Adrenal insufficiency in thyroid cancer patients treated with tyrosine kinase inhibitors and detected by ACTH stimulation test.

PURPOSE: Advanced thyroid cancer patients treated with tyrosine kinase inhibitors (TKI) can develop several adverse events (AEs), including adrenal insufficiency (AI). METHODS: We studied 55 patients treated with TKI for radioiodine-refractory or medullary thyroid cancer. The adrenal function was evaluated during follow-up by performing serum basal ACTH, and basal and ACTH-stimulated cortisol. RESULTS: Twenty-nine/55 (52.7%) patients developed subclinical AI during TKI treatment as demonstrated by a blunted cortisol response to ACTH stimulation. All cases showed normal values of serum sodium, potassium and blood pressure. All patients were immediately treated, and none showed an overt AI. Cases with AI were all negative for adrenal antibodies and did not show any adrenal gland alteration. Other causes of AI were excluded. The onset time of the AI, as measured in the subgroup with a first negative ACTH test, was < 12 months in 5/9 (55.6%), between 12 and 36 months in 2/9 (22.2%) and > 36 months in 2/9 (22.2%) cases. In our series, the only prognostic factor of AI was the elevated, although moderate, basal level of ACTH when the basal and stimulated cortisol were still normal. The glucocorticoid therapy improved fatigue in most patients. CONCLUSIONS: Subclinical AI can be developed in > 50% of advanced thyroid cancer patients treated with TKI. This AE can develop in a wide period ranging from < 12 to > 36 months. For this reason, AI must be looked for throughout the follow-up to be early recognized and treated. A periodic ACTH stimulation test, every 6-8 months, can be helpful.

Radio-iodine refractory thyroid cancer patients: a tailored follow-up based on clinicopathological features.

OBJECTIVE: To report the experience of a single center for the selection of radioiodine-refractory (RAIR) thyroid cancer patients (RAIR-TC) who needed tyrosine kinase inhibitor (TKIs) treatment. PATIENTS AND METHODS: We evaluated all features of 279 RAIR-TC patients both at the time of diagnosis and at the RAIR diagnosis. RESULTS: Ninety-nine patients received indication to TKIs (Group A), while 180 remained under active surveillance (Group B). Group A had greater tumor size, more aggressive histotype, more frequent macroscopic extrathyroidal extension, distant metastases, advanced AJCC stage, and higher ATA risk of recurrence. After RAIR diagnosis, 93.9% of Group A had progression of disease (PD) after which TKIs' therapy was started. The remaining 6.1% of patients had a so severe disease at the time of RAIR diagnosis that TKIs' therapy was immediately started. Among Group B, 42.7% had up to 5 PD, but the majority underwent local treatments. The mean time from RAIR diagnosis to the first PD was shorter in Group A, and the evidence of PD within 25 months from RAIR diagnosis was associated with the decision to start TKIs. CONCLUSIONS: According to our results, a more tailored follow-up should be applied to RAIR-TC patients. A too strict monitoring and too many imaging evaluations might be avoided in those with less-aggressive features and low rate of progression. Conversely, RAIR-TC with an advanced stage at diagnosis and a first PD occurring within 25 months from RAIR diagnosis would require a more stringent follow-up to avoid a late start of TKIs.

Lenvatinib as a salvage therapy for advanced metastatic medullary thyroid cancer.

PURPOSE: Patients with advanced progressive metastatic medullary thyroid cancer (MTC), show poor prognosis and few available systemic therapeutic options. After the loss of clinical benefit with other tyrosine kinase inhibitors (TKI), we evaluated the use of lenvatinib as salvage therapy. METHODS: Ten patients who experienced the loss of clinical benefit after treatment with at least one previous TKI, were treated with lenvatinib. We assessed patient's response immediately before, at the first (first-EV) and last (last-EV) evaluation, after the beginning of treatment. RESULTS: At first-EV, one patient died, while all the remaining 9 showed a stable disease (SD) in the target lesions. At last-EV, SD was still observed in seven patients, while partial response (PR) and progressive disease (PD), in one patient each. Conversely, analyzing all target and non-target lesions, at first-EV, we observed PR in one patient and SD in eight patients. At last-EV, PR was shown in two patients and SD was shown in seven. Bone metastases showed stable disease control at both first-EV and last-EV in only approximately 60% of cases. Tumor markers (CTN and CEA) decreased at first-EV, while they increased at last-EV. Seven patients experienced at least one dose reduction during treatment with lenvatinib. CONCLUSIONS: In this real-life clinical experience, lenvatinib showed interesting results as salvage therapy in patients with advanced progressive metastatic MTC patients. Its usefulness could be effective in patients without any other available treatment, because previously used or unsuitable, especially with negative RET status with no access to the new highly selective targeted therapies.

