Otopalatodigital Syndrome Type I: Novel Characteristics and Prenatal Manifestations in two Siblings.

Otopalatodigital spectrum disorder (OPDSD) is rare group of X-linked disorders caused by mutations in the filamin A (FLNA) gene. It is characterized by skeletal dysplasia of variable severity and different extra skeletal manifestations. Its presentation in the fetal period is quite unspecific, so diagnosis is usually made after birth. We present prenatal ultrasonography and postmortem findings that led us to a diagnosis of the mildest form of OPDSD (OPD type I) in two consecutive pregnancies. This is the first report on prenatal diagnosis (PND) of OPD type I. Affected fetuses showed facial dysmorphy (hypertelorism, micrognathia, cleft palate) and digital anomalies, features typical of OPD type I. In addition, microphtalmia and early neonatal death due to severe respiratory distress syndrome are described as a novel characteristics of the disorder. Clinical exome sequencing revealed a hemizygous missense pathogenic variant in the FLNA gene (NM_ 001110556.1: c.620C>T). We suggest that the presence of hypertelorism, micrognathia, digital anomalies on prenatal ultrasound examination should alert suspicion to OPDSD. Detailed clinical examination of mother and other female relatives is of great importance in establishing definitive diagnosis of OPD type I.

Non-diethylstilbestrol exposed vaginal adenocarcinoma in young patients associated with unilateral renal agenesis: two case reports and literature review.

BACKGROUND: Adenocarcinoma, accounts for up to 14% of all vaginal cancer. In young patients, common histological feature is clear cell adenocarcinoma (CCA) while mesonephric adenocarcinoma (MA) is very rare. The authors report two patients in their early twenties with unilateral renal agenesis and vaginal adenocarcinoma not exposed to diethylstilbestrol (DES). CASES: Two patients with vaginal adenocarcinoma were treated, with external beam radiotherapy of pelvis combined with brachytherapy to a radical dose. In 2000, 25-year-old female, was admitted for radiotherapy after incomplete excision of the tumor localized in left vaginal apex and fornix. Histopathology confirmed CCA and classified as clinical Stage II. CT revealed left renal agenesis.The patient is alive and disease-free 15 years after therapy. Vaginal, urethral stenosis, and hydronephrosis occurred and ureteral stent was inserted. In the second patient, 22-year-old, in 2004, after biopsy of bulky tumor of vagina and histology, revealed MA in Stage III and CT scan also confirmed right renal agenesis. Radiotherapy was followed by chemotherapy. After 11 years, patient is disease-free with vaginal stenosis and incipient renal hydronephrosis. CONCLUSION: Radiotherapy is effective treatment in advance vaginal adenocarcinoma, however, with high morbidity. The authors advise rigorous gynecologic exams in young females with renal agenesis as there may be a risk of malignant changes in vagina.

Incidence of brain metastases in early stage HER2 3+ breast cancer patients; is there a role for brain CT in asymptomatic patients?

PURPOSE: Human epidermal growth factor receptor 2 overexpression (HER2 3+) is reported in retrospective studies as a factor that contributes to higher incidence of brain metastases (BM) in patients with metastatic breast carcinoma. Although there are some reports suggesting higher incidence of BM in adjuvant trastuzumab trials, the true incidence, as well as the time of occurrence of BM in early-stage high risk breast carcinoma patients, has not been widely prospectively explored. The main objective of this study was to prospectively explore the incidence of BM during and after adjuvant trastuzumab administration in HER2 3+ early-breast carcinoma patients. METHODS: Two hundred and fifty-eight patients with early, HER2 3+ breast carcinoma have been included in this analysis. Brain computed tomography (CT) scan was scheduled once during adjuvant trastuzumab therapy and thereafter only if central nervous system (CNS) symptoms occurred. RESULTS: Eighty-five patients (33%) underwent brain CT in the absence of CNS symptoms. The median number of trastuzumab cycles at the time of brain CT was 9 (range 4-18). There were no BM detected by brain CT in these 85 asymptomatic patients. However, during a median follow up of 18 months 5/258 patients (1.93%) developed BM, but only 2 (0.77%) while still receiving adjuvant trastuzumab. The median time from breast cancer diagnosis to BM was 24 months (range 14-43). CONCLUSION: BM are a rare event during adjuvant trastuzumab treatment and brain CT screening is not justified in asymptomatic patients with early HER2 3+ breast carcinoma.

PTEN protein expression in postmenopausal steroid receptor positive early breast cancer patients treated with adjuvant tamoxifen.

