Clinical pattern of primary systemic therapy and outcomes of estrogen receptor-positive, HER2-negative metastatic breast cancer: a review of a single institution.

PURPOSE: In the management of estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer (ER+HER2-MBC) patients, endocrine therapy (ET) is preferred to chemotherapy (CT) as a primary systemic therapy (PST) when tumor burden is not high. However, there are no definite criteria for choosing a PST, transitioning from ET to CT or using maintenance ET subsequent to CT. METHODS: We reviewed the medical records of 311 ER+HER2-MBC patients who underwent CT from September 2002 to December 2016 and assessed their outcomes. RESULTS: Of the 311 patients, 178 (57%) received ET as a PST (ET-first group), and 133 (43%) received CT prior to ET (CT-first group). The ET-first group showed a median overall survival (OS) from the diagnosis of MBC (OSMBC) of 1593 days, and the median OS from the initiation of CT (OSCT) was 938 days. Patients with visceral involvement, liver metastasis, soft tissue metastasis, ≥3 organ involvement, or primary advanced BC at the MBC diagnosis showed a significantly higher tendency to be assigned to the CT-first group (P < 0.01 for any visceral involvement, P < 0.05 for all others). Maintenance ET was available in 74 (55.6%) patients in the CT-first group, who showed a significantly better OSMBC and OSCT than patients without maintenance ET (median OSMBC 1423 and 867 days, respectively, P < 0.0001; median OSCT 1350 and 637 days, respectively, P < 0.0001). CONCLUSION: Our findings suggest the possibility for changing the treatment paradigm of patients with ER+HER2-MBC, so a randomized prospective study is warranted to determine the optimum sequence of systemic therapies.

In vivo and in vitro constant expression of GATA-4 in mouse postnatal Sertoli cells.

In the mammalian postnatal testis, the biochemical and structural features of Sertoli cells change, depending on developmental stage and spermatogenic cycle, to support efficient spermatogenesis. Consequently, basic transcription factors that determine fundamental properties should be strictly maintained in postnatal Sertoli cells. We have confirmed that GATA-4 expression is kept at a constant level in mouse Sertoli cells during postnatal development, and is also maintained at a constant level in primary cultures, independent of treatment with hormones or the addition of germ cell fractions. In transient transfection assays with the testicular cell line TM3, established from Leydig cells, GATA-4 induced several Sertoli cell-specific genes. In the Sertoli cell line TM4, and in Sertoli cells in primary culture, GATA-4 slightly up-regulated these genes. These results suggest that GATA-4 plays an important role in the regulation of Sertoli cell function, and is exactly regulated in these cells.

Two mouse piwi-related genes: miwi and mili.

Genes belonging to the piwi family are required for stem cell self-renewal in diverse organisms. We cloned mouse homologues of piwi by RT-PCR using degenerative primers. The deduced amino acid sequences of mouse homologues MIWI and MILI showed that each contains a well-conserved C-terminal PIWI domain and that each shares significant homology with PIWI and their human counterparts HIWI. Both miwi and mili were found in germ cells of adult testis by in situ hybridization, suggesting that these genes may function in spermatogenesis. Furthermore, mili was expressed in primordial germ cells (PGCs) of developing mouse embryos and may therefore play a role during germ cell formation. MIWI may be involved in RNA processing or translational regulation, since MIWI was found to possess RNA binding activity. Our data suggest that miwi and mili regulate spermatogenesis and primordial germ cell production.

Testosterone suppresses spermatogenesis in juvenile spermatogonial depletion (jsd ) mice.

Male juvenile spermatogonial depletion (jsd/jsd) mice are sterile because of a failure of spermatogonial differentiation. We have previously reported the recovery of spermatogonial differentiation by suppressing the levels of gonadotropins and testosterone with Nal-Glu, a GnRH antagonist. To determine whether suppression of testosterone or the gonadotropins was responsible for spermatogenic recovery, we examined the effect of supplementation of LH or FSH along with Nal-Glu treatment. Systemic administration of flutamide, an androgen receptor antagonist, was also examined. LH supplementation elevated both serum and intratesticular testosterone levels and suppressed the recovery of spermatogonial differentiation in a dose-dependent manner. Supplementation with FSH did not affect either testosterone levels or spermatogonial differentiation. Furthermore, the mice treated with flutamide showed some recovery of spermatogonial differentiation. The overall findings revealed that testosterone action mediated by androgen receptors suppressed the spermatogonial differentiation in jsd/jsd mice and suggested that spermatogonial differentiation in the jsd mutant is highly sensitive to testosterone suppression.

Defect in germ cells, not in supporting cells, is the cause of male infertility in the jsd mutant mouse: proliferation of spermatogonial stem cells without differentiation.

