Right ventricular outflow tract obstruction in twin-to-twin transfusion syndrome undergoing laser surgery: A systematic review and meta-analysis.

INTRODUCTION: We aimed to investigate the incidence, prenatal factors and outcomes of twin-to-twin transfusion (TTTS) with right ventricular outflow tract obstruction (RVOTO). MATERIAL AND METHODS: A systematic search was conducted to identify relevant studies published until February 2023 in English using the databases PubMed, Scopus and Web of Science. Studies reporting on pregnancies with TTTS and RVOTO were included. The random-effect model pooled the mean differences or odds ratios (OR) and the corresponding 95% confidence intervals. Heterogeneity was assessed using the I2 value. RESULTS: A total of 17 studies encompassing 4332 TTTS pregnancies, of which 225 cases had RVOTO, were included. Incidence of RVOTO at time of TTTS diagnosis was 6%. In all, 134/197 (68%) had functional pulmonary stenosis and 62/197 (32%) had functional pulmonary atresia. Of these, 27% resolved following laser and 55% persisted after birth. Of those persisting, 27% required cardiac valve procedures. Prenatal associations were TTTS stage III (53% vs 39% in no-RVOTO), stage IV TTTS (28% in RVOTO vs 12% in no-RVOTO) and ductus venosus reversed a-wave (60% in RVOTO vs 19% in no-RVOTO). Gestational age at laser and gestational age at delivery were comparable between groups. Survival outcomes were also comparable between groups, including fetal demise of 26%, neonatal death of 12% and 6-month survival of 82% in RVOTO group. Findings were similar when subgroup analysis was done for studies including head-to-head analysis. CONCLUSIONS: RVOT occurs in about 6% of the recipient twins with TTTS, especially in stages III and IV and those with reversed ductus venosus a-wave. The findings from this systematic review support the need for a thorough cardiac assessment of pregnancies complicated by TTTS, both before and after laser, to maximize perinatal outcome, and the importance of early diagnosis of TTTS and timely management.

CM from intact hAM: an easily obtained product with relevant implications for translation in regenerative medicine.

BACKGROUND: It is now well established that factors (free or in extracellular vesicles) secreted by mesenchymal stromal cells (MSC) are important mediators of MSC regenerative actions. Herein we produced the secretome (conditioned medium, CM) from MSC isolated from the amniotic membrane (hAMSC) and CM from the intact amniotic membrane (hAM, no manipulation or enzymatic digestion) in order to potentially identify an effective, easy and less expensive secretome to produce for potential applications in regenerative medicine. Given that immunomodulation is a key mechanism of action through which hAMSC contributes to tissue regeneration, we used a comprehensive panel of in vitro immunomodulatory tests to compare the CMs. METHODS: Amniotic membranes were either cut into fragments or used for hAMSC isolation. CMs from hAMSC at passages 0 and 2 were collected after a standard 5-day culture while CM from hAM was collected after a 2- and 5-day culture. Immunomodulation was assessed in terms of PBMC and T-cell proliferation, T-cell subset polarization, T-regulatory cell induction, cell cytotoxicity and monocyte differentiation toward antigen-presenting cells. Furthermore, we performed a comparison between CM obtained from single donors and pooled CM. We also assessed the impact of lyophilization on the immunomodulatory properties of CM. RESULTS: We demonstrate that CM from hAM has comparable immunomodulatory properties to CM from hAMSC at passages 0 and 2. Furthermore, we demonstrate that pooled CMs have similar effects when compared to CM from single donors used separately. Finally, we demonstrate that lyophilization does not alter the in vitro immunomodulatory properties of CM from hAM and hAMSC. CONCLUSIONS: The results presented herein support the possibility to produce secretome from intact hAM and open the prospect to highly improve the scalability of the GMP production process while reducing the costs and time related to the process of cell isolation and expansion. Moreover, the possibility of having a lyophilized secretome that maintains its original properties would allow for a ready-to-use product with easier handling, shipping and storage. The use of a lyophilized product will also facilitate clinicians by permitting customized reconstitution volumes and methods according to the most suitable formula required by the clinical application.

