Teriparatide and pelvic fracture healing: a phase 2 randomized controlled trial.

Pelvic fracture patients were randomized to blinded daily subcutaneous teriparatide (TPTD) or placebo to assess healing and functional outcomes over 3 months. With TPTD, there was no evidence of improved healing by CT or pain reduction; however, physical performance improved with TPTD but not placebo (group difference p < 0.03). INTRODUCTION: To determine if teriparatide (20 µg/day; TPTD) results in improved radiologic healing, reduced pain, and improved functional outcome vs placebo over 3 months in pelvic fracture patients. METHODS: This randomized, placebo-controlled study enrolled 35 patients (women and men >50 years old) within 4 weeks of pelvic fracture and evaluated the effect of blinded TPTD vs placebo over 3 months on fracture healing. Fracture healing from CT images at 0 and 3 months was assessed as cortical bridging using a 5-point scale. The numeric rating scale (NRS) for pain was administered monthly. Physical performance was assessed monthly by Continuous Summary Physical Performance Score (based on 4 m walk speed, timed repeated chair stands, and balance) and the Timed Up and Go (TUG) test. RESULTS: The mean age was 82, and >80% were female. The intention to treat analysis showed no group difference in cortical bridging score, and 50% of fractures in TPTD-treated and 53% of fractures in placebo-treated patients were healed at 3 months, unchanged after adjustment for age, sacral fracture, and fracture displacement. Median pain score dropped significantly in both groups with no group differences. Both CSPPS and TUG improved in the teriparatide group, whereas there was no improvement in the placebo group (group difference p < 0.03 for CSPPS at 2 and 3 months). CONCLUSION: In this small randomized, blinded study, there was no improvement in radiographic healing (CT at 3 months) or pain with TPTD vs placebo; however, there was improved physical performance in TPTD-treated subjects that was not evident in the placebo group.

Efficacy of PD-1 blockade in cervical cancer is related to a CD8+FoxP3+CD25+ T-cell subset with operational effector functions despite high immune checkpoint levels.

BACKGROUND: Cervical cancer (CxCa) is mainly a locally invading disease that metastasizes to loco-regional lymph node basins before involving distant organs in more advanced stages. Local immune potentiation of tumor-draining lymph nodes (TDLN) may thus protect against tumor progression. METHODS: To identify therapeutic targets for local immune modulation, multi-parameter flow cytometric T-cell profiling of primary cervical tumors (PT) and TDLN (n = 37) was performed. The in-vitro effect of PD-1 blockade on T-cell reactivity to HPV16 E6 oncoproteins was determined in cultures of TDLN and PT single cell suspensions (n = 19). Also, intracellular cytokine staining (ICS) upon anti-CD3 stimulation was performed in metastatic TDLN (LN+) and PT (n = 7), as well as multiplexed immunofluorescence histochemistry staining (n = 8). RESULTS: Our data revealed elevated rates of activated regulatory T cells (aTregs) and of central or effector memory CD8+ T cells in metastatic TDLN (LN+) as compared to tumor-free TDLN (LN-), and equally high or even higher rates of these subsets in PT. Both memory subsets co-expressed multiple immune checkpoints. PD-1 blockade significantly enhanced detectable E6-specific T-cell responses in 4/5 HPV16+ LN+ and in 1/5 HPV16+ PT. Whereas aTreg rates were higher in anti-PD-1 non-responders, in responders elevated levels of CD8+FoxP3+CD25+ T cells were observed, which correlated with the efficacy of PD-1 blockade (P = 0.018). This subset was characterized by an early effector memory phenotype with particularly high levels of co-expressed PD-1, CTLA-4, TIM-3 and LAG-3 checkpoints, but, rather than exhausted, was shown upon polyclonal activation to produce higher levels of Granzyme-B and effector cytokines as compared to its CD8+FoxP3- counterparts. CONCLUSION: These observations support local PD-(L)1 blockade to interrupt loco-regional immune suppression in CxCa and control metastatic spread to TDLN. Furthermore, our data identify CD8+FoxP3+CD25+ T cells as therapeutic targets, which may also serve as predictive biomarker for PD-(L)1 checkpoint blockade.

'DURVIT': a phase-I trial of single low-dose durvalumab (Medi4736) IntraTumourally injected in cervical cancer: safety, toxicity and effect on the primary tumour- and lymph node microenvironment.