C57BL/6 (B6)-jsd/jsd male mice are sterile because of lack of spermatogenesis. To find the cause of the deficient spermatogenesis, we have examined whether the mutation phenotype is the result of a defect in germ cells or in supporting cells using germ cell transplantation. In the seminiferous tubules of B6-jsd/jsd mutant mice, donor germ cells derived from the wild type GFP transgenic mouse (B6-+/+GFP) were able to undergo complete spermatogenesis, indicating that the juvenile spermatogonial depletion (jsd/jsd) mouse possesses normal supporting cell functions. In contrast, undifferentiated spermatogonia derived from B6-jsd/jsd mice were unable to differentiate in the seminiferous tubules of W/W v mice, even if the mutant germ cells successfully settled in the tubules. These results demonstrate that the deficiency in spermatogenesis of B6-jsd/jsd mice can be ascribed to a defect in spermatogonia but not in their supporting cell environment. Furthermore, the defect in B6-jsd/jsd spermatogonia is not in their ability to proliferate, but in their differentiation and may result from their hypersensitivity to high concentrations of androgen in the testis.

Regulation of cigarette smoke-induced cytochrome P4501A1 gene expression in osteogenic disorder Shionogi rat liver and in lung by large ascorbic acid dose.

The effects of a large ascorbic acid dose on cytochrome P4501A1 gene expression induced by cigarette smoke exposure was studied in Osteogenic Disorder Shionogi rats, which lack ascorbic acid biosynthesis. The rats were divided into four groups and were administered either a minimal amount (4 mg/day, 4S and 4C) or a large amount (40 mg/day, 40S and 40C) of ascorbic acid. The 4S group and 40S group were daily exposed to cigarette smoke for 2 hours, while the 4C group and 40C group were not. At the end of the 25-day experiment, the rats were killed. The cytochrome P4501A1 mRNA level both in the liver and lung was measured by a competitive reverse transcription-polymerase chain reaction method. When a minimal amount of ascorbic acid was administered, the cytochrome P4501A1 mRNA increased in the liver of the cigarette smoke-exposed group (4S) compared with the control group (4C). On the other hand, when a large amount of ascorbic acid was administered, this increase was not observed in the cigarette smoke-induced group (40S) in liver. On the other hand, in lung, an increased mRNA level in 4S group was not decreased by large ascorbic acid administration (40S). This is the first direct mRNA-level evidence of the effects of a large ascorbic acid dose on the gene expression stimulated by cigarette smoke.

The reliability of a video-enhanced Hirschberg test under clinical conditions.

PURPOSE: To examine the reliability and usefulness of a video-based Hirschberg test under clinical conditions. METHODS: The authors estimated ocular deviation in 87 patients with strabismus through automated analysis of corneal reflex displacement using a video refractor. The reproducibility of measurement, the comparison with the prism and alternate cover test (PACT), and the distribution of the Hirschberg ratio were investigated. RESULTS: The 95% limits of agreement of the video-based Hirschberg test evaluated by repeated measurements were +/- 0.18 mm (equivalent to +/- 2.2 degrees or +/- 3.8 prism diopters [PD] of calculated strabismic deviation) for the horizontal deviation and +/- 0.28 mm (equivalent to +/- 3.4 degrees or +/- 5.9 PD) for the vertical deviation. The 95% limits of agreement between the Hirschberg measures and the PACT were within +/- 7.8 degrees or +/- 13.7 PD. The average (+/- SD) Hirschberg ratio was 12.3 +/- 1.2 degrees/mm or 21.8 +/- 2.1 PD/mm. CONCLUSIONS: The video-enhanced Hirschberg measurement shows good reproducibility and ease of application, even in the testing of infants. In quantitative analysis, however, systematic measurement error resulting from intersubject variance of the Hirschberg ratio should be taken into consideration.

Advancement of medial rectus muscle to the original insertion for consecutive exotropia.

Twenty-four patients who underwent surgery to correct consecutive exotropia that developed iatrogenically after surgical overcorrection were studied retrospectively. All patients underwent single or bilateral advancement of the medial rectus muscle to the original muscle insertion. The mean preoperative exodeviation was 26.7 prism diopters at distance and 35.2 delta at near. Postoperatively, in cases receiving advancement of a single medial rectus, the mean amount of correction was 23.2 delta at distance and 29.6 delta at near. In cases receiving bilateral medial rectus advancement, the mean amount of postoperative correction was 26.3 delta at distance and 39.8 delta at near. Adduction deficiency was normalized in five patients (71%), while convergence insufficiency was improved in only nine patients (45%) after surgery. Twelve (50%) patients had binocular single vision at distance on a normal or abnormal basis as determined by the Bagolini lens test.

Preoperative prism correction in patients with acquired esotropia.

