Size-dependent growth of polymorphs in nanopores and Ostwald's step rule of stages.

More than 100 years after Ostwald postulated his step rule of stages, predictive understanding as to early crystallization stages of polymorphic materials is still premature. We studied crystallization of the polymorphic pharmaceutical acetaminophen in nanoporous glasses as a model for early stages of bulk crystallization since the surface energy significantly contributes to the total Gibbs free energy of nanosized crystals in both cases. Systematic studies of transitions between different polymorphs inside nanoporous glasses show that the thermodynamic stability of the polymorphs depends on the crystal size. Accordingly, the transient occurrence of different polymorphs during crystal growth in bulk systems can be related to surface energy contributions to the total Gibbs free energy of the developing crystals. In nanosized early-stage crystals with high surface-to-volume ratios other polymorphs may be stable than in large crystals with low surface-to-volume ratios. Improved control of the crystallization of polymorphic materials by imposing well-defined confinement is a promising strategy to tailor release of polymorphic drugs and to optimize optical, electronic, magnetic and ferroelectric properties of polymorphic materials.

Radical vaginal trachelectomy vs. radical hysterectomy for small early stage cervical cancer: a matched case-control study.

OBJECTIVE: To determine the efficacy and outcome from radical vaginal trachelectomy (RVT) compared to a matched group of patients undergoing radical hysterectomy for small early stage cervical cancer. METHODS: All patient data were entered prospectively. Patients wishing preservation of fertility with cervical cancer, tumor <2 cm, and not meeting the definition of microinvasive cancer were offered RVT. The outcomes were compared to a matched group of patients who underwent radical hysterectomy for stage IA/IB cervical cancer. Groups were matched 1:1 for age (+/-5 years), tumor size (+/-1 mm), histology, grade, depth of invasion (+/-1 mm), presence of capillary lymphatic space invasion, pelvic lymph node metastasis, and adjuvant radiotherapy. RESULTS: A total of 137 patients underwent RVT between 1994 and 2007. Of them, 90 patients were successfully matched. Median tumor size was microscopic. Moreover, 43% and 49% were squamous and had adeno/adenosquamous histology. Median depth of invasion was 3.1 mm. Capillary lymphatic space invasion was present in 68% of cases. Of the tumors, 60% were grade 1, 29% were grade 2, and 11% were grade 3. After a median follow-up of 51 and 58 months, 5 and 1 recurrences were diagnosed in the RVT and radical hysterectomy groups, respectively. Five-year recurrence-free survival rates were present in 95% and 100% of the groups, respectively (p=0.17). In addition, 3 and 1 deaths occurred in the RVT and radical hysterectomy groups, resulting in 5-year survival rates of 99% and 100%, respectively (p=0.55). CONCLUSIONS: RVT seems to be the procedure of choice for women with small early stage cervical cancers wishing to preserve fertility.

Pharmaceutical nanocrystals confined in porous host systems--interfacial effects and amorphous interphases.

DSC and NMR results prove the existence of an amorphous acetaminophen nanolayer between acetaminophen nanocrystals (form I and form III) and pore walls in controlled porous glasses. This nanolayer controls the surface energy. This finding is highly relevant for approaches towards crystal engineering in nanopores and indicates similarities to the situation during the early stages of crystallization in polymorphic bulk samples.

[Perinatal group B streptococcal disease: a review and revised guidelines for prevention].

Group B Streptococcus (GBS) is a common inhabitant of the maternal genital and gastrointestinal tracts, and colonizes approximately 20% of pregnant women. About 50% of infants born to colonized women will become colonized at birth. Early onset GBS disease affects 5/1000 newborns, and is related to a 5-16% mortality rate and severe morbidity. Selective intra-partum chemoprophylaxis can prevent most cases of GBS early-onset disease. In 1996, the federal Centers for Disease Control and Prevention (CDC), the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP) recommended either a culture-based or risk-based approach for prevention of early onset GBS disease. Understanding the epidemiology of the disease and comparing efficacy of the two prevention strategies may elucidate the dispute surrounding this issue. Accordingly, new recommendations from the CDC and the ACOG were published, and their implementation in Israel should now be considered.

