to negative spectacle lenses. These data suggest that the increase in induction of neuroendocrine-specific proteins is not a secondary consequence of ocular elongation or myopic refraction. Induction of neuroendocrine-specific proteins in form-deprived eyes may be causally related to the development of myopia or may be an unrelated effect of form deprivation.

Effect of p-chloroamphetamine administration on monoamine metabolism in the rat nucleus accumbens and locomotor activity: studies with intracerebral dialysis in freely moving rats.

Changes in the level of dopamine (DA) and its metabolites [3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)] and serotonin (5-HT) and its metabolite [5-hydroxyindoleacetic acid (5-HIAA)] were determined sequentially in freely moving rats by using a brain dialysis method. The purpose of the study was to find the relationship between changes in the monoamine metabolism in the nucleus accumbens and locomotor activities following PCA administration. Subsequently it was found that locomotor activity significantly increased 1 and 2 h after PCA administration (2 mg/kg, i.p.) while the DA content in the dialysis fluid rose significantly after 1 and 2 h. On the other hand, the 5-HT level did not show significant changes. The DOPAC, HVA, and 5-HIAA levels were significantly reduced 1 to 6 h after PCA administration. It was suggested that the increase in locomotor activity caused by PCA administration is an expression of abnormal behavior caused by DA release from the nucleus accumbens.

Differential expression of nitric oxide synthase isoforms in form-deprived chick eyes.

PURPOSE: To clarify whether nitric oxide synthase (NOS) is involved in development of myopia, we examined the influence of form deprivation on the expressions of NOS isoform mRNA. METHODS: NOS isoform cDNAs were amplified from total RNA extracted from control and 7-day-form-deprived chick retina-RPE (retinal pigment epithelium)-choroid, using competitive RT-PCR (reverse-transcription polymerase chain reaction). Each NOS isoform protein was also analyzed by Western blotting and immunohistochemistry. RESULT: Expression of inducible NOS (iNOS) mRNA was highest in the control chick retina-RPE-choroid, followed by the expression of brain NOS (bNOS) mRNA. Expression of endothelial NOS (eNOS) mRNA was faint. The iNOS protein level, however, was only slightly higher than the levels of the bNOS and eNOS proteins and was found mainly in the outer part of the photoreceptor layer and inner and outer parts of RPE and choroid. bNOS alone was found in the outer nuclear layer. Although form deprivation reduced the iNOS and bNOS mRNA expressions, only the iNOS protein showed significant reduction. CONCLUSION: All three NOS isoforms were expressed in chick retina-RPE-choroid. Predominant expression of iNOS, instead of bNOS and eNOS, suggested the existence of ocular tissue-specific regulation of the iNOS gene. In addition to differences in expression level, bNOS displayed regional differential expression. Moreover, only iNOS was reduced in response to form deprivation. It is suggested that NOS isoforms may be differentially involved in the mechanisms regulating the posterior eye tissues, including myopic eye growth.

In vivo characteristics of a transplantable Marek's disease lymphoblastoid cell line, MDCC-MSB1-41C.

A Marek's disease (MD) lymphoblastoid cell line, MDCC-MSB1-41C, was highly transplantable and lethal for chickens. Autopsies showed extensive metastasis in various organs. The transplantabilities of the parent cell line, MDCC-MSB1, and another derivative line, MDCC-MSB1-33C, were transient. MD virus (MDV) could be isolated from the kidneys but not from the peripheral blood leukocytes of chickens inoculated with the MSB1-41C cell line. In addition, anti-MDV antibodies were produced both in chickens inoculated with this cell line and in controls raised with inoculated chickens, but several attempts to isolate MDV from this cell line in vitro failed.

Intraorbital arteriovenous malformation: case report.

A case of intraorbital arteriovenous malformation presenting with visual loss, exophthalmos, and chemosis of the right eye is reported. Enhanced computer tomography and magnetic resonance imaging showed extraocular muscle enlargement and vascular abnormality in the right retrobulbar space. Angiography revealed an abnormal intraorbital vascular stain with an extremely dilated right ophthalmic artery. Total removal of the intraorbital contents was performed after unsuccessful endovascular and surgical treatment of arteriovenous malformation (AVM). Histopathological examination disclosed an AVM in the retrobulbar fatty tissue with extension into the extraocular muscles and optic nerve.

Visual function following congenital cataract surgery.