Relationship between natural and intrauterine insemination-assisted live births and the degree of sperm autoimmunisation.

STUDY QUESTION: What is the relationship between the degree of sperm autoimmunisation, as assessed by IgG-mixed antiglobulin reaction (MAR) test, and natural and intrauterine insemination (IUI)-assisted live births? SUMMARY ANSWER: Compared with a lower degree of positivity (50-99%), a 100%-positive MAR test was associated with a much lower occurrence of natural live births in infertile couples, who could be successfully treated with IUI, as first-line treatment. WHAT IS KNOWN ALREADY: The World Health Organization (WHO) has recommended screening for antisperm antibodies, through either the IgG-MAR test or an immunobead-binding test, as an integral part of semen analysis, with 50% antibody-coated motile spermatozoa considered to be the clinically relevant threshold. However, the predictive value of the degree of positivity of the MAR test above such a cut-off on the occurrence of natural pregnancies remains largely undetermined. Furthermore, the effectiveness of IUI in cases of strong sperm autoimmunisation is not yet well-established. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study on 108 men with a ≥50%-positive MAR test, where the couple had attended a university/hospital andrology/infertility clinic for the management of infertility from March 1994 to September 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: The IgG-MAR test was carried out as an integral part of semen analysis. The patients were divided into two groups: 100% and 50%-99%-positive MAR test. The post-coital test (PCT) was performed in all the couples, and IUI was offered as the first-line treatment. Laboratory and other clinical data were retrieved from a computerised database. Data on subsequent pregnancies were obtained by contacting patients over the telephone. MAIN RESULTS AND THE ROLE OF CHANGE: A total of 84 men (77.8%) were successfully contacted by telephone, and they agreed to participate. Of these, 44 men belonged to the group with a 100%-positive MAR test, while 40 showed lower MAR test positivity. The couples with a 100%-positive MAR test showed a natural live birth rate per couple (LBR) that was considerably lower than that observed with a lower degree of positivity (4.5% vs. 30.0%; P = 0.00001). Among the clinical variables, a significant difference between the two groups was observed only for the PCT outcome, which was poor in the 100%-positive MAR test group. Better PCT outcomes (categorised as negative, subnormal and good) were positively associated with the occurrence of natural live births (6.3, 21.7 and 46.2%, respectively; P = 0.0005 for trend), for which the sole independent negative predictor was the degree of sperm autoimmunisation. IUI was performed as the first-line treatment in 38 out of 44 couples with a 100%-positive MAR test, yielding 14 live births (36.8%). In couples with lower MAR test positivity, the LBR after IUI (26.9%) was similar to the natural LBR in this group (30.0%). LIMITATIONS, REASONS FOR CAUTION: Given the retrospective nature of the study, we cannot exclude uncontrolled variables that may have affected natural pregnancies during the follow up or a selection bias from the comparison of natural live births with those after IUI. WIDER IMPLICATIONS OF THE FINDINGS: The routine use of the IgG-MAR test in the basic fertility workup is justified as it influences decision making. A 100%-positive IgG-MAR test can represent the sole cause of a couple's infertility, which could be successfully treated with IUI. On the other hand, a lower degree of positivity may only represent a contributing factor to a couple's infertility, and so the decision to treat or wait also depends on the evaluation of conventional prognostic factors including the PCT outcome. STUDY FUNDING, COMPETING INTEREST(S): This study was supported by PRIN 2017, Ministero dell'Università e della Ricerca Scientifica (MIUR), Italy. On behalf of all authors, the corresponding author states that there is no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Thyroid autoimmunity and risk of post-partum depression: a systematic review and meta-analysis of longitudinal studies.

PURPOSE: The aim of this study was to systematically investigate whether, and to what extent, the detection of thyroid autoimmunity during pregnancy and in the weeks after childbirth is associated with an increased risk of developing post-partum depression (PPD), a condition associated with possible adverse outcomes for both mother and offspring. We performed a systematic review and meta-analysis of longitudinal studies, assessing the incidence of PPD in women with and without anti-thyroperoxidase antibody (TPOAb) positivity. METHODS: We searched MEDLINE, EMBASE, Web of Science, Cochrane Library, and CINAHL. Methodological quality of the studies was assessed by the Newcastle-Ottawa Scale. In the presence of even modest between-studies heterogeneity, assessed by Cochrane Q and I2 tests, risk ratios (RRs) for PPD were combined using a random effects model. Funnel plot and trim-and-fill analysis were used to assess publication bias. RESULTS: Five included studies provided information on 449 women with TPOAb-positive and 2483 TPOAb-negative women. Pooled RR indicated a significantly increased risk to develop PPD in TPOAb-positive group (RR 1.49, 95% CI 1.11-2.00; P = 0.008; I2 = 47%, Pfor heterogeneity = 0.11). Consistent with a possible publication bias, the trim-and-fill test detected two putative missing studies in the funnel plot. Nevertheless, the adjustment for publication bias produced a negligible effect on the pooled estimate (adjusted RR 1.41, 95% CI 1.18-1.68, P = 0.0002). CONCLUSIONS: Thyroid autoimmunity during pregnancy and in the weeks after childbirth is associated with an increased risk of developing PPD. Further well-designed studies are warranted to confirm this association and elucidate underlying pathophysiological mechanisms. PROSPERO REGISTRATION: CRD42019129643.