[Aromatase inhibitors--new applications in gynecology].

P-450 aromatase inhibitors, designed for suppressing estradiol production, were first approved for the treatment of advanced breast cancer. Recent studies have provided evidence that aromatase inhibitors may be effective in the short term for induction of ovulation and in the long-term for treatment of endometriosis. Based on current data, the role of aromatase inhibitors in the management of various gynecological conditions may soon be widely determined.

Detection of Surface-Immobilized Components and Their Role in Viscoelastic Reinforcement of Rubber-Silica Nanocomposites.

Immobilized polymer fractions have been claimed to be of pivotal importance for the large mechanical reinforcement observed in nanoparticle-filled elastomers but remained elusive in actual application-relevant materials. We here isolate the additive filler network contribution to the storage modulus of industrial styrene-butadiene rubber (SBR) nanocomposites filled with silica at different frequencies and temperatures and demonstrate that it is viscoelastic in nature. We further quantify the amount of immobilized polymer using solid-state NMR and establish a correlation with the mechanical reinforcement, identifying a direct, strongly nonlinear dependence on the immobilized polymer fraction. The observation of a temperature-independent filler percolation threshold suggests that immobilized polymer fractions may not necessarily form contiguous layers around the filler particles but could only reside in highly confined regions between closely packed filler particles, where they dominate the bending modulus of aggregated particles.

Bowel obstruction in recurrent gynecologic malignancies: defining who will benefit from surgical intervention.

AIM: To define factors that could help select, in a cohort of gynecologic cancer patients with malignant gastro-intestinal obstruction, those most likely to benefit from palliative surgery. METHODS: In this retrospective study of patients with malignant gastro-intestinal obstruction who underwent palliative surgery in our institute over 7 years, outcome measures were oral intake, chemotherapy, and 30-day, 60-day and overall survival. Based on Cox proportional-hazards regression models and Kaplan-Meier curves with log-rank tests, a prognostic score was developed to identify those most likely to benefit from surgery. RESULTS: Sixty-eight palliative surgeries were performed in 62 patients with ovarian (69.1%), primary-peritoneal (8.8%), cervical (11.8%) or uterine (10.3%) malignancies. Procedures were colostomy (26.5%), ileostomy (39.7%), colonic stent (1.5%), gastrostomy (7.3%), gastroenterostomy (5.9%) and bypass/resection and anastomosis (19.1%). Eighteen patients died prior to discharge, within 3-81 days (median 25 days). The 30-day and 60-day mortality rates were 14.7% and 29.4%, respectively. Postoperative oral-intake and chemotherapy rates were 65% and 53%, respectively, with albumin level identified on multivariate analysis as the only significant predictor of both. Median postoperative survival was 106 days (3-1342). Bypass/resection and anastomosis was associated with improved survival. Ascites below 2 L, younger age, ovarian primary tumor, and higher blood albumin correlated with longer postoperative survival. A prognostic index based on these factors was found to identify patients with increased 30-day and 60-day mortality. CONCLUSIONS: Our proposed prognostic index, based on age, primary tumor, albumin and ascites, might help select those gynecological cancer patients most likely to benefit from palliative surgery.

Manipulating the crystalline state of pharmaceuticals by nanoconfinement.

We show that nanoconfinement is a handle to rationally produce and stabilize otherwise metastable or transient polymorphs of pharmaceuticals, as required for controllable and efficient drug delivery. The systematic investigation of crystallization under confinement unveils thermodynamic properties of metastable polymorphs not accessible otherwise and may enhance the understanding of the crystallization behavior of pharmaceuticals in general. As an example in this case, we studied acetaminophen confined to inexpensive and biocompatible nanoporous host systems. Calorimetric and X-ray scattering data clearly evidence that either the stable polymorph form I or the metastable polymorph form III can be stabilized in high yields. Thermodynamic parameters for form III of acetaminophen are reported, and strategies to manipulate the crystalline state in pores by thermal treatments are presented.