We performed a prospective study of preoperative prism adaptation in 77 patients with acquired esotropia. Sixty-three of them increased their angle of squint when wearing Fresnel press-on prisms for 5-7 days. After the angle had stabilized to a point that did not exceed the press-on prisms by more than 10 prism D, they were randomly divided into two groups. Thirty-two patients underwent surgery based on the prism-adapted angle. The other 31 patients underwent surgery based on their initially measured angle. Fourteen patients who did not respond to prism correction underwent surgery based on the angle before prism correction. Success rates with deviations between 0 and 10 prism diopters measured 1 year after surgery were highest in those in whom surgery was based on the prism-determined angle and were lowest in the nonresponders, who had no fusion response to the prisms.

[Evaluation of preoperative prism adaptation in patients with acquired esotropia].

A prospective study was carried out of the evaluation preoperative prism adaptation in 77 patients with acquired esotropia. Sixty-three patients who showed a stable esodeviation with prisms of 10 prism diopter or less by alternate prism cover test and fusion response to the prisms were classified as prism responders and were randomly classified into two groups. Thirty-one patients of prism responders underwent surgery based on the prism adapted angle. Patients in the other 32 cases were assigned to undergo surgery for their initially measured angle. On the other hand, 14 patients who did not respond to prism adaptation underwent surgery for their preoperative measured angle of deviation. Success rates with deviations of 0 to 10 prism diopters measured 1 year after surgery by the alternative prism cover test at 5 m and with fusion on Bagolini's striated glasses test were highest (26 [84%] of 31 patients) in prism adaptation responders who underwent surgery for prism determined angle and lowest (3 [21%] of 14 patients) in the prism adaptation nonresponder who showed no fusion response to the prisms.

Distribution of efferent neurons projecting to the tectum and cerebellum in the rat prepositus hypoglossi nucleus.

Distributions of efferent neurons projecting to the superior colliculus (SC), the pretectum, and the cerebellar cortex were studied in the rat prepositus hypoglossi nucleus (PRH) by retrograde labeling with wheat germ agglutinin-horseradish peroxidase (WGA-HRP). After injection of the tracer into the unilateral SC, small- and medium-sized neurons were labeled throughout the entire rostrocaudal extent of the PRH, with the highest proportion in the middle part of the nucleus. After application of WGA-HRP to the unilateral pretectal region, including the nucleus of the optic tract, numerous labeled neurons appeared in the bilateral PRH. The highest distribution was found in the most rostral part of this nucleus. Furthermore, small neurons of the supragenual nucleus of the facial nerve also were labeled. Injection of WGA-HRP into lobules VI-VII of the cerebellar vermis resulted in the labeling of mainly medium-sized neurons in the bilateral PRH, primarily in the caudal third. WGA-HRP-labeled neurons were less frequently observed in the PRH after unilateral injection into the flocculus and paraflocculus. Retrograde double labeling by fluorescent dyes showed that a few neurons in the middle part of the PRH sent divergent axons to vermal lobules VI-VII and the SC.

Synoptometer analysis of vertical shoot in Duane's retraction syndrome.

Vertical deviation of the affected eye caused by horizontal change of gaze was measured with a synoptometer in 5 cases of Duane's retraction syndrome type III. Step-by-step measurement clearly showed two types of incomitance patterns, i.e. upshoot and up- and downshoot in adduction. The former suggests a paradoxical synergistic innervation between the medial rectus and superior rectus muscles, and the latter suggests an abnormal vertical movement of the lateral rectus muscle over the globe on elevation or depression of the eye. Recession of the lateral rectus muscle, however, reduced the vertical deviation regardless of the incomitance pattern.

[Pointing response in normal subjects].

Eye-hand open-loop pointing responses were examined in five normal subjects, with visual cues for relative target localization. Pointing errors differed significantly with the position of the target. In some cases, pointing responses in the dark were significantly different from those in the light. Pointing shifts were also significant between the responses immediately after putting the experimental device on and those 15 minutes after. From these results, it was speculated that visual localization and eye-hand coordination may be influenced by the visual context and the passage of time.

[Advancement of the anterior portion of the superior oblique tendon in case of traumatic bilateral trochlear palsy].

The effect of the advancement of the anterior portion of the superior oblique tendon on cyclovertical and horizontal deviation was studied in seven cases of traumatic bilateral trochlear palsy by using a synoptometer (Cüppers) and cyclodevinometer (Kolling). The anterior portion of the superior oblique tendon was disinserted and advanced laterally according to the amount of the cyclodeviation in primary position with 1 degree/mm. Surgery was done in 5 cases on both eyes, in 2 cases on one eye. The age of the patients ranged from 20 to 64 years (mean 45 years). The excyclodeviation was significantly reduced (p less than .01), however overcorrection was found in the upward gaze. The mean reduction of excyclodeviation in diagnostic positions of gaze was approximately 10-12 degrees. The vertical deviation was significantly reduced in up and downward gaze (p less than .05), nevertheless overcorrection was found in the upward gaze. The mean reduction of the vertical deviation differed according to their positions of gaze. V-pattern esotropia could not be reduced significantly. Therefore an alternative operative approach must be found which can avoid overcorrection in the upward gaze and moreover correct V-pattern esotropia in the downward gaze.