Diagnostic accuracy of ultrasound in detecting the depth of invasion in women at risk of abnormally invasive placenta: A prospective longitudinal study.

INTRODUCTION: The aim of this study was to assess the diagnostic accuracy of ultrasound in detecting the depth of abnormally invasive placenta in women at risk. MATERIAL AND METHODS: Prospective longitudinal study including women with placenta previa and at least one prior cesarean delivery or uterine surgery. Depth of abnormally invasive placenta was defined as the degree of trophoblastic invasion through the myometrium and was assessed with histopathological analysis. The ultrasound signs explored were: loss of clear zone, placental lacunae, bladder wall interruption, uterovesical hypervascularity, and increased vascularity in the parametrial region. RESULTS: In all, 210 women were included in the analysis. When using at least one sign, ultrasound had an overall sensitivity of 100% (95% CI 96.5-100) and overall specificity of 61.9 (95% CI 51.9-71.2) for all types of abnormally invasive placenta. Using two ultrasound signs increased the diagnostic accuracy in terms of specificity (100%, 95% CI 96.5-100) but did not affect sensitivity. When stratifying the analysis according to the depth of placental invasion, using at least one sign had a sensitivity of 100% (95% CI 93.7-100) and 100% (95% CI 92.6-100) for placenta accreta/increta and percreta, respectively. Using three ultrasound signs improved the detection rate for placenta percreta with a sensitivity of 100% (95% CI 92.6-100) and a specificity of 77.2% (95% CI 69.9-83.4). CONCLUSION: Ultrasound has a high diagnostic accuracy in detecting the depth of placental invasion when applied to a population with specific risk factors for anomalies such as placenta previa and prior cesarean delivery or uterine surgery.

Diagnostic accuracy of magnetic resonance imaging in detecting the severity of abnormal invasive placenta: a systematic review and meta-analysis.

INTRODUCTION: Accurate prenatal diagnosis of abnormally invasive placenta (AIP) is fundamental because it significantly reduces maternal morbidities. MATERIAL AND METHODS: Medline, Embase, CINAHL and the Cochrane databases were searched. The primary aim of the present review was to elucidate the diagnostic accuracy of prenatal magnetic resonance imaging (MRI) in recognizing the severity of AIP, defined as the depth and topography of invasion. The secondary aim was to ascertain the strength of association between each MRI sign and the depth of placental invasion and to test their individual predictive accuracy in detecting such invasion. Inclusion criteria were studies on women who had prenatal MRI for ultrasound suspicion or the presence of clinical risk factors for AIP. Estimates of sensitivity, specificity, positive and negative likelihood ratios and diagnostic odds ratio were calculated using the hierarchical summary receiver characteristics curve model, and individual data random-effect logistic regression was used to calculate OR. RESULTS: Twenty studies (1080 pregnancies undergoing MRI mainly for the ultrasound suspicion of AIP) were included. MRI showed a sensitivity of 94.4% [95% confidence interval (CI) 15.8-99.9], 100% (95% CI 75.3-100) and 86.5% (95% CI 74.2-94.4) for detection of placenta accreta, increta and percreta, respectively; the corresponding values for specificity were 98.8% (95% CI 70.7-100), 97.3% (95% CI 93.3-99.3), 96.8% (95% CI 93.5-98.7). MRI identified 100% of cases with S1 and 100% of those with S2 invasion confirmed at surgery. Among the different MRI signs, intra-placental dark bands showed the best sensitivity for the detection of placenta accreta, increta and percreta; as well as abnormal intra-placental vascularity, uterine bulging was associated with a higher risk of increta and percreta, exophitic mass and bladder tenting with placenta percreta. CONCLUSION: Prenatal MRI has an excellent diagnostic accuracy in identifying the depth and the topography of placental invasion. However, these findings come mainly from studies in which MRI was performed as a secondary imaging tool in women already screened for AIP on ultrasound and might not reflect its actual diagnostic performance in detecting the severity of these disorders.

