Endothelin-1 genetic polymorphism as predictive marker for bevacizumab in metastatic breast cancer.

Biomarkers for bevacizumab efficacy in metastatic breast cancer (MBC) are of urgent need. The genetic variability of genes involved in angiogenesis could explain the interpatient variability of drug effects. For this biomarker study DNA was extracted from tumor blocks or blood samples of patients with human epidermal growth factor receptor 2 (HER2)-negative MBC treated with bevacizumab in combination with chemotherapy (bevacizumab cohort, 163 patients) or chemotherapy only (control cohort, 105 patients). We assessed the correlation of 10 single-nucleotide polymorphisms (SNPs) in genes modulating angiogenesis (vascular endothelial growth factor-A (VEGF-A), VEGF receptor 1 (VEGFR-1), serine threonine kinase 39 (STK39)) or hypertension (endothelin-1 and uromodulin) with outcome and toxicity. In the bevacizumab cohort, the SNP rs5370-TT in endothelin-1 (EDN1) showed a significantly shorter median overall survival (OS, 6.3 vs 21.3 months; hazard ratio (HR) 2.89, 95% confidence interval (CI) 1.34-6.26; log-rank P=0.0069) and a trend toward worse median progression-free survival (3.5 vs 7.9 months; HR 2.05, 95% CI 0.96-4.39; log-rank P=0.065) compared with the alternate genotypes combined. Similarly, patients harboring the VEGF-936 (rs3025039) TT alleles showed a significantly shorter median OS than patients with VEGF-936 CC or CT (14.9 vs 21.3 months; HR 2.37, 95% CI 1.09-5.13; P=0.0286). In multivariate analysis including important clinical parameters like disease-free survival (DFS), adjuvant chemotherapy, ECOG (Eastern Cooperative Oncology Group) performance score, histologic subtype, grade, hormone receptor status, visceral metastases and treatment line, only the association of rs5370 (EDN1) with OS was still statistically significant (P=0.012). In the control cohort, no association of the EDN1 genotype with outcome was seen, suggesting a predictive value for bevacizumab. In conclusion, the SNP rs5370 in endothelin-1 could help identifying patients who unlikely gain any benefit from bevacizumab.

Overexpression of KCNJ3 gene splice variants affects vital parameters of the malignant breast cancer cell line MCF-7 in an opposing manner.

BACKGROUND: Overexpression the KCNJ3, a gene that encodes subunit 1 of G-protein activated inwardly rectifying K(+) channel (GIRK1) in the primary tumor has been found to be associated with reduced survival times and increased lymph node metastasis in breast cancer patients. METHODS: In order to survey possible tumorigenic properties of GIRK1 overexpression, a range of malignant mammary epithelial cells, based on the MCF-7 cell line that permanently overexpress different splice variants of the KCNJ3 gene (GIRK1a, GIRK1c, GIRK1d and as a control, eYFP) were produced. Subsequently, selected cardinal neoplasia associated cellular parameters were assessed and compared. RESULTS: Adhesion to fibronectin coated surface as well as cell proliferation remained unaffected. Other vital parameters intimately linked to malignancy, i.e. wound healing, chemoinvasion, cellular velocities / motilities and angiogenesis were massively affected by GIRK1 overexpression. Overexpression of different GIRK1 splice variants exerted differential actions. While GIRK1a and GIRK1c overexpression reinforced the affected parameters towards malignancy, overexpression of GIRK1d resulted in the opposite. Single channel recording using the patch clamp technique revealed functional GIRK channels in the plasma membrane of MCF-7 cells albeit at very low frequency. DISCUSSION: We conclude that GIRK1d acts as a dominant negative constituent of functional GIRK complexes present in the plasma membrane of MCF-7 cells, while overexpression of GIRK1a and GIRK1c augmented their activity. The core component responsible for the cancerogenic action of GIRK1 is apparently presented by a segment comprising aminoacids 235-402, that is present exclusively in GIRK1a and GIRK1c, but not GIRK1d (positions according to GIRK1a primary structure). CONCLUSIONS: The current study provides insight into the cellular and molecular consequences of KCNJ3 overexpression in breast cancer cells and the mechanism upon clinical outcome in patients suffering from breast cancer.

Soluble PD-L1 shows no association to relapse and overall survival in early stage non-small cell lung cancer (NSCLC).