Sentinel lymph nodes in early stage cervical cancer.

OBJECTIVES: Lymph node status is the most important prognostic factor in cervical cancer. Sentinel lymph node (SLN) procedures have been purported to reduce peri- and postoperative morbidity and operative time. METHODS: All patients with surgically managed clinical FIGO stage IA/B1 cervical cancer underwent SLN followed by pelvic lymphadenectomy with technetium+/-lymphazurin from April 2004 to April 2006. 0.1-0.2 mci of filtered sulfur colloid technetium was injected submucosally into 4 quadrants of the exocervix. Lymphazurin (4cc) was only used if technetium was unsuccessful in identifying bilateral sentinel lymph nodes. Serial microsections at 5 microm intervals were performed and stained intraoperatively. Complete pelvic node dissections were performed in all patients. RESULTS: Forty-two patients underwent SLN, prior to full pelvic lymphadenectomy. Thirty-nine patients were included for the purposes of this study. The incidence in detecting at least one sentinel node was 98% per patient, and 85% per side. Identification of bilateral sentinel lymph nodes was successful in 28 cases (72%). The median number of SLN/side was 2. Three patients were found to have metastatic tumor to lymph nodes. No false negatives were identified. No adverse effects were noted. CONCLUSIONS: SLN biopsy in cervical cancer is feasible to do, with a low false negative rate. We believe SLN should be evaluated per side and not per patient, that a pelvic lymphadenectomy is otherwise required. By following this protocol, the false negative rate can be minimized. The combined reported FN rate in the literature is 1.8%. If our definition is applied, the majority of reported false negative SLN is not actual false negatives.

Ras antagonist inhibits growth and chemosensitizes human epithelial ovarian cancer cells.

The objective of this article was to determine whether human ovarian carcinoma cells (OVCAR-3) express significant amounts of Ras oncogene and active Ras-guanosine triphosphate (GTP) and, if so, whether the Ras inhibitor farnesyl thiosalicylic acid (FTS) inhibits their growth and chemosensitizes them to cisplatin. We assayed Ras and Ras-GTP in OVCAR-3 cells before and after FTS treatment. The effect of FTS on OVCAR-3 cell growth was assessed in terms of cell number. Because the OVCAR-3 cell line was derived from a patient who was refractory to cisplatin, we examined whether FTS enables cisplatin to induce death of these cells. Significant amounts of Ras and active Ras-GTP were expressed by OVCAR-3 cells and were reduced by 40% by FTS. FTS inhibited OVCAR-3 cell growth in a dose-dependent manner. When combined with cisplatin, FTS reduced the number of OVCAR-3 cells by 80%, demonstrating synergism between FTS and cisplatin. FTS, at a concentration range that allows downregulation of Ras and Ras-GTP in OVCAR-3 cells, also chemosensitizes these cells and inhibits their growth. These results suggest that ovarian carcinomas might respond well to Ras inhibition, both alone and when combined with cisplatin. The combined treatment would allow the use of smaller doses of chemotherapy, resulting in decreased cytotoxicity.

Infertility treatment after conservative management of borderline ovarian tumors.