How to perform transabdominal chorionic villus sampling: a practical guideline.

The spread of both first trimester screening for chromosomal abnormalities and the possibility to check for single gene disorders at DNA-analysis has increased the request for chorionic villus sampling (CVS) in the first trimester. In order to perform placental biopsy, two routes are possible: the transcervical (TC) and the transabdominal (TA). In early days, the trancervical technique was the most diffused, but since its introduction into clinical practice, the TA technique has become the approach of choice in detriment of the TC technique. In our institution, we have a 30-year experience in TA-CVS with more than 26 000 procedures performed. Considering the expertise and the volume of procedures undertaken at our unit, we suggest a practical guideline for novel operators in TA-CVS.

Photooxidation and Phototoxicity of pi-extended squaraines.

This paper describes the synthesis of pi-extended squaraines and their photooxidation properties and gives an in-depth characterization of these molecules as photosensitizing agents. Squaraines show a strong absorption in the tissue transparency window (600-800 nm), and upon irradiation, they undergo a photooxidation process, leading to the formation of peroxide and hydroperoxide radicals according to a type I radical chain process. Confocal laser microscopy demonstrates that the designed squaraines efficiently internalize in the cytoplasm and not in the nucleus of the cell. In the dark, they are scarcely cytotoxic, but after irradition, they promote a strong dose-dependent phototoxic effect in four different cancer cells. In HeLa and MCF-7 cells, squaraines 4 and 5, thanks to their hydrocarbon tails, associate to the membranes and induce lipid peroxidation, as indicated by a marked increase of malonyldialdehyde after photodynamic treatment, in agreement with in vitro photooxidation studies. FACS, caspase-3/7 assays and time-lapse microscopy demonstrate that the designed squaraines cause cell death primarily by necrosis.

An audit of treatment outcome in acromegalic patients attending our center at Bergamo, Italy.

BACKGROUND: Acromegaly is a chronic disease impacting on morbidity and mortality. Increased mortality is reverted after the achievement of hormonal targets. The relative role of treatment options is still matter of debate. METHODS: A retrospective chart review was performed on all the acromegalic patients attending our center along the last 20 years. RESULTS: Data about 159 patients (83 F) were retrieved and analyzed: 18% had been lost to follow-up, while follow-up was >5 years in 79%. Growth hormone (GH) at diagnosis was 24 microg/L (median, range 3-239). Pituitary MRI showed a macro-, micro-adenoma or no lesion in 73.6, 22.9, and 3.5%, respectively. Hyperprolactinemia (hyperPRL) was present in 20.8%. Ninety-six and 29 patients had been treated by neurosurgery (NS) and irradiated (RT), respectively. Drugs had been employed in 149 patients (in 58 as the only treatment). At the last evaluation, 22% of patients were cured (hypopituitarism and GH deficiency in 6.3%), 37.1% were controlled by ongoing pharmacological treatment, 22.6% had discordant GH and Insulin-like growth factor I (IGF-I) values, and 18.2% had still active disease (median follow-up in this last group was 9 months). By evaluating the outcome with a multimodal approach, safe GH and normal IGF-I had been achieved in 78 and 63.5% of the whole series, 80.5 and 59.7% in patients submitted to NS (and adjuvantly treated with drugs), 95.8 and 91.7% in those submitted to NS + RT (and drugs as well), 70.2 and 55.2% in those treated only with drugs (increased to 82.2 and 60.9% if considering only patients treated with modern long-acting drugs). Hypopituitarism had occurred in 25, 66.6, and 13.8% in the three groups, respectively. At multivariate analysis, previous RT and NS were significant positive predictors of cure, whereas previous NS, follow-up, and year of diagnosis were significant positive predictors of control. Diabetes was a negative predictor both of cure and control. Sex, age, baseline GH levels, hyperPRL, tumor size, extrasellar extension, and invasiveness were not independent predictors of either cure or control. CONCLUSION: This series seems to indicate that a multimodal approach can achieve control of disease in most patients.