BACKGROUND: Cancer immune evasion is critical in non-small cell lung cancer (NSCLC) and has been targeted by immunotherapy. High soluble (s)PD-L1 is associated with reduced survival and treatment failure in advanced stages. Here we evaluated the effects of sPD-L1 on T cells, relapse free survival, and overall survival in early stage NSCLC. METHODS: In vitro T cell stimulation was performed in the presence of sPD-L1 to evaluate its immunomodulatory activity. Data from The Cancer Genome Atlas (TCGA) were investigated for PD-L1 splice variants and enzymes involved in proteolytic cleavage (i.e. ADAM10). Plasma from 74 NSCLC (stage IA-IIIB), as well as an additional 73 (control cohort) patients was collected prior to curative surgery. Thereafter sPD-L1 levels from an immunosorbent assay were correlated with patient outcome. RESULTS: In vitro sPD-L1 inhibited IFN-γ production and proliferation of T cells and induced a terminal effector CD4 T cell subtype expressing CD27. Data from the TCGA demonstrated that elevated mRNA levels of ADAM10 is a negative predictor of outcome in NSCLC patients. To investigate the clinical relevance of these in vitro and TCGA findings, we quantified sPD-L1 in the plasma of early-stage NSCLC patients. In the first cohort we found significantly higher sPD-L1 levels in relapsing NSCLC patients, with a multivariate analysis revealing high sPD-L1 (>1000 pg/mL) as an independent predictor of survival. However, these findings could not be validated in two independent control cohorts. DISCUSSION: Although in vitro and TCGA data support the suppressive effect of sPD-L1 we were unable to translate this in our clinical setting. These results may be due to the small patient number and their heterogeneity as well as the lack of a standardized sPD-L1 ELISA. Our inconclusive results regarding the value of sPD-L1 in early stage NSCLC warrant assay validation and further investigation in larger (neo-)adjuvant trials.

Combined APRI/ALBI score to predict mortality after hepatic resection.

BACKGROUND: Aspartate aminotransferase/platelet ratio index (APRI) and albumin-bilirubin grade (ALBI) are validated prognostic indices implicated as predictors of postoperative liver dysfunction after hepatic resection. The aim of this study was to evaluate the relevance of the combined APRI/ALBI score for postoperative clinically meaningful outcomes. METHODS: Patients undergoing hepatectomy were included from the American College of Surgeons National Surgical Quality Improvement Program database. The association between APRI/ALBI score and postoperative grade C liver dysfunction, liver dysfunction-associated and overall 30-day mortality was assessed. RESULTS: A total of 12 055 patients undergoing hepatic resection from 2014 to 2017 with preoperative blood values and detailed 30-day postoperative outcomes were included (exploration cohort: January 2014 to December 2016; validation cohort: 2017). In the exploration cohort (8538 patients), the combination of both scores (APRI/ALBI) was significantly associated with postoperative grade C liver dysfunction, 30-day mortality, and liver dysfunction-associated 30-day mortality, and was superior to either score alone. The association with postoperative 30-day mortality was confirmed in multivariable analysis. A predictive model was generated using the exploration cohort. The predicted incidence of events closely followed the observed incidence in the validation cohort (3517 patients). Subgroup analyses of tumour types were used to generate disease-specific risk models to assess risk in different clinical scenarios. These findings informed development of a smartphone application (https://tellaprialbi.37binary.com). CONCLUSION: The predictive potential of the combined APRI/ALBI score for clinically relevant outcomes such as mortality was demonstrated. An evidence-based smartphone application will allow clinical translation and facilitation of risk assessment before hepatic resection using routine laboratory parameters.

Pulmonary meningioma. Immunohistochemical and ultrastructural features.

Two cases of solitary primary pulmonary tumors showing the immunohistochemical and ultrastructural features of meningothelial meningiomas are presented. The benign clinical and radiologic course, the negative computed tomography scan of the brain (case 1), and negative neuropathologic investigation (case 2) support the diagnosis of a primary pulmonary meningioma rather than a metastazing malignant intracranial meningioma. Negative neuroendocrine markers (neuron-specific enolase, chromogranin, bombesin) and the lack of neurosecretory granules by electron microscopy confirm the diagnosis of this rare pulmonary tumor.

Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients.