BACKGROUND: Treatment with programmed cell death receptor (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors is a promising strategy to lift tumour-induced immune response suppression. However, the current systemic treatment often causes autoimmune side effects. In more than 50% of squamous cell cervical cancer, PD-L1 expression is detected. Moreover, we observed high and interrelated rates of PD-L1 positive macrophages and regulatory T cells in metastatic lymph nodes of cervical cancer patients. As cervical cancer in general initially metastasizes to regional lymph nodes, local administration of durvalumab (a PD-L1 checkpoint inhibitor) at an early stage will deliver these antibodies exactly where they are needed, facilitating immune protection. This may result in a clinical benefit while reducing undesirable side effects. METHODS: DURVIT is a non-randomized, single-arm, open-label, phase I study. Three escalating dose levels of intratumourally (i.t.) injected durvalumab will be tested, i.e. 5, 10 and 20 mg (three patients per dose level, with an additional three at the highest tolerated dose). The primary endpoint of this phase-I study is safety. Immune monitoring will consist of flow cytometric, immunohistochemical and functional T cell reactivity testing. The first patient has been included in this trial in November 2017. DISCUSSION: Evidence of safety and biological efficacy of this locally administered checkpoint blockade may expand adjuvant therapy options for cervical cancer patients. Early metastatic spread of cervical cancer cells may thus be controlled in the draining lymph node basin, and beyond, and hopefully delay or even prevent the onset of disease recurrence. TRIAL REGISTRATION: NTR6119 , 1-nov-2016.

[Twin pregnancy with acardiac fetus. Contribution of echography to the diagnosis. Review of the literature apropos of a case]. / Grossesse gémellaire avec foetus acardiaque. Apport de l'échographie au diagnostic. Revue de la littérature à propos d'un cas.

An acardiac fetus is an extremely rare anomaly occurring only in twin pregnancies and its etiology is still controverted. Sonography must permit an early diagnosis, in order to anticipate the risks of the pregnancy and the delivery, as well as the future of the second twin.

Testicular secretion of conjugated and unconjugated steroids in normal adults and in patients with varicocele. Baseline levels and time-course response to hCG administration.

The effects of a single im injection of 10,000 IU of hCG on testicular steroid secretions were studied in 15 normal men and 54 patients with varicocele. Plasma levels of the following steroids were determined by radioimmunoassay: T, DHT, A, DHA, 5Adiol, E1, E2, 5P, 170H5P, 170HP, E1S, E2S, TE1, TE2, DHAS, 5AdiolS and hCG as well as FSH and LH in baseline samples. In normal men, peripheral venous blood was collected at 0, 1, 2, 4, 6, 8, 24, 36, 48, 72 and 96 h after hCG. Three types of steroid response were observed. The first, biphasic with an early peak within 2 h and a delayed one after 24 h, was shown by T, its unconjugated precursors and DHT. The second with an early rise plateauing for 6 h and followed by a 36 h peak characterized the estrogen pattern. Finally DHAS did not demonstrate a significant increase but 5AdiolS fluctuated at higher levels than the baseline ones. A significant correlation was only observed between hCG maximum value and E2 and TE1 maximum relative responses. In the patient group, peripheral blood was collected at 0, 1, 1.5, 2, 4, 6, 8, 10, 24 and 48 h after hCG. Baseline levels of all steroids were similar in the two groups. After hCG the same delayed pattern was observed as in the controls. The early relative response was low for T while A, DHT, E2 and E1S levels decreased. Conversely 170HP was higher until 24 h. Spermatic vein blood was collected before and at 1.5, 24 and 48 h after hCG. Steroid baseline levels in the varicocele side were similar to the other. After hCG, despite very large variations, general steroid patterns were comparable to those observed in peripheral vein blood. The important fall at 24 h of T/170HP and T/170H5P concomitant with that of T/E2 might be related to an inhibition of C17-20 lyase activity. The testicular secretion of all the measured steroids, including E1S, could be demonstrated except for DHAS. From our findings, a biogenetic defect evidenced by the fast response to hCG administration might exist in varicocele patients. In view of these results, the protocol of the hCG test should be improved using more frequent blood sampling and determining, besides T, its precursors and estrogen conjugates.

[Vasomotor sudden flushes (author's transl)]. / Les bouffées vasomotrices de la Ménopause.

The most typical disorder encountered during the menopause is the sudden flush, but the etiopathogenicity of these disorders is still a matter of hypotheses only. Increased levels of FSH and LH have been evoked ; recent cutaneous temperature studies have demonstrated a significant increase in LH but not of FSH, E1, and E2, during sudden flushes. The degree and rapidity of estradiol level variations have also been suggested as relevant factors. Current opinion conduces to be favoured with the involvement of gonadotropins, catecholamines, and indolamines, and perhaps prostaglandins at the hypothalamic level. Whatever the cause may be, vasomotor flushes are present in 55 to 75 % of menopausal women, and may be accompanied with sudoral crises, palpitations, or lipothymia. Women with a harmonious family life are better able to endure these disorders, treatment being most necessary when they result from a greatest disorder. Therapy is essentially estrogen therapy (after exclusion of cancer), progestogens, or veralipride, a non hormonal agent which produces 80 % of positive results, without apparently the disadvantage of estrogen therapy.