[Pointing response before and after strabismus surgery].

Eye-hand open-loop pointing responses were measured in eight patients before and after unilateral strabismus surgery. They showed large shifts in pointing responses with the operated eye and relatively small ones with the non-operated eye. The same pointing responses were examined in five normal subjects. Statistically significant shifts were found even in cases of normal subjects. From these results, it was speculated that visual localization and eye-hand coordination may change by some unknown factors or under casual conditions.

[Measurement of incomitance patterns of vertical deviation in superior oblique palsy with a synoptometer].

By using a synoptometer we tried to compare the incomitance pattern of the vertical deviation in congenital superior oblique palsy with that of the vertical deviation in acquired superior oblique palsy. The data were transformed to a three-dimensional format by a computer to classify the incomitance pattern. With this method we found a difference in the incomitance pattern between congenital and acquired superior oblique palsy. In cases of congenital superior oblique palsy the vertical deviation increased proportionately with the change of gaze from abduction to adduction, since the incomitance caused by the horizontal change of gaze was more marked than that of the vertical change of gaze. However in cases of acquired superior oblique palsy the vertical deviation increased proportionately with change of gaze from up- to downward positions, therefore the incomitance caused by vertical change of gaze was more marked than that of the horizontal change of gaze. Moreover congenital superior oblique palsy was classified into three types according to the classification of Wieser and their incomitance patterns of vertical deviation were compared with each other.

[Surgical effect on incomitance of vertical deviation in superior oblique palsy measured by a synoptometer].

Using a synoptometer we evaluated the surgical effect on the incomitance of the vertical deviation in 26 patients with congenital superior oblique palsy. Either an inferior oblique recession or a superior oblique plication was performed. The two operative procedures reduced the incomitance caused by horizontal change of gaze, but produced incomitance by the vertical change of gaze and the incomitance increased proportionately with change of gaze from down to upward positions, which was not recognized preoperatively. As a result, the hyperdeviation was markedly reduced in the field of action of the overacting inferior oblique muscle. Moreover the surgical effect on the incomitance of the vertical deviation was studied in 13 patients with acquired superior oblique palsy treated with superior oblique plication. This procedure increased not only the incomitance in the upward positions by horizontal change of gaze, but also produced incomitance in adductive positions by vertical change of gaze. Therefore the hyperdeviation of the paretic eye was remarkably overcorrected in the field of action of the antagonist of the paretic superior oblique muscle.

Anomalous posterior insertion of medial rectus muscle simulating congenital oculomotor palsy.

An unusual case was examined in our Hospital showing severe exotropia with adduction palsy. However, during surgery, anomalous posterior insertion of the medial rectus muscle was found, and the Hummelsheim operation was performed to correct the exotropia. To the best of the authors' knowledge, this is the first report of anomalous posterior insertion of the medial rectus muscle as a cause for congenital exotropia with adduction palsy.

[Surgical treatment of torticollis in cases of congenital nystagmus with strabismus].

To correct compensatory head turn in twelve cases with congenital nystagmus, they were classified into two types according to the relative visual lines of both eyes to each other with respect to the sagittal axis of the head or the median plane of the body. One was termed the symmetrical pattern and the other was termed the asymmetrical pattern. In cases of the symmetrical pattern, a neutral zone exists in which the dominant eye in in the adducted position of gaze with esotropia and in the abducted position of gaze with exotropia. However, in the case of the asymmetrical pattern the neutral zone of the dominant eye is located in the abducted position of gaze with esotropia and in the abducted position of gaze with exotropia. Surgery was performed by shifting the dominant eye to the direction of the sagittal axis of the head in accordance with the degree of ocular deviation in the primary position. In asymmetrical pattern cares, both eyes were surgically shifted in parallel to the direction of the sagittal axis of the head without regard to the types of strabismus. The operation was based on the degree of compensatory head turn. We compared the surgical results the two types. In symmetrical cases, decreasing strabismus was disappointing compared to the head turn, while in asymmetrical cases decreasing head turn was disappointing as compared to strabismus. From these results surgery should be confined to the dominant eye in symmetrical cases, taking as the basis for operation the degree of head turn and not the ocular deviation.(ABSTRACT TRUNCATED AT 250 WORDS)