Search

BACKGROUND Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).

Background Genomic aberrations affecting the repair of DNA double-strand breaks by homologous recombination (HR) are found in various cancers and result in sensitivity to inhibitors of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP). DNA double-strand breaks and activation of PARP can be induced by trabectedin, a cytotoxic agent used in soft-tissue sarcoma. In HR-deficient cancers that depend on PARP activity, trabectedin may thus increase the effect of PARP inhibitors such as olaparib. Next-generation sequencing techniques allow rapid identification of mutations in DNA repair pathways and mutational signatures that are generated by these aberrations. Trial design We present a randomized phase II trial comparing a combination of trabectedin and olaparib with treatment of physician’s choice in adult patients with advanced or metastatic tumors with genomic imprints of defective HR DNA repair (“BRCAness”), as determined by whole-exome or genome sequencing. A dedicated BRCAness score incorporates germline and somatic mutations in HR-relevant genes, mutational signatures, and measures of genomic instability; scores equal or above 3 allow for inclusion. Main exclusion criteria are hematologic and primary brain cancers, progressive/symptomatic brain metastases, ECOG PS > 1, severe organ insufficiencies, and prior treatment with a PARP inhibitor. Patients are randomized 1:1 to treatment with trabectedin (day 1) and olaparib (days 1-21) in a 21-day cycle vs. physician’s choice, both until disease progression. Cross-over upon disease progression is allowed. The primary endpoint is disease control (including CR, PR and SD according to RECIST v1.1) after 16 weeks. Secondary endpoints are tumor response, PFS, OS and quality of life. Efficacy evaluation involves a 2-group comparison between treatment arms in 102 patients. The statistical test used is a one-sided test of differences in disease control rates (alpha = 0.025). An interim analysis for futility will be conducted after 30% of patients are evaluable for the primary endpoint. The trial is active within the German Cancer Consortium, and thus far nine patients have been randomized. Clinical trial identification EudraCT: 2017-001755-31; NCT03127215. Legal entity responsible for the study Heidelberg University Hospital, Heidelberg, Germany. Funding AstraZeneca, ParmaMar and German Cancer Research Center (DKFZ). Disclosure C.E. Heilig: Honoraria (self), Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Teva; Honoraria (institution), Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Novartis. H. Kopp: Advisory / Consultancy: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck-MSD; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Boehringer-Ingelheim. K.H. Metzeler: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy: Novartis; Advisory / Consultancy: Jazz; Research grant / Funding (institution): Agios. S. Richter: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self), Travel / Accommodation / Expenses: Lilly. B. Hermes: Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Lilly. N. von Bubnoff: Honoraria (self): AstraZeneca; Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self): BMS. T. Kindler: Advisory / Consultancy: Novartis; Travel / Accommodation / Expenses: PharmaMar. J. Siveke: Advisory / Consultancy: Baxalta; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Travel / Accommodation / Expenses: Shire; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Research grant / Funding (self), Travel / Accommodation / Expenses: BMS. S. Wagner: Advisory / Consultancy: Takeda. S. Ochsenreither: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: BMS; Advisory / Consultancy: AstraZeneca. B. Brors: Research grant / Funding (institution): SAP. D. Jager: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: CureVac; Advisory / Consultancy: Definiens; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS. C. Von Kalle: Advisory / Consultancy: Roche; Advisory / Consultancy: Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Shareholder / Stockholder / Stock options: Genewerk. H. Glimm: Honoraria (self), Research grant / Funding (self): Bayer. S. Frohling: Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Travel / Accommodation / Expenses: PharmaMar; Honoraria (self), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Bayer. R.F. Schlenk: Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (institution): Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Daiichi Synkyo. All other authors have declared no conflicts of interest.