PURPOSE: Since one of possible causes of resistance to antiestrogen therapy in steroid receptor positive (SR+) breast cancer (BC) patients is an alteration of PTEN (phosphatase and tensin homolog deleted on chromosome 10) signaling pathways, the aim of this study was to determine the PTEN protein expression in postmenopausal patients with steroid SR+ BC treated with adjuvant tamoxifen, to investigate the association of PTEN protein expression with tumor histology, size and grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) statuses and disease outcome. METHODS: This was a retrospective analysis of 78 postmenopausal stage I/II SR(+)BC patients treated with adjuvant tamoxifen. PTEN protein expression and ER, PR and HER2 status were determined using immunohistochemistry. RESULTS: The distribution of PTEN protein expression according to tumor histology was as follows: PTEN+ status in 27/43 (62.8%) patients with ductal and in 26/35 (74.3%) patients with lobular carcinomas; and PTEN(-) status in 16/43 (37.2%) patients with ductal and in 9/35 (25.7%) patients with lobular carcinomas. Disease relapse was observed in 38/78 patients: 14/53 (26.4%) of PTEN(+) BC subgroup and 24/25 (96%) of PTEN(-) subgroup (x(2), p=0.018). There were no significant associations between PTEN protein expression and tumor histology, size and grade, and ER, PR and HER2 expression. Patients with PTEN(-) had significantly shorter disease-free interval (DFI) and overall survival (OS) (for both, log rank test, p <0.01) compared to PTEN(+) BC patients. CONCLUSION: Our results suggest that PTEN protein expression might be of prognostic significance in postmenopausal SR(+) BC patients treated with adjuvant tamoxifen.

Percutaneous nephrostomy in the management of advanced and terminal-stage gynecologic malignancies: outcome and complications.

PURPOSE: The goal of the study was to evaluate the outcome and complications after percutaneous nephrostomy (PCN) insertion in advanced and terminal-stage gynecological malignancies with ureteral obstruction (UO). MATERIALS AND METHODS: We analyzed data of 117 patients with UO due to gynecological malignancies, who had undergone PCN between 1996 and 2006. Cervical cancer was evidenced in 108 patients, uterine carcinoma in six and ovarian cancer in three patients. Eighty-nine had UO at the initial manifestation of the disease, 22 had persistent or recurrent cancer, and six were disease-free after initial therapy. Oliguria was observed in 22.2% and creatine elevation in 79.5%. Mean follow-up was 11.43 months (range 0-112). RESULTS: The median age was 51 years (range 28-85). Bilateral nephrostomy was performed in 36.7% and unilateral in 63.3%. Renal function normalization occurred in 24.8%. Overall two-year survival (OS) was 16.8%. Higher OS occurred in patients without initial azotemia versus those with azotemia (26.8% vs 13.9%). Median survival time for all the patients was seven months, eight in primary cases versus six in recurrent ones, and eight months in patients after initial therapy. Complications appeared in 53.85%. Most frequent were the loss of the nephrostomy catheter in 37.61% and urinary tract infections in 19.6%. CONCLUSION: Improvement of renal function after PCN can be of clinical benefit in patients who might be cured or for prolonged palliative care. Azotemia seems to be poor prognostic sign.

Radiotherapy-induced changes of peripheral blood lymphocyte subpopulations in cervical cancer patients: relationship to clinical response.

PURPOSE: To determine the absolute number and percentage of peripheral blood lymphocyte subpopulations positive (+) cells CD8(+), CD8(+)NKG2D(+), CD8(+), Granzyme B(+) (GrB), CD16(+), CD16(+)NKG2D(+), CD56(+) and CD56(+)NKG2D(+) in cervical cancer patients before and after radiotherapy (RT), and to analyze whether their changes are related to the clinical response. MATERIALS AND METHODS: Stage IIB - IVA cervical cancer patients received external irradiation and concomitant intracavitary brachytherapy. Blood samples for immunophenotypic analysis by flow cytometry were collected from each patient one day before starting RT and one day after completing RT. Fifteen healthy volunteers served as controls. Surface marker expression and granzyme B positivity were quantified on FACSCalibur flow cytometer. RESULTS: Unlike their absolute numbers, the percentages of all analyzed lymphocyte subsets of all patients, including those with complete response (CR), were significantly increased (p <0.05) after RT. Only in patients with progressive disease (PD), CD8(+), CD8(+)NKG2D(+), CD16(+) and CD56(+)NKG2D(+) lymphocytes were not significantly increased. In healthy volunteers, the percentage of CD8(+)GrB(+) lymphocytes was lower than in patients after RT, while the percentages of CD56(+) and CD56(+)NKG2D(+) cells were higher than in patients before RT (p <0.05). CONCLUSION: Our data indicate that RT, besides its direct cytoreductive effect on tumor cells, may contribute to better immunological control of cervical cancer.

Brain metastases as late breast cancer relapse. Single institution experience and review of the literature.