To evaluate the results of congenital cataract extraction and postoperative visual function, we retrospectively reviewed the records of 95 patients who underwent pars plana (plicata) lensectomy or aspiration surgery. Forty-nine percent of the patients with bilateral aphakia and 25% with bilateral pseudophakia had a Landolt visual acuity of 0.5 or above at the final visit. The figures were 31% and 66% for patients with unilateral aphakia and pseudophakia, respectively. Eight patients (16.3%) with bilateral and 2 patients (5.8%) with unilateral cataract for whom contact lenses were prescribed after surgery attained fine stereopsis. Five of 8 patients (62.5%) with unilateral cataract who had intraocular lens implantation ended up with gross or fine stereopsis. We stress that very early surgery and optical correction in the sensitive period of binocular visual development should be instituted, especially in the presence of dense opacities. A good postoperative visual outcome can be achieved in patients undergoing late surgery if the opacities are light or partial in nature. We also reemphasize the importance of aggressive and diligent visual rehabilitation and occlusion therapy against amblyopia.

Altered expression of genes in experimentally induced myopic chick eyes.

PURPOSE: To identify a casual pathway between the alteration in visual experience, due to form deprivation and hyperopic defocus, and the increase in eye growth, we searched for candidate genes having regulatory effects on eye growth under myopic conditions. METHODS: The expression of the brain-derived neurotrophic factor, neurotrophin-3, sonic hedgehog, nerve growth factor, Six-3 and the Lh-2 group of genes in the transcriptional level after experimentally induced myopia (form-deprivation by goggles and by hyperopic defocus using negative spectacle lenses) were evaluated by semiquantitative reverse transcriptional polymerase chain reaction and Northern blot analysis. RESULTS: Results showed that only the sonic hedgehog gene was differentially expressed in the experimentally induced myopic retinal samples compared with controls. CONCLUSIONS: The sonic hedgehog gene may have regulatory functions in the signaling of the cascade of events that leads to axial elongation and vitreous enlargement of the eye under myopic conditions.

[Event-related potentials in anisometropic amblyopia].

Event-related potentials were recorded from 20 neurologically normal children with anisometropic amblyopia. Stimulation was performed with an 'odd-ball' paradigm counting Randolts' circle, and in all cases N200 and P300 were recorded as event-related potentials. The latencies of N200 showed statistically significant delay (p < 0.001: Wilcoxson signed rank test), but P100 and P300 were not delayed in the stimulus input from amblyopic eyes. The degree of delay has no relationship with visual acuity or anisometropic differences. The results suggest that the cortical sensory processing functions represented by P300 were not damaged in the amblyopic cases observed in this study.

[Roles of outpatient nurses in the care of cancer patients receiving MS Contin tablets].

Pain relief is very important to improve the QOL of cancer patients. Accurate pain assessment and offering suitable drug information on MS Contin tablets (MSC) are important roles of outpatient nurses for the effective use of MSC. We examined the present status of symptom relief among cancer outpatients and from this discuss the practice of outpatient nursing. Forty-eight outpatients receiving MSC were interviewed by mail with regard to pain relief, the side effects of MSC, and the drug information they had been provided. Cancer pain was well controlled in 68% of outpatients by MSC, but MSC was not effective in 13%. Some side effects were observed in 68% of patients, 10% of which were poorly controlled. Sixty-five percent of patients were informed about MSC, but only 47% were informed about measures against these side effects. The following conclusions were reached: 1) MSC should be explained individually and repeatedly, 2) exact informations on a patient's status should be collected using scales and charts, 3) nurse charts should record when MSC is initially administered and when the dosage is changed, and 4) the cases of poorly controlled patients should be studied and specialists consulted if necessary.

[Terminal care of the cancer patient at home--patient and family spending the last moments together].

Some 129 cancer patients were taken care of at home by the visiting nurse team of our hospital since 1994 to 1997; 116 patients have already died, 50 of them at home (group A), and 66 at the hospital (group B). We analyze the differences the between two groups in nutritional assistance, pain control and manpower in looking after a patient. Twice as many patients in group A took nutritional medication (drip infusion or intravenous hyperalimentation, for example) than group B. More patients in group A used oral and suppository morphine than group B. In group A 70% of patients (56% in group B) had more than two persons looking after at home. The important factors for a good recuperation at home are: 1. Available nutritional assist available. 2. Good control. 3. Less burden and anxiety of the person looked after. To spend pain desirable last moments together, it is important for the visiting nurse team to take proper care and to confirm the wishes of the patient and family, considering the rapidly changing conditions of the individual patient.