Background There is a need for novel therapies in metastatic STS, rendering checkpoint inhibitors (CPI) of interest in STS. Immune cell infiltrates are thought as a prerequisite for CPI efficacy and its role remains vague in STS. We analyzed whether the immune profile differed for STS treated within the phase II EPAZ study (NCT01861951). Methods RNA samples were measured using the PanCancer Immune Profiling Panel from the nCounter® Analysis System. FCF1, HDAC3, ZKSCAN5, MRPS5 and EIF2B4 were used as housekeeping genes. Samples were categorized in three groups based on their overall mRNA expression via unsupervised random forest analysis. Differences in gene expression were tested by T-tests or ANOVA, with correction for multiple testing. Ingenuity Pathway Analysis (IPA) were performed for activity prediction. K-M plots were used for survival estimates and log-rank analyses for comparisons. Results Specimens were available in 70/120 patients and 31 were assessable by immune profiling. 12 pts. received doxorubicin (DOX) and 18 pazopanib (PAZ). Median progression free survival (PFS) and median overall survival (OS) for the total cohort were 2.6 mo. and 11.6 mo., respectively. Patients were clustered in high (n = 4)/mixed (n = 20)/low (n = 7) mRNA profile expressions. While OS varied numerically between clusters (11.1/9.0/28.9 mo.), values were not significant (P = 0.5573). A similar pattern was detected for PFS (4.2/1.5/8.9 mo.; P = 0.4127). Conclusions Our study indicates that STS express a differential mRNA immune profile. However, clusters were not associated with outcome measures. A major limitation is the small sample size. Clinical trial identification NCT01861951. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure V. Grunwald: Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self): PharmaMar. M. Schuler: Research grant / Funding (institution): Novartis. P. Schoeffski: Honoraria (institution), Advisory / Consultancy: Daiichi; Honoraria (institution), Advisory / Consultancy: Eisai; Honoraria (institution), Advisory / Consultancy: Lilly; Honoraria (institution), Advisory / Consultancy: Medpace; Honoraria (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (institution): Biovitrium; Honoraria (institution): 6th element capital; Advisory / Consultancy, Travel / Accommodation / Expenses: Adaptimmune; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Blueprint; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: BoBoehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: Cristal Therapeutics; Advisory / Consultancy, Travel / Accommodation / Expenses: Epizyme; Advisory / Consultancy, Travel / Accommodation / Expenses: Genzyme; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Loxo Oncology; Advisory / Consultancy, Travel / Accommodation / Expenses: Nektar; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis. H. Kopp: Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Speaker Bureau / Expert testimony: LeoPharma; Speaker Bureau / Expert testimony: Pfizer; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Amgen. B. Kasper: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Eisai ; Honoraria (self), Research grant / Funding (institution): PharmaMar. L. Lindner: Advisory / Consultancy: Novartis; Honoraria (self): Lilly; Honoraria (self): Eisai; Honoraria (self): EZ Medconsultant; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): Sennewald. J.M. Chemnitz: Honoraria (self): Ablynx; Advisory / Consultancy: Amgen; Advisory / Consultancy: Ablynx; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: PharmaMar. G. Egerer: Honoraria (self): MSD; Advisory / Consultancy: MSD; Honoraria (self): PharmaMar; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Astellas. All other authors have declared no conflicts of interest.

Background. Paratesticular liposarcomas are almost always mistakenly diagnosed as inguinal hernias subsequently followed by inadequate operation.Methods. 14 consecutive patients with paratesticular liposarcoma were retrospectively reviewed. Preoperative management was evaluated. Disease-free and overall survival were determined.Results. In 11 patients primary and in 3 patients recurrent liposarcoma of the spermatic cord were diagnosed. Regarding primary treatment in primary surgical intervention resection was radical (R0) in 7 of 14 (50%) patients, marginal (R1) in 6 (43%) patients, and incomplete with macroscopic residual tumour (R2) in 1 (7%) patient. Primary treatment secondary surgical intervention was performed in 4 patients: resection was radical (R0) in 3 (75%) patients and marginal (R1) in 1 (25%) patient. Regarding secondary treatment in recurrent disease resection was marginal (R1) in 3 patients (100%). Final histologic margins were negative in 10 patients with primary disease (71%) and positive in 4 patients with subsequent recurrent disease. After radical resection disease-free survival rates at 3 years were 100%. Overall survival at 4.5 years (54 (18–180) months) was 64%.Conclusion. An incomplete first surgical step increases the number of positive margins leading to local recurrences and adverse prognoses. Aggressive surgery should be attempted to attain 3-dimensional negative margins.