PURPOSE: Approximately 40% of HER2-positive breast cancer patients will develop brain metastases, usually during the first 2-3 years following initial diagnosis and up to 2 years after overt metastatic spread. However, there are no data about brain metastases development as a late disease relapse. In addition, there are no data whether the high incidence of brain metastases is maintained in patients with HER2 overexpression even in late brain metastases. The aim of this paper was to determine the incidence of brain metastases and the HER2 status in patients who developed late relapse, at least 5 years after the initial diagnosis. PATIENTS AND METHODS: Among 384 consecutive breast cancer patients with late relapse, only 8 developed brain metastases. Archival pathological specimens of the primary tumors of those 8 patients were tested by immunohistochemistry (IHC) for HER2 status. RESULTS: The incidence of late brain metastases was 2% (8/384). None of these patients had HER2 3+ primary breast cancer. CONCLUSION: This study shows that the risk for brain metastases in HER2 3+ breast cancer patients is very low or might be even absent as a late relapse. Absence of late brain metastases in HER2 3+ breast cancer might be attributed to specific biological characteristics of HER2 3+ carcinomas to develop brain metastases mostly in the early course of metastatic disease.

Invasive inflammatory pseudotumor of the pelvis: a case report with review of the literature.

Inflammatory pseudotumor (IPT) is a rare benign lesion of unknown etiology, which mimics malignant neoplasm and may arise from various organs. A 53-year-old woman was submitted to diagnostic evaluation because of bilateral, hydroureteronephrosis and oedema of the left leg after a 3-month history of fever of unknown origin. On bimanual vaginal and rectal examination, a mass was involving the uterus, parametria and mostly left adnexa, while the cervix appeared normal. Computed tomographic (CT) scan revealed a 13x10.5 cm mass in the pelvis, mostly at the place of the left adnexa, uterus and both parametria, also involving the surrounding tissues and producing bilateral hydroureteronephrosis. At laparotomy, a grey solid mass was seen, mainly involving the reproductive system. As no radical operation could be performed, the mass was only biopsied and histology showed an inflammatory pseudotumor. Antibiotic therapy was given for one month. Follow-up CT 4 and 8 months after laparotomy showed local regression of IPT. The last follow-up CT, 20 months after laparotomy, revealed no evidence of tumor.

Learning curve for Doppler assessment of ductus venosus flow at 11 + 0 to 13 + 6 weeks' gestation.

OBJECTIVE: To determine the number of scans necessary for training sonographers to examine accurately the ductus venosus at 11 + 0 to 13 + 6 weeks' gestation. METHODS: Ten sonographers with prior extensive experience in the measurement of nuchal translucency thickness were given practical training in the accurate assessment of the ductus venosus. They were then asked to examine the ductus venosus during the routine 11 + 0 to 13 + 6 weeks' scan. Each scan was assessed by an experienced sonographer and classified as being successful or unsuccessful (failure to obtain a waveform, poor quality image with contamination or wrong classification of the A-wave). Each sonographer performed a total of 300 examinations, the data were analyzed in 15 groups of 20 examinations and in each group the percentage of unsuccessful examinations was calculated. RESULTS: In the total 3000 cases examined by the 10 sonographers there were 2849 (95.0%) successful examinations and 151 unsuccessful, including 104 failures to obtain a waveform, 30 cases where the quality of the image was considered to be inadequate and 17 cases in which the classification of the A-wave was wrong. The overall frequency of unsuccessful examinations decreased significantly with the number of scans carried out (r = 0.982, P < 0.0001). The sonographers required an average of 80 examinations before they could successfully examine the ductus in at least 19 of a group of 20 scans. Although one of the 10 trainees achieved this standard within the first block of 20 scans some of the sonographers required training in 100 cases. CONCLUSION: Competence in Doppler assessment of the ductus venosus is achieved only after extensive supervised training.

Accelerated onset of viral transcription in adenovirus-infected HeLa cells treated with the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate.

When adenovirus type 5-infected HeLa cells were exposed to the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate, short pulse-labeling with [3H]uridine in vivo and [3H]UTP incorporation by isolated nuclei in vitro were both consistent with a decreased latent period before initiation by RNA polymerase at early viral promoters. Acceleration was not dependent upon concurrent protein synthesis and could not be attributed to rapid entry of virus into the cell nucleus. 12-O-tetradecanoyl-phorbol-13-acetate suppressed the transcription-delay phenotype of the E1a mutant, hr1, without restoring its ability to replicate.

Polyhydramnios and arterio-arterial placental anastomoses may beneficially affect monochorionic twin pregnancies.