BACKGROUND: Young patients with ovarian tumors of low malignant potential usually undergo conservative surgery because of the excellent prognosis of these tumors. Patients wishing to conceive after diagnosis occasionally require ovulation induction, but data regarding the safety of assisted reproductive technologies in this situation remains anecdotal. The current study analyzes the outcome of a group of patients who received infertility treatment after the conservative management of borderline ovarian tumors. METHODS: The clinical and pathologic records of 104 patients with a borderline tumor of the ovary who were treated and followed over a 20-year period (1979--1999) were reviewed. Forty-three patients who underwent conservative management were the subjects of the current study. RESULTS: Follow-up was available for 95% of the patients, giving a total of 270 women-years of follow-up. Nine of the 43 patients developed a local recurrence, 8 of which occurred in patients with serous tumors. Five of these 9 patients underwent cystectomy only at the time of recurrence, and all were without evidence of disease at a mean follow-up of 75 months (range, 25--93 months). Nineteen patients delivered a total of 25 healthy children after diagnosis of a borderline ovarian tumor; 7 of these patients were treated with in vitro fertilization (IVF) after diagnosis. Four of these patients developed a recurrence, two patients before the IVF treatment and two patients after the IVF treatment. The latter two patients were without evidence of disease at the time of last follow-up (15 months and 26 months, respectively, after the recurrence). CONCLUSIONS: The results of the current study suggest that ovulation induction may be considered after the diagnosis of a borderline ovarian tumor. Recurrences were observed in two of seven patients, all of which remained histologically borderline.

Outcome of twin pregnancies with extreme weight discordancy.

The objective of this paper is to examine the outcome of pregnancies with extreme weight-discordant twins. Percentage of birth weight discordancy was defined as the birth weight difference between the twins divided by the larger twin's weight and multiplied by 100. Discordancy was calculated for all twin births in which both fetuses were live born. In 33 pairs, the discordancy was defined as extreme (>35%) and they constituted the study group. Thirty-three pairs of twin defined with mild weight discordancy (15-25%), and 33 pairs defined as concordant to birth weight (<15% difference) were matched to the study group patients based on gestational age at delivery (+/- 7 days) and on the mode of delivery, and constituted the control groups. The records of all the patients were reviewed for pregnancy complications and for major and minor neonatal outcome variables. Significantly more parturients in the study groups were primiparous undergoing in vitro fertilization treatments to conceive. Significantly more women in the study group had severe preeclampsia compared with women with mild discordancy or concordant twins (12.1 vs. 3.0% and 0%, respectively, p <0.025). No significant differences were encountered between the groups in neonatal mortality or morbidity factors except an increased rate of hyperbilirubinemia in the study group, p = 0.006. Using logistic regression analysis, discordancy was not defined as an efficient predictor for adverse neonatal outcome. Twin pregnancies with extreme discordancy have a favorable neonatal outcome in correlation with gestational age and not with the percentage of discordancy.

Neonatal outcome in growth-restricted versus appropriately grown preterm infants.

The objective of this paper is to examine whether growth-restricted preterm infants have a different neonatal outcome than appropriately grown preterm infants. All consecutive, singleton preterm deliveries between 27-35 weeks' gestation were included over a 4-year period. Infants with congenital anomalies and infants of diabetic mothers were excluded. Infants were categorized as small-for-gestational-age (SGA) when birth weight was at or below the 10th percentile, and appropriate-for-gestational-age (AGA) when between the 11th and 90th percentiles. Outcome variables included: neonatal death, respiratory distress syndrome (RDS), sepsis, intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC). Neonatal morbidity and mortality were examined by univariate and stepwise multivariate logistic regression analyses. Factors controlled for during the analysis included: maternal age; gestational age; mode of delivery; presence of preeclampsia, HELLP syndrome, prolonged premature rupture of membranes (PROM), placental abruption, placenta previa, prenatal steroid exposure, infant gender, and low Apgar score. Seventy-six infants were included in the SGA group and 209 in the AGA group. SGA infants had a higher mortality rate (p = 0.003). They also had more culture-proven sepsis episodes (p = 0.001). No differences were found with respect to the other outcomes. The results were similar when analyzed separately for the group of infants born at or below 32 weeks' gestation. Growth-restricted preterm infants were found to have both higher mortality and infection rates compared with AGA preterm infants. Growth restriction in the preterm neonate was not found to protect against other neonatal outcomes associated with prematurity. When considering elective preterm delivery for this high-risk group of pregnancies, the increased risks in the neonatal period should be taken into account.