MEDICAL HISTORY AND CLINICAL COURSE: A 42-year-old patient with hairy cell leukemia had been treated for 3 years by a hematologist in private practice. Initially the patient received 1 course of cladribine upon which the disease went into complete remission. 6 weeks ago a relapse was diagnosed and combination therapy with cladibrin and rituximab was initiated. Now the patient presented to the emergency room with shortness of breath and pain when breathing.In the chest x-ray, patchy infiltrates and pleural effusions were found on both sides. The subsequently performed computed tomography showed bilateral compactions with an Halo suspicious for fungal infiltrates. Upon admission to the hospital, an empirical antibiotic therapy with clarithromycin and piperacillin/tazobactam was initiated, which was later escalated to meropenem and linezolid. Additionally, an antifungal therapy with voriconazole was started and later switched to liposomal amphotericin B. At his admission, a positive aspergillus antigen could be detected in the microbiological laboratory. Under antimycotic treatment the aspergillus antigen was repeatedly negative. The patient presented with pronounced cytopenias and after a switch of therapy to vemurafenib and filgrastim, the hematopoiesis could only be stimulated insufficiently. The patient was transferred to the intensive care unit three days after admission with severe respiratory failure. He died on day 8 after admission. AUTOPSY AND DIAGNOSIS: Diagnosis was consistent with relapse of hairy cell leukemia with positive BRAF mutation and a bone marrow infiltration 80 %. Autopsy revealed a significant hepato-splenomegaly, a lack of erythro-, granulo- and thrombopoiesis. Clots interspersed with fungal hyphae were found in both lungs and an infarction of the spleen with evidence of fungal hyphae was detected. The cultural findings post mortem on yeast or mold were negative.Patients with refractory hairy cell leukemia and prolonged neutropenia are at increased risk for systemic fungal infections. Therefore, prohylactic antimycotic therapy should be considered early in this group of patients. The therapeutic approach of vemurafenib in treatment-refractory hairy cell leukemia is promising and offers an additional treatment option. In the present case, the patient could unfortunately not be stabilized due to the septic complications.

The size of the primary tumour is considered the most important risk factor for the development of metastasis or local recurrence in case of gastrointestinal stromal tumour (GIST). Until now no prospective data are available in the literature about the role of neadjuvant therapy with Imatinib. Between 2009 and 2012 seven patients with a giant GIST 20 cm underwent a neadjuvant treatment with Imatinib, a radical operation, followed by an adjuvant therapy. These patients were controlled with regard to peri- and postoperative morbidity and disease-free survival. Two patients were considered not resectable and one patient showed liver metastasis at the time of diagnosis. RECIST responses to the neoadjuvant Imatinib were: 2/7 patients with stable disease, 3/7 partial response, 2/7 partial response with down-staging (resectable disease). Because of the following tumour localisations (6 gastric and 1 rectal), six gastrectomies (one en-bloc with left pancreas) and one Holm operation were performed. The patient with simultaneous liver metastasis developed a tumour progression during the follow-up but the others are still tumour free after 2 years. We detected a significant tumour volume regression due to the neadjuvant chemotherapy in cases of GIST 20 cm (30 %). Our series showed good results for a neadjuvant therapy in cases of giant GIST with the achievement of 100 % R0 resection without a high morbidity rate (in the literature a tumor size 10 cm and poor localisation is associated to a high risk of R1 - 2 and high morbidity). Peri- and postoperative morbidity are acceptable and the tumour free survival at 2 years is 85 %.

Clear-cell sarcomas account for less than 1% of all soft tissue tumours. They most often occur in middle-aged adults as a deeply located lesion with predilection to the tendons and aponeuroses. The aim of the present study was to show possible influencing factors on the outcome after surgical treatment in a detailed case series. We reviewed the medical records of 11 patients with the diagnosis of a clear-cell sarcoma of the soft tissue. These cases were analysed with regard to age, gender, localisation, tumour size, recurrence free survival and overall survival. A minimum follow up of 12 months was achieved. The mean age at the point of diagnosis was 47.9 years. Metastases occurred after a mean of 19.2 months. In the cases with a tumour diameter5 cm, metastases occurred earlier. When treated in a specialist centre, metastases occurred later. Patients died a mean of 18.4 months after developing metastatic disease. Patients with tumour size5 cm at the point of primary diagnosis died earlier than patients with a tumour size5 cm. It is important to detect clear-cell sarcomas as soon as possible and the final surgical treatment should be performed in a centre familiar with the treatment of soft tissue tumours not only to prolong overall survival, but also to treat the patient in a multiprofessional team.