[Tubo-uterin implantation: microsurgical technic (author's transl)]. / Implantation tubo-utérine: technique microchirurgicale.

Fourteen tubo-uterin implantations for endometriosis of the horn and infertility have been carried out. They have been made with microsugery with a reversed transcornual T access. The setting of a retractor pushing off the edges of the uterin muscle allows the removing of the pathological zone, allows also not to hurt the vascularisation during the dissection of the nodule, and allows also to suture edge to edge the tube to the uterus under microsurgical control. This original process allows a new setting up of the continuity (Ten permeabilities cheked with hysterography 2 pregnancies and 2 obstructions among 14 cases after a passing of less than 1 year).

[An analysis of 65 cases of salpingostomy carried out using microsurgical techniques (author's transl)]. / Analyse de 65 salpingostomies microchirurgicales.

65 salpingostomies were carried out using microsurgical techniques between 1976 and 1978. The patency rate was 89 p. 100. There were 30 p. 100 intra-uterine pregnancies and 4 p. 100 ectopic pregnancies. The authors emphasize the prognosis that can be obtained from hysterosalpingography, laparoscopy and histological examination of the tissues and the very poor results that are obtained even using these methods when a second operation is undertaken.

[A histological study of a microsurgical tubo-tubal anastomosis (author's transl)]. / Etude histologique d'une anastomose tubo-tubaire microchirurgicale.

We report a histological study of a microsurgical tubo-tubal anastomosis undertaken to restore patency after ligation. It confirms the good level of tissue tolerance of the suture material employed. It emphasizes the difficulty of anastomosis in the ampulloisthmial region because of the discrepancy in size of the parts that have to be brought together. From this we can emphasize the need for carrying out sterilizations only on a limited lenght of the isthmus.

[Preliminary trials of an oral chemical contraceptive for men]. / Premiers essais d'une contraception chimique par voie orale chez l'homme

PIP: R 2323 (13-ethyl, 17 alpha-ethyl, 18-hydroxy-gona-4,9,11-trien-3-one) was administered orally, 50, 75, or 100 mcg/week in 2 or 3 divided doses with or without 3 100 mg testosterone implants to arrest spermatogenesis, to 20 healthy men 25-35 years of age with at least 2 children. There were 3 dropouts, 1 for a high triglyceride level. 7 men became azoospermic within 2-3 months after the combined treatment and 8 after receiving 75 or 100 mg/week of R 2323 only. No abnormal sperm forms appeared. Side effects were weight gain of 2-8 kg chiefly with the combined schedule. Libido declined in 3, erective capacity decreased in 2, and coital frequency fell in 8. 1 case of gynecomastia appeared after 4 months. 1 man had a superficial thrombosis in the left arm at the site of a biopsy for polyadenopathy. Testosterone fell from 5 to .5 ng/ml and follicle stimulating hormone and luteinizing hormone from 5-1 mIU/ml in both groups. The only remarkable change in a biological parameter was an increase in transaminase, especially SGPT, 25-50%. Testosterone and gonadotropins returned to normal within 1 month after stopping steroids, and sperm counts within 3-4 months. The testosterone implants failed to prevent plasma testosterone levels from falling, and seemed to cause more side effects such as weight gain and loss of libido than did R 2323 alone.^ieng

[Role of varicocele in male sterility]. / Responsabilité effective du varicocèle dans la stérilité masculine

After they had analysed 50 cases of varicocoele the authors decided to put in writing some of their ideas. They conclude that varicocoele is often sub-clinical, localised to the right side, bilateral only in a number of cases. Although neither the sperm count nor the histology of the testes show specific pathological features, treatment of the condition brings worthwhile rewards. About 40% of patients father pregnancies.

[Secretion into the plasma of testosterone and estradiol 17 beta by the human testicle. Value of the study in male sterility]. / Sécrétions plasmatiques de la testostérone et de l'oestradiol 17 beta par le testicule humain

The levels of oestradiol and of testosterone were estimated in the spermatic and in the perpheral veins in two series of 13 subjects. The one was a control group and the other stimulated with 10,000 International Units of chorionic gonadontrophir (II.C.G). The follwing conclusions can be drawn. --the first is that the testis secretes simultaneously testosterone and oestradiol 17 beta --the second is that the level of oestradiol is significantly raised after the administration of II.C.G. whereas the level of testosterone hardly alters. This leads on to the supposition that oestradiol does not arise from the same source in the testis as testosterone.