Our objective was to appraise whether an increased amniotic fluid pressure by polyhydramnios can beneficially affect monochorionic twins that are haemodynamically connected by arterio-venous plus arterio-arterial placental anastomoses. We assessed the effects of polyhydramnios in monochorionic twin placentas, combining (a) data from previous in vitro placental perfusion experiments in singleton term placentas under simulated normal and increased amniotic fluid pressures with (b) logical deduction from observations made in monochorionic twins. Our hypothesis is that in monochorionic placentas, an increased amniotic fluid pressure increases the placental microvascular resistance but not the resistance of placental chorionic plate arteries. Hence, an increased amniotic fluid pressure increases the microvascular resistance of the joint cotyledon, the arterio-venous resistance, but not the arterioarterial resistance. This proposed mechanism reduces arterio-venous but not oppositely directed arterio-arterial transfusion. Therefore, reversal of the normal direction of net foeto-foetal transfusion may develop, which will reduce the circulatory imbalance that evolved between the monochorionic foetal twins. In contrast, in monochorionic twins connected by unidirectional or bidirectional arterio-venous anastomoses reversal of the normal direction of net foeto-foetal transfusion will not occur. In conclusion, reversal of the normal direction of net foeto-foetal transfusion, induced by polyhydramnios, is protective against the onset and severity of twin-twin transfusion syndrome in monochorionic twins connected by arterio-venous plus arterio-arterial anastomoses, but not by unidirectional or bidirectional arterio-venous anastomoses.

Diuretic activity of Maydis stigma extract in rats.

Maydis stigma (corn silk) is a herbal drug reputed for the treatment of urinary ailments in various traditional medicine systems. To determine its influence on urinary volume and the excretion of sodium, potassium and chloride, 5% and 10% decoctions were administered daily to adult male Wistar rats for eight days. The concentration of electrolytes and urea in plasma, the influence of treatment on urinary pH value as well as creatinine clearance were also investigated. Daily oral administration of 5% decoction at the dose of 10 ml/kg led to a significant and acute diuresis in rats, reaching the peak value in the first 24 h of treatment. Over a similar period, application of 10% decoction did not affect urinary excretion of water, but significantly increased the pH value of excreted urine. A significant decrease in sodium and chloride plasma levels was observed in both treated groups. The creatinine clearance was markedly increased after the treatment with both extracts. Our findings indicate that the diuretic effect of 5% aqueous Maydis stigma extract is in accordance with the increase in glomerular filtration rate and inhibition of sodium and chloride tubular reabsorption, caused a by still unidentified intrinsic factor, but not the salt-loading effect.

[Principles of lymph node surgery in differentiated thyroid carcinoma]. / Principi hirurgije limfnih nodusa kod diferentovanog tiroidnog karcinoma.

Surgery is the initial therapy in differentiated thyroid carcinoma (DTC). The surgery is performed on organ of tumor origin and regional lymphatic basins. The aim of surgery in DTC is to eradicate all tumor foci, cure the most number of patients, reduce recurrence and mortality rate, and provide good quality of life. There is no doubt between oncologists that the surgery for thyroid carcinoma has no alternative. The extent of surgery is matter of actual controversies. It should be performed by well trained surgeons. Dissection of central and biopsy of supraclavicular and lower third of jugulo-carotid chain of neck lymph nodes is the integral part of surgery in DTC, together with total thyroidectomy. If lymph node metastases are found in jugulo-carotid chain, modified radical neck dissection, unilateral or bilateral is indicated. Dissection of mediastinal lymph nodes should be performed too in cases of involvement. The extent of primary surgery should be dictated by stage of disease and prognostic factors. The quality of surgery and incidence of complications depends prognostic factors, as well as on surgeon's skill and experience. That is why the surgeon is factor of prognosis in treatment of patients with DTC.

[Identification of sentinel lymph nodes in thyroid carcinoma]. / Provera strazarskih limfnih nodusa kod tiroidnog karcinoma.

Sentinel lymph node (SLN) was defined as the first lymph node that the tumor would drain to, within that tumors regional lymphatic basin. In 1998, Kelemen and coworkers have published the first results on SLN lymphonodectomy in thyroid carcinomas. Different methods have been used in a goal of lymphatic mapping (application of vital blue dye and/or radiocolloid). In a period from 2001 to 2003 we have performed SLN biopsy in 64 patients with thyroid tumors. There were 12 cases of thyroid carcinoma. SLN identification rate was 73.44%. We found no false positive or negative results on definitive histopathology. The impact of lymph node metastases in differentiated thyroid carcinoma is still controversial. The management of cervical lymph nodes varies from berry picking to modified radical neck dissection. There is a significant disproportion in percentage of pre and intraoperatively enlarged lymph nodes (27-45%) and histologically confirmed lymph node metastases (80-90%) in papillary thyroid carcinoma. In the current literature the average rate of SLN identification is 91% (66-100%) and when identified, the SLN accurately predicts the disease status of the neck in most patients (80-100%). The SLN biopsy for thyroid carcinoma is good and feasible technique for estimating the cervical lymph node status.