The enzyme beta-galactosidase, encoded by the bacterial gene lac-Z, is commonly used as a histochemical reporter to track transplanted cells in vivo or to analyze temporospatial gene expression patterns by coupling expression of specific target genes to beta-galactosidase activity. Previously, endogenous beta-galactosidase activity has been recognized as a confounding factor in the study of different soft tissues, but there is no description of the typical background on bone marrow sections when using the chromogenic substrate 5-Bromo-4-chloro-3-indolyl beta-D-Galactoside (X-Gal). In this report, we show that osteoclasts in bone marrow sections specifically and robustly stain blue with X-Gal. This leads to a typical background when bone marrow is examined that is present from the first day post partum throughout the adult life of experimental mice and can be confused with transgenic, bacterial beta-galactosidase expressing hematopoietic or stromal cells. Experimental variations in the X-Gal staining procedure, such as pH and time of exposure to substrate, were not sufficient to avoid this background. Therefore, these data demonstrate the need for strenuous controls when evaluating beta-galactosidase positive bone marrow cells. Verifiable bacterial beta-galactosidase positive bone marrow cells should be further identified using immunohistological or other approaches. Specifically, beta-galactosidase positive hematopoietic or stromal cells should be proven specifically not to be osteoclasts by co-staining or staining adjacent sections for specific markers of hematopoietic and stromal cells.

Megakaryocytes and platelets have been known to secrete angiogenic growth factors for a long time. However, there is little in vivo data on the regulation of angiogenesis by thrombopoietic cells. Both megakaryocytes and platelets are known to carry and release a multitude of both pro- and antiangiogenic mediators. Thus, it remained unknown how the “angiogenic phenotype” of thrombopoietic cells would be determined. Our group established that platelets contribute to angiogenesis as carriers of SDF-1, which is released by platelets in response to stimulation with hematopoietic cytokines. Indeed, even the action of VEGF-A seems to be mediated in part by the release of SDF-1 from stimulated platelets, thereby attracting proangiogenic hematopoietic cells. Moreover, the analysis of murine plasma and serum showed that similar to VEGF-A, SDF-1 is almost exclusively derived from platelets, and only trace amounts are detectable in platelet poor plasma. Because tumor patients' platelets have been shown to contain lower amounts of thrombospondin (Tsp), we generated Tsp-1 and Tsp-2 double knockout mice by crossing the single knockout lines. Interestingly, megakaryocytes and platelets derived from these mice confer a proangiogenic phenotype both in the bone marrow and in reperfusion of ischemic hindlimbs, thereby verifying the hypothesis of pro- and antiangiogenic platelet constituents “in balance.”

Medico-legal assessment for long-term disability benefits in patients with mainly somatoform pain disorders is in increasing demand. Since impairment does not explain the loss of function in somatoform disorders, the expert must determine to what extent the patient is able to cope more actively with pain in order to attain a higher level of functioning. Consistency of behavioral signs, flexibility and initiative in the way of coping are helpful criteria in this respect. Special attention is given to problems in the assessment of migrants with these disorders. We strongly support the concept of an interdisciplinary approach in medico-legal assessment. Postgraduate medical training in this field should receive greater attention accordingly.

The so-called psychosomatic or functional conditions (notably somatoform pain disorders) often cause difficulties in diagnostic classification, clinical management and assessment of disability. Recent trends in diagnosis are reviewed. We describe our first clinical experience of interdisciplinary evaluation of pain patients by functional capacity evaluation and an ergonomically oriented rehabilitation program. This interdisciplinary approach could constitute a new field of close collaboration between physiatry/physical medicine, physiotherapy and psychiatry.