RATIONALE: Previous studies showed that adjunctive paroxetine increases tricyclic antidepressant (TCA) serum levels by inhibiting cytochrome P4502D6. This effect has, however, been examined only in experimental studies using low doses of TCAs in healthy volunteers. OBJECTIVE: The present study investigated TCA serum level changes and side-effects after the addition of paroxetine in depressed patients treated with doses customarily used for inpatients. METHODS: 14 patients who had a moderate or severe depressive episode according to ICD-10 and who had not sufficiently responded (< or = 25% reduction of the Hamilton depression scale) to 3-week monotherapy with amitriptyline (n = 9) or imipramine (n = 5) with daily doses between 125 and 200 mg/day, received 20 mg/day paroxetine additionally under steady state conditions. RESULTS: After 2 weeks the serum levels of the metabolites nortriptyline (from 88 +/- 49 ng/ml to 176 +/- 57 ng/ml) and desipramine (from 152 +/- 78 ng/ml to 338 +/- 104 ng/ml) had risen to a significantly greater extent than those of the parent compounds amitriptyline (123 +/- 50 ng/ml to 195 +/- 128 ng/ml) and imipramine (from 75 +/- 36 ng/ml to 98 +/- 51 ng/ml). It is noteworthy that, with the exception of one case of incipient delirium, the combination therapy was well tolerated despite high TCA serum level rises. CONCLUSION: The higher increase of the metabolites as compared with the parent compounds can be explained by a paroxetine-induced inhibition of the liver enzyme cytochrome P4502D6, which catalyses the second step of the TCA metabolism, i.e. the hydroxylation of the metabolites. Blood levels should be meticulously monitored, if TCAs are combined with paroxetine.

A comparison of two different dosages of pivampicillin and doxycycline in patients with gynaecological infections.

The efficacy of 500 mg pivampicillin twice daily, 350 mg pivampicillin 3-times daily and 100 mg doxycycline daily was compared in 106 patients with salpingitis, parametritis or endometritis. Both the pivampicillin regimens were equally effective. The average duration of therapy needed to produce a satisfactory clinical response was shorter with pivampicillin (14 days) than with doxycycline (21 days). Pivampicillin improved the patients' gynaecological status in 90% of the subjects treated compared to only 70% of patients given doxycycline. Fewer relapses were recorded in women given pivampicillin (4%) than in subjects treated with doxycycline (15%). Gonococci were isolated from 10% of vaginal swabs. The involvement of Chlamydia and Mycoplasma was not studied. However, the high cure rate indicated that, if present, they did not pose a therapeutic problem. Side-effects, mainly dyspepsia, were observed in 2 patients in each group. The twice-daily administration of pivampicillin is recommended, since it is more practical and increases patient compliance.

Catabolic effects and the influence on hormonal variables under treatment with Gynodian-Depot or dehydroepiandrosterone (DHEA) oenanthate.

53 patients from a mainly climacteric population were treated monthly with 200 mg dehydroepiandrosterone (DHEA) oenanthate or with 1 ampoule Gynodian-Depot. Pronounced adiposity was present in 15 of these cases. Hormonal variables were determined before the treatment and during the depot effect of the preparations in order to study the principle which supports the oestrogenic influence and any weight-reducing influence under administration of DHEA. The elimination of low-polar oestrogens increased considerably in 4 out of 13 post-menopausal cases treated with DHEA. This effect is probably indirect and presupposes intact ovaries. The incorporation of exogenous DHEA into the excretion of 17-ketosteroids and of 17-ketogenic steroids, such as those of androsterone + aethio-cholanolone, depends on the size of the initial pool inasmuch as it is higher in small initial pools than in saturated pools- the size of the pool being age-dependent. An average weight loss of greater than 1 kg/mth was observed under DHEA treatment in 7 out of 15 adipose cases. In comparison to the other 8 adipose cases, these 7 were younger and therefore also displayed higher values for 17-ketosteroids and their individual fractions. These circumstances appeared to explain why the administration of DHEA resulted in higher levels of free plasma DHEA which, in contrast to the cases without loss of weight, also resulted in an increase of renal DHEA-sulphate clearance. It was concluded from the findings that this is the explanation for the catabolic effect of exogenous DHEA. Post-menopausally increased FSH and LH fractions were markedly suppressed in about half of the determinations after Gynodian-Depot administration, the findings indicating that DHEA is probably involved in suppression of the LH fraction.

[Non-virilizing hormonal therapy in women with secondary disorders of sexual responsiveness]. / Nichtvirilisierende Hormontherapie bei sekundär gestörter weiblicher Sexualbereitschaft.