Primary treatment of acromegaly with octreotide LAR: a long-term (up to nine years) prospective study of its efficacy in the control of disease activity and tumor shrinkage.

CONTEXT: Neurosurgery is regarded as the first-line treatment of acromegaly. Because of its low cure rate in macro and invasive adenoma, the role of primary medical treatment is debated. OBJECTIVE: Our objective was to evaluate primary pharmacological treatment in acromegaly. DESIGN AND SETTING: We conducted an open prospective study at two Italian tertiary level centers. PATIENTS: We studied 67 consecutive patients (36 women; age, 54.9 +/- 14.2 yr; 72% bearing macroadenoma). INTERVENTION: Individually tailored octreotide LAR (OCLAR) was administered. MAIN OUTCOME MEASURES: Outcomes included safe GH (<2.5 mug/liter), normal age-matched IGF-I levels, and tumor shrinkage. RESULTS: After a median follow-up of 48 months (range, 6-108 months), safe GH levels and normal age-matched IGF-I values were obtained by 68.7 and 70.1% of patients, respectively. Hormonal endpoints were achieved regardless of basal levels, and early results were predictive of outcome. Tumor shrank in 82.1% of patients by 62 +/- 31% (range, 0-100%), decreasing from 2101 +/- 2912 to 1010 +/- 2196 mm(3) (P < 0.0001). The higher the basal GH values and the greater the GH/IGF-I changes on treatment, the greater the tumor shrinkage. Tumor disappeared in three patients and was progressively reduced to empty sella in five patients; apparent magnetic resonance imaging cavernous sinus invasion disappeared in three. In males, testosterone increased, restoring eugonadism in 64% of hypogonadal patients. CONCLUSIONS: The efficacy on GH/IGF-I levels in unselected patients and the outstanding volumetric control indicate that treatment with OCLAR may be the first therapeutic approach to all acromegalic patients not amenable to surgical cure. Tumor shrinkage might also encourage the evaluation of primary OCLAR adoption in patients with initial visual field defects.

Four-year treatment with octreotide-long-acting repeatable in 110 acromegalic patients: predictive value of short-term results?

The effects of a very prolonged treatment with octreotide (OC)-long-acting repeatable (LAR) were retrospectively evaluated in 110 patients with acromegaly, showing a GH/IGF-I decrease of at least 20% vs. baseline after a short-term (6-month) OC-LAR challenge. OC-LAR was given (20 mg, im, every 28 d for 3 injections, then individually tailored) as adjuvant treatment (AT) in 59. The other 51 [primary treatment (PT)] were naive or previously treated by pharmacotherapy. IGF-I normalized in 83 patients [75%; from 770 +/- 26 (mean +/- SE) to 276 +/- 15 micro g/liter; P < 0.0001; median follow-up, 30 months; range, 18-54 months). A progressive increase in the rate of IGF-I normalization was observed. GH fell to less than 2.5 micro g/liter in 72% and to less than 1 micro g/liter in 27% (from 20.7 +/- 2.4 to 2.2 +/- 0.2 micro g/liter; P < 0.0001). PT and AT patients achieved similar final GH/IGF-I levels and rates of normalization. Patients attaining safe GH and normal IGF-I had GH levels below 5 micro g/liter after 3 months and IGF-I levels below 550 micro g/liter after 6 months. No tachyphylaxis was observed. The up-titration to 30 mg improved IGF-I suppression. Elderly patients had greater sensitivity. Tumor shrank in 46% of assessable patients, in 77% of PT patients, and in 91% of naive patients. The powerful suppression of GH/IGF-I levels without tachyphylaxis, the finding of progressive increase in the rate of IGF-I normalization and of superimposable effects in PT and AT patients, and the predictive value of short-term results support the role of PT of acromegaly with OC-LAR in at least some patients.