1. The effects of isosorbiddinitrate (ISDN) were tested on membrane currents and resting potential in Xenopus laevis oocytes which were either uninjected or injected with cRNA encoding for K+ channels from three distinct families (slowly activating I-sK channels, delayed- rectifying Kv1.1 or inwardly rectifying IRK1 K+ channels). 2. In uninjected oocytes ISDN (1 mM) resulted in a decrease of the holding current at potentials more positive than -100 mV and in an increase at potentials below -100 mV. Increasing extracellular K+ to 100 mM shifted the reversal potential for ISDN-mediated effects to approximately -12 mV, suggesting an inhibition of a K+ conductance by ISDN. 3. In current clamp studies ISDN (1 mM) and Ba2+ (3 mM) depolarized cell membrane. ISDN and Ba2+ had no additive effects on membrane potential when applied simultaneously. In voltage clamp studies, corresponding results were observed for the effects of ISDN and Ba2+ on the holding current with an apparent K-m of 0.21 and 0.08 mM, respectively. 4. In contrast to ISDN, the nitric oxide (NO) donors isosorbidmononitrate (ISMN) and S- nitrosocysteine (SNOC) had no effects on the holding currents in Xenopus oocytes. Moreover, the guanylate inhibitor LY 83583 did not affect ISDN-mediated holding current alterations, suggesting that ISDN acts independently of the second messenger NO. 5. ISDN inhibited exogenously expressed I-sK channels with an apparent K-m of 0.15 mM, but at 1 mM only weakly inhibited Kv1.1 and IRK1 channels. 6. It is concluded that ISDN inhibits an endogenous K+ conductance in Xenopus oocytes with a similar potency to that shown by expressed I-sK channels. These effects are independent of the second messenger NO.

Corrigendum: Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4 + hemangiocytes

Permanent changes in the endocrine status of female SJL/J and CR mice were induced by masculinization, ablation of endocrine glands, inoculation of hormones, or feeding of the chemical carcinogen DMBA. All these procedures resulted in modification of the host hormonal milieu, as shown by blood hormone determination. Masculinization reduced drastically the onset of lymphosarcoma and increased the incidence of systemic neoplasms respectively in DMBA-treated female SJL/J and CR mice. Continued administration of gonadotrophins increased the incidence of systemic neoplasia in CR mice. A direct correlation is suggested between onset of lymphosarcoma or other tumours in mice and a specific shift to an abnormal hormonal environment.

Die Regulation der Aldosteronsekretion wurde schon wiederholt bei Patienten mit termi-nalem Nierenversagen untersucht (Weidmann et al., 1973; Vetter et al., 1977). Dabei zeigte sich, das bei diesen Patienten die renale Reninsekretion der Hauptfaktor in der Steuerung der adrenalen Aldosteronausschuttung ist.

Osteoporosis is occasionally seen in young women with episodes of anorexia nervosa. To study anorectic osteopenia we have examined 10 patients aged 18 to 37 years before, during and after treatment. Treatment consisted of hospitalization for correction of underweight by tube feeding and subsequent psychotherapy. Bone-density measurements performed with high-precision, low-dose, quantitative computed tomography of the distal radius and the distal tibia before treatment showed an age-dependent pattern. Linear regression suggests a trabecular bone loss of approximately 3% per year. This loss might be caused by low estrogens, because all patients were amenorrheic. After tube-feeding periods of 27 to 89 days (5 patients), trabecular bone density of the tibia was further reduced by 10.3% (range 6-13%) below pretreatment values. One year later average trabecular bone diminution was 17.3% (range 8-28%). Such rapid bone loss may cause osteoporosis within a few years, and treatment is therefore required for prevention of this skeletal deterioration.

The immunological blockade of the adenohypophysis of athymic nude mice bearing allogeneic skin grafts prevents the reconstitution of transplantation immunity when such animals grafted with thymus, and the grafts are permanently accepted. Newborn and adult athymic mice have markedly diminished levels of prolactin in blood and abnormally high levels of luteotropic hormone. Implantation of the thymus normalizes blood levels of these two hormones. These findings affirm the role of the thymus in the organization of the maturing brain for endocrine functions and identify prolactin as one of the hormones which play a major role in immune differentiation in early ontogeny.

Diagnostic and therapeutic uses of synthetic luteinizing hormone-releasing hormone are evaluated. Most important are functional tests of the hypothalamo-hypophyseal axis in menstrual disorders and female sterility; results may also help indicate the therapeutic approach. Rigorous standardization of the test and the assessment of normal and pathological patterns is essential. The therapeutic use of t his hormone is still limited chiefly to the timing of ovulation in women selected for artificial insemination and as an additional treatment in clomiphene failures. Other indications are highly speculative.