26 women with secondary disturbance of sexual responsiveness were treated mainly with dehydroepiandrosterone preparations. The sexual tonus was tested before and after treatment by a sexual score system previously described. Urinary 17-ketosteroid and plasma testosterone fractions were controlled in 17 patients; these values were, in general, below the normal range before treatment. Treatment was considered to be successful in 17 patients, while in the remaining 9, who mainly belonged to the group of younger patients, no success was achieved. However, the results point out that therapeutic success with hormones of low biological activity can be expected only after numerous months of treatment. The pattern obtained on determination of hormonal parameters usually corresponded to the results of treatment.

[Effects of antiandrogenic treatment with cyproterone acetate on the sexual tonus in virilized women]. / Einflüsse antiandrogener Behandlung mit Cyproteronazetat (CA) auf den Sexualtonus virilisierter Frauen.

Sexual responsiveness was assessed in 46 virilized women during cyproterone acetate treatment over a period of several years according to a sexual score previously described. In general, sexual tonus was depressed by intensive cyproterone acetate medication of several months' duration without concurrent oestrogen. By changing to sequential therapy according to Hammerstein, however, sexual tonus returned to initial levels in the group with normal pre-medication responsiveness. Furthermore, in another group with diminished sexual tonus before treatment, sexual responsiveness, in particular the capacity for orgasm, was stimulated to the level of the first group. The endocrinological basis for this observation is discussed with aid of results of the plasma testosterone/sex hormone binding globulin complex.

[Neurohumoral influences of steroid hormones on sexual responsiveness in women (author's transl)]. / Uber neuro-humorale Einflüsse von Steroidhormonen auf die Sexualsphäre der Frau

An analysis has been carried out on the basis of endocrinological and psychosomatic studies of the influence of steroid hormones, acting via probable transmitter substances, on the sexual response in women. From a review in the literature it can be concluded that among other factors the endocrine state of the women determines her sexual response and behaviour. However, the present lack of specific psychological tests is pointed out, as well as the absence of relevant hormonal data to the sexual sphere, both normal and pathological.

PIP: Based on current literature on the subject, an analysis is made of the endocrinological and psychosomatic aspects of the influence of steroid hormones, which probably act through the action of transmitter substances, upon the sexual responsiveness of women. Endocrinological studies center on the role of androgens, estrogens, and progesterones, and the possible transmitter substances. The physiological basis of abnormal changes in the sexual responsiveness, such as frigidity, is the prime concern of such studies. Among other factors, it is concluded that the state of the endocrinal system does determine a woman's sexual responsiveness and behavior. The present lack of psychological tests is noted as relevant, however, as well as the absence of hormonal data relevant to the sexual sphere, both for normal and pathological states.

[Clinical results and hormonal aspects of the treatment of virilizing symptoms in women with cyproterone acetate (author's transl)]. / Klinische Erfahrungen und hormonelle Aspekte bei der Behandlung von Virilisierungserscheinungen bei der Frau mit Cyproteronazetat.

28 cases of moderate to severe hirsutism, two cases of acne and one case of axilary hidrosadenitis were tested continuously on average over 6 months by the daily administration of 100 mg cyproterone acetate. This drug was then given together with 1-2 mg oestradiol valerate over a further 6 month period by reversed sequential therapy. The effect of treatment was judged as being moderate only in 7 cases of idiopathic and one case of adrenal hirsutism and good in the remaining cases. However, this regimen caused a marked lowering of the urinary dehydroepiandrosterone sulphate and low polar oestrogen levels and also the plasma testosterone level. At the same time, according to preliminary results, the fraction of sex hormone binding globulin was raised. The plasma hydrocortisone level was depressed by about 20%. The fractions of 17-KS and 17-KGS decreased slightly at first, but then returned to normal. The side effects of continuous treatment were mainly gestagenic and of reversed sequential therapy mainly oestrogenic in nature. The continuation rate was 81% during a treatment period of two years.

[Long-term treatment of virilized women with cyproterone acetate (author's transl)]. / Langzeitbehandlung virilisierter Frauen mit Cyproteronazetat (CA).