Testosterone, level of the lesion and age are independently associated with prostate volume in men with chronic spinal cord injury.

PURPOSE: Although men with spinal cord injury (SCI) exhibit a prostate volume significantly smaller compared to age-matched able-bodied men, the independent association of lower prostate volume with its putative determinants has never been analyzed in this population. This study was designed to identify variables independently associated with prostate volume in men with chronic SCI. METHODS: In this cross-sectional study, prostate volume of 138 men with chronic (> 1 years) SCI, aged 54.5 (25th-75th percentile: 36.0-66.0) years, was evaluated with trans-rectal ultrasonography. All patients underwent a complete neurological exam, as well as biochemical and hormonal assessment, including total testosterone (TT) levels. Free testosterone levels were calculated (cFT) by the Vermeulen formula. RESULTS: The median prostate volume was 23.4 mL. At the univariate analysis, a larger prostate volume was associated with higher TT (p = 0.00001) and cFT (p = 0.001), SCI level below T12 (p = 0.007), more advanced age (p = 0.04), lower body mass index (p = 0.04), higher functional independence score (p = 0.06), higher values of prostate-specific antigen (p = 0.12) and shorter duration of the injury (p = 0.21). However, at the multiple regression analyses, an independent and positive association only persisted between the prostate volume with either TT or cFT levels, and, to a lesser extent, with age and a level of spinal lesion below T12. A prostate volume below the median value was observed in 91.4% (32/35) of patients with both androgen deficiency (TT < 264 ng/dL) and spinal lesion level ≥ T12, but only in 16.5% (2/12) of patients with both normal androgen levels and spinal lesion level below T12 (p < 0.001). CONCLUSIONS: Our data indicate that lower testosterone levels and, to a lesser extent, a younger age and a spinal lesion level ≥ T12 represent the only variables exhibiting an independent association with a smaller prostate volume in men with SCI.

Left spermatic vein reflux after varicocele repair predicts pregnancies and live births in subfertile couples.

PURPOSE: Varicocele repair (VR) is proposed to improve fertility in subfertile couples with a poor semen quality. We explored whether the disappearance of a left continuous spermatic venous reflux (SVR) at scrotal colour-Doppler ultrasound (CDUS), an objective evidence for a VR, is predictive for improved fertility outcome in subfertile couples. METHODS: VR was performed by left internal spermatic vein sclero-embolisation in 88 males seeking a consultation for subfertility. Semen analysis and scrotal CDUS were evaluated before and 6 months after VR. Serum levels of FSH and total testosterone (TT) were obtained at baseline. Telephone interview was used to obtain information about fertility outcome. Significant predictors of pregnancy and live births, selected by univariate analyses, were included into multiple logistic regression models to assess independent associations. RESULTS: At the adjusted model, independent significant predictors of pregnancy after VR were a disappeared SVR at CDUS (OR = 5.5, 97.5% CI 2.01-15.4; p = 0.0009) and an improved sperm total motile count (TMC) (OR = 5.5, 97.5% CI 1.4-27.9; p = 0.02). Even live births were independently associated with both disappeared left SVR at CDUS (OR = 4.3, 97.5% CI = 1.6-11.8; p = 0.003) and improved TMC after VR (OR = 4.8, 97.5% CI 1.3-24.2; p = 0.02). CONCLUSION: The still controversial effect of varicocele repair on fertility in subfertile couples may reside on the undefined objective methods to document a successful VR and its effect on couple fertility. The disappearance of a continuous left SVR at CDUS after VR was the objective best predictor for subsequent improved fertility in subfertile couples.

Tall cell and diffuse sclerosing variants of papillary thyroid cancer: outcome and predicting value of risk stratification methods.