[Visiting nurse support for patients wishing to die at home].

Thirty-two (1994) and 55 (1995) patients in the terminal stage of many kinds of cancer were cared for satisfactorily at home by a visiting team of nurses from Niigata Cancer Center Hospital. A prostate cancer patient with multiple bone metastasis was suffering from morphine-resistant intractable pain, and highly dependent on medical care. We continued to take care of him by frequent visitation and psychological assist until he eventually died at home according to his wishes. It is important to create a suitable support team for the continual difficult home care of each terminal patient.

[Evaluation by visiting nurse in end-stage cancers--family questionnaire for patients who died after visiting nurse].

Since April 1994, we have provided visiting nurse care for patients with end-stage of cancers. A questionnaire was sent to 72 families of patients who died of cancer and who received after visiting nurse care. The response rate to the questionnaire was 76.4% (55 patients). One group of 27 patients died at home (Group A), and the other group of 28 patients died in the hospital (Group B). Patients who knew they had cancer accounted for 85.2% in Group A, and 57.1% in Group B. Of all patients, 69.1% desired home nursing, with 77.8% in Group A, and 60.7% in Group B. The satisfaction of families with the visiting nurse was evaluated. In Group A, satisfaction was 66.7% and relative satisfaction was 18.5%. In Group B, satisfaction was 50.0% and relative satisfaction was 25.0%. Satisfaction of patients with the place of death was 81.5% in Group A, and 35.7% in Group B. Many families wished to have the nurse visit 2 times a week, and an hour at each visit. The great mental burden on the families who provide home care for patients with terminal cancer was clear for the questionnaire. Arrangement for a support system for patients and families, through visiting nurse services, is necessary in our hospital.

[Effect of low-dose sulpiride on dopamine metabolism in rat nucleus accumbens and locomotor activity: studies with intracerebral dialysis].

Changes in the concentration of dopamine (DA) and its metabolites, 3, 4-dihydroxyphenyl-acetic acid (DOPAC) and homovanillic acid (HVA), were determined sequentially in freely moving rats by using a brain dialysis method. The purpose of this study was to investigate the relationship between changes in the dopamine metabolism in the nucleus accumbens and locomotor activities following low-dose (5 mg/kg) sulpiride administration. The DA content in the dialysis fluid rose significantly 4 to 6 h after sulpiride administration. The DOPAC content rose significantly 6 h after sulpiride administration. The HVA content did not show a significant change. A slight increase of locomotor activity was found, but it was not statistically significant. The elevation of DA release in nucleus accumbens by sulpiride might relate to the clinical efficacy of low-dose administration of this drug for mood disorders.

[Effects of desipramine and clomipramine on alpha 2-adrenergic receptor function in nucleus accumbens: studies with intracerebral dialysis in freely moving rats].

The effect of alpha 2-adrenoceptor agonist, clonidine (CLN) (100 micrograms/kg, i.p.), on the noradrenalin metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG)-total in the rat nucleus accumbens after desipramine (DMI) (20 mg/kg, i.p.) and clomipramine (CMI) (20 mg/kg, i.p.) treatment was estimated in the freely moving rat by intracerebral dialysis. Locomotor activity was measured simultaneously by the Animex. Locomotor activity in the control decreased after CLN administration, in accordance with the decrease in MHPG. The difference of locomotor activity and MHPG between the single dose trial with DMI, CMI and the control did not reach statistical significance throughout the experiment. The results suggest that a single injection of DMI and CMI have not an inhibitory effect on presynaptic alpha 2-adrenergic receptor in the nucleus accumbens. Next, DMI (20 mg/kg, i.p.) and CMI (20 mg/kg, i.p.) were injected once daily for 14 days and experiments, the same method as used on the single dose trial. A difference in locomotor activity and MHPG between the chronic DMI treatment and the control reached statistical significance. A significant reduction of locomotor activity was found during the 60 min period of the experiment. In addition, a significant reduction of MHPG was found during the 30-90 min period. A difference in locomotor activity and MHPG between the chronic CMI treatment and the control reached statistical significance. A significant reduction of locomotor activity was found during the 60 min period of the experiment. In addition, a significant reduction of MHPG was found during the 30-120 min period. The results suggest that the chronic DMI treatment and the chronic CMI treatment may diminish the CLN-induced reduction of MHPG via the subsensitivity of presynaptic alpha 2-adrenergic receptor in the nucleus accumbens.