76 women with virilizing features (68 women suffering from hirsutism and 8 from acne) were treated on average for 25 months according to different models of Androcur medication. Success of treatment was clinically assessed as good in 3/4 of the cases and slight in the remaining 1/4. However, treatment is more successful in cases of adrenal hirsutism than in idiopathic hirsutism. Moreover, success of treatment seems to be better in women below 35 than over 35 years of age. Side effects, mostly bleeding anomalies and fatigue, were found in 31 women; these must be attributed to the gestagenic component of cyproterone acetate. By contrast, 12 women showed positive side effects such as weight reduction, improvement in depression states and reversal of hair loss, which must be attributed to the antiandrogenic component. The selected continuation rate in all subjects was 86% and the unselected 72%, over a treatment period of 4.5 years. Furthermore, hormonal controls were carried out under treatment. These showed, on average, a depression of plasma androstendione of 17%, of total plasma testosterone of 47%, as well as an inhibition of the testosterone/sex hormone-binding globulin quotient of 58%. These inhibition effects speak in favour of alterations taking place in steroid metabolism. However, by inhibition of androgenic serum levels, the mechanism of cyproterone acetate is only assisted, while the main mechanism is based on peripheral receptor inhibition. Furthermore, as additional component in this action a slight increase in plasma binding capacity was found during combined cyproterone-oestrogen treatment.

[Clinical screening of sterility cases for the possible presence of luteal phase defect (author's transl)]. / Klinischer Test auf mögliches Vorliegen einer Corpus-Luteum-Insuffizienz bei Sterilitätsfällen

Eighty consecutive cases of sterility was screened for suspected insufficiency of luteal function. The parameters used in the assessment were one value each for pregnandiol and oestrogen excretion, the basal temperature, the histological picture of secretory endometrium, as well as the activity of endometrial malate dehydrogenase and carbonanhydrase, or malate dehydrogenase and succinic dehydrogenase. Histological irregularities, a short luteal phase as indicated by the basal temperature, early abortion and a pregnandiol excretion of less than 1.9 mg were usually accompanied by low endometrial enzymatic acitvity. A comparison of pregnandiol excretion levels with the other four investigated parameters indicated that the number of negative findings increased with decreasing pregnandiol values. In this way, low oestrogen excretion values occurred more frequently with low pregnandiol values. However, when taken in conjunction with other findings, a low oestrogen value does not seem to be characteristic of luteal insufficiency. In certain cases the suspicion of luteal insufficiency increases with decreasing pregnandiol values and with the number of negative findings concerning basal temperature, endometrial histology and enzymatic activity, as well as oestrogen excretion. According to this point of view the incidence of a presumptive luteal phase defect was 33% in the present investigation.

[Pelvic pain syndrome in women--a psychiatric-gynaecological study (author's transl)]. / Uber den Beckenschmerz bei der Frau--Eine psychiatrisch-gynäkologische Studie.

77 selected patients suffering from dyspareunia and pelvic pain on moving, with normal findings on gynaecological palpation were submitted to laparoscopy or laparotomy, as well as to a psychiatric investigation. In 25% of the cases no pathological changes were seen--group I; in a further 40% signs of slight--group II--and in the remaining 35% of cases signs of serious pelvic congestion were present--group III. Serious pelvic congestion occurred most frequently between 26 and 35 years of age and seemed to be connected with more than one delivery. Furthermore, in the total material, 65% of patients showed psychologically inadequate personalities whereby nearly 90% of the women in group I, but only a little over 40% in group III, displayed psychological inadequacy, with the women in group II occupying an intermediate position. On the basis of this observation and other investigated personality variables, pelvic pain without pathological findings seems to be caused by neuromuscular spasm in psychologically vulnerable persons. Pelvic pain with different degrees of pelvic congestion cannot be entirely dissociated from the possibility of psychological overlay, which may, however, be of a secondary nature.

[The high autopsy rate in Vienna]. / Zur hohen Autopsierate in Wien.

In 1983 34% of all persons who died in the Republic of Austria were autopsied. We examined the frequency of postmortem examinations in the capital city, Vienna, between 1983 and 1987 in view of this high overall autopsy rate. The annual autopsy rate in all 9 pathology institutes and the department of legal medicine of the University of Vienna was on average 51 to 53%. There was a slight statistically verifiable decline in 1987. The reason for this high necropsy rate is that Austrian law permits the autopsies without the consent of next of kin if it appears indicated for medical, scientific or educational reasons; further more the fact, that the chairman of the department is at the same time the coroner for the hospital. A high autopsy rate is necessary to maintain a high standard of diagnostic accuracy even in modern medicine. The diagnoses were inaccurate or incomplete in 15% of all cases. The high autopsy rate is the basis for extremely accurate mortality and morbidity statistics and provides the basis for long range public health planning. Medical students develop an insight in disease patterns, which cannot be gained in any other way. The pathology departments of Vienna introduce a new city-wide computer-supported diagnostic file system, which will provide a baseline for comparative scientific studies.