PURPOSE: Tall cell (TCV) and diffuse sclerosing (DSV) variants are aggressive variants of papillary thyroid cancer (PTC). We compared the risk of recurrent/persistent disease in patients with TCV, DSV and classical PTC (cPTC) and evaluated the prognostic accuracy of initial vs. ongoing risk stratification. METHODS: A consecutive series of DSV (n = 54), TCV (n = 72) and cPTC (n = 184) patients was retrospectively analyzed. TCV and DSV patients were first risk stratified for recurrent/persistent disease without considering the histotype as a risk factor and subsequently, 6-24 months after initial treatment, re-classified on the basis of the response to therapy (ongoing risk stratification). RESULTS: Extrathyroidal extension was more frequent in DSV than in TCV and cPTC patients (p < 0.05); moreover, only DSV tumors had a higher rate of recurrent/persistent disease when compared to cPTC treated with the same protocol (total thyroidectomy followed by 131I treatment) (p < 0.01). After initial treatment, 54.2% of TCV and 20.4% of DSV patients were classified at low risk, while at ongoing risk stratification, the excellent response (low risk) was higher for both TCV (77.8%) and DSV (50.0%) patients relative to initial stratification (both p < 0.01). Using ongoing risk classification, positive predictive value (PPV) for persistent/recurrent disease was higher relative to initial risk stratification for both TCV (PPV = 93.8 vs. 39.4%) and DSV (PPV = 63.0 vs. 34.9%), p < 0.05 for both. CONCLUSIONS: In our series DSV, but not TCV patients, had poorer outcome than cPTC treated with the same protocol. Moreover, the ongoing risk stratification predicted outcome better than the initial classification in both TCV and DSV patients.

Relationship of Vitamin D status with testosterone levels: a systematic review and meta-analysis.

PURPOSE: Despite a biological plausibility of a direct link between low vitamin D and androgen deficiency, the association remains inconclusive in epidemiological studies. Therefore, this systematic review and meta-analysis of case-control studies aim to assess whether and in what populations such an association can be demonstrated. METHODS: A systematic search was performed in PubMed, EMBASE, Cochrane Library, Web of science, Science Direct, and CINAHL. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) in total testosterone (TT) levels between men with 25-hydroxyvitamin D (25(OH)D) <20 and ≥20 ng/mL were combined using random-effects models. Funnel plot and trim-and-fill analysis were used to assess publication bias. Heterogeneity source was explored by a sub-group analysis according to health-related characteristics of the study populations. RESULTS: Eighteen included studies collectively gave information on 9892 men with vitamin D deficiency and 10,675 controls. The pooled SMD revealed a slight, albeit just significant, positive association between 25(OH)D and TT (pooled SMD: -0.23, 95% CI: -0.45 to -0.01; P = 0.04) with a large between-study heterogeneity (I2 = 98%, Pfor heterogeneity < 0.00001). At the sub-group analysis, a significant positive association, along with noticeable decrease in heterogeneity, could only be demonstrated in studies of patients with frailty states (pooled SMD: -0.19; 95% CI: -0.27, -0.10, P < 0.0001; I2 = 51%, Pfor heterogeneity = 0.06). A sensitivity analysis revealed a high stability of the result and the trim-and-fill adjustment for publication bias did not affect pooled estimate. CONCLUSIONS: Both hypovitaminosis D and androgen deficiency should be regarded as markers of a poor health status, sharing common underlying aetiologies and risk factors.

Relationship between leukocytospermia, reproductive potential after assisted reproductive technology, and sperm parameters: a systematic review and meta-analysis of case-control studies.

BACKGROUND: The association of leukocytospermia with male fertility is still under debate. OBJECTIVE: To evaluate the impact of leukocytospermia (≥1 × 106  white blood cells/mL of semen, according to the World Health Organization) in men attending a fertility clinic for couple subfertility, on fertility outcomes after assisted reproductive technology (ART) and on semen quality. MATERIALS AND METHODS: A systematic review with meta-analysis of case-control studies reporting mean ± standard deviation for values of different seminal parameters (sperm concentration, progressive motility, sperm morphology, sperm DNA fragmentation, semen volume, and Ph) and fertilization rate (FR), or the odds ratio (OR) for clinical pregnancy rate (PR) per cycle after ART in leukocytospermic and non-leukocytospermic patients was performed. A literature search was carried out in MEDLINE and SCOPUS for English-language studies published till June 2018. RESULTS: Twenty-eight case-controlled retrospective studies met the inclusion criteria, comparing fertility outcomes after ART or semen parameters in men with or without leukocytospermia. FR and PR after ART were not significantly different in the two groups. Leukocytospermic samples showed a lower sperm concentration (pooled SMD = -0.14; 95% CI: -0.28, -0.01, I2  = 71%, pfor heterogeneity  < 0.00001) and a lower progressive motility (pooled SMD = -0.18; 95% CI: -0.29, -0.06; I2  = 59%, pfor heterogeneity  < 0.0001). However, the significant differences disappeared, along with the large inter-study heterogeneity, when analyses were restricted to studies clearly reporting the inclusion of men without clinical evidence of seminal tract infection. DISCUSSION AND CONCLUSION: Leukocytospermia in men seeking consultation for couple subfertility is not associated with a reduced fertility after ART and with altered semen quality in populations asymptomatic for genital tract infection. Therefore, the current clinical criteria for definition of leukocytospermia should be re-assessed in subfertile couples attending a fertility clinic.