Reproductive Outcomes of Hysteroscopic Septoplasty Techniques

Background and Objectives:

Since little is known regarding the correlation between different techniques used during hysteroscopic septoplasty and reproductives outcomes, we amied to evaluate the results of two different techniques of hysteroscopic septoplasty (HS).

Methods:

Data were retrospectively reviewed on 49 patients who underwent HS for symptomatic septate uterus from January 1, 2010, through April 30, 2014. The patients were divided into 2 groups based on the HS technique used. Group I consisted of 27 patients who underwent HS by monopolar hook cautery with the operating hysteroscope. Group II consisted of 22 patients who had the procedure performed with scissors and guided by an office hysteroscope. All the procedures in the both groups were performed in the operating room under general anesthesia. Pregnancy outcomes within the first year after HS for both groups were evaluated.

Results:

Reproductive outcomes were obtained from 44 patients who attempted to conceive after HS within the first year. In the 25 patients in group I, 23 had pregnancies, of which 15 (65.2%) continued to term, 3 (13%) ended in a preterm live birth, and 5 (21.7%) ended in loss of pregnancy (abortion). In the 19 patients in group II, there were 17 pregnancies, of which 11 (64.7%) continued to term, 2 (11.7%) ended in a preterm live birth, and 4 (23.5%) ended in first- or second-trimester abortion. The overall live-birth rate was 78.2% in group I and 76.4% in group II (P = .85).

Conclusions:

Our data show that the rates of pregnancy that reach term and overall rates of live births are similar between the 2 HS techniques. Additional studies are needed to evaluate the impact of the techniques on reproductive outcomes.     

The Impact of Membrane Permeability and Dialysate Purity on Cardiovascular Outcomes

The effects of high-flux dialysis and ultrapure dialysate on survival of hemodialysis patients are incompletely understood. We conducted a randomized controlled trial to investigate the effects of both membrane permeability and dialysate purity on cardiovascular outcomes. We randomly assigned 704 patients on three times per week hemodialysis to either high- or low-flux dialyzers and either ultrapure or standard dialysate using a two-by-two factorial design. The primary outcome was a composite of fatal and nonfatal cardiovascular events during a minimum 3 years follow-up. We did not detect statistically significant differences in the primary outcome between high- and low-flux (HR=0.73, 95% CI=0.49 to 1.08, P=0.12) and between ultrapure and standard dialysate (HR=0.90, 95% CI=0.61 to 1.32, P=0.60). Posthoc analyses suggested that cardiovascular event-free survival was significantly better in the high-flux group compared with the low-flux group for the subgroup with arteriovenous fistulas, which constituted 82% of the study population (adjusted HR=0.61, 95% CI=0.38 to 0.97, P=0.03). Furthermore, high-flux dialysis associated with a lower risk for cardiovascular events among diabetic subjects (adjusted HR=0.49, 95% CI=0.25 to 0.94, P=0.03), and ultrapure dialysate associated with a lower risk for cardiovascular events among subjects with more than 3 years of dialysis (adjusted HR=0.55, 95% CI=0.31 to 0.97, P=0.04). In conclusion, this trial did not detect a difference in cardiovascular event-free survival between flux and dialysate groups. Posthoc analyses suggest that high-flux hemodialysis may benefit patients with an arteriovenous fistula and patients with diabetes and that ultrapure dialysate may benefit patients with longer dialysis vintage.Cardiovascular mortality is substantially higher in patients undergoing maintenance hemodialysis (HD) compared with the nonuremic population.¹ Several risk factors unique to uremia are implicated in the high rates of cardiovascular disease (CVD) and mortality in these patients (for example, accumulation of medium-sized or large middle molecules and predominance of a chronic inflammatory state).² Consequently, use of high-flux synthetic membranes, providing enhanced removal of higher-molecular weight uremic toxins coupled with better biocompatibility, together with ultrapure dialysis fluid might be expected to improve patient outcomes.Because of proven clinical benefits and a possible survival advantage reported by several observational studies,^3–5 high-flux HD is increasingly the most common dialysis treatment modality.⁶ Although the Hemodialysis (HEMO) Study was not able to confirm superiority of high- over low-flux HD,⁷ a survival benefit was reported in long-term HD patients in a posthoc analysis of the study, where high-flux dialyzers showed reduced cardiovascular mortality.^8–11 In the multicenter European Membrane Permeability Outcome (MPO) Study, subgroup analyses showed better survival rates with high-flux HD in patients with hypoalbuminemia and patients with diabetes.¹²Ultrapure dialysis fluid has also been associated with less inflammation, resulting in clinically relevant improvements, including amelioration of erythropoietin response,¹³ better nutritional status,^14,15 and reduction in the incidence of β₂-microglobulin amyloidosis.¹⁶ Although preliminary reports suggested lower cardiovascular morbidity with the use of ultrapure dialysis fluid,¹⁷ no randomized and controlled trial has been performed addressing hard clinical outcomes.This randomized controlled trial was designed to determine whether membrane permeability and dialysate purity affect the incidence of fatal and nonfatal cardiovascular events and overall survival in prevalent maintenance HD patients.     

Diffusion-weighted magnetic resonance imaging in evaluation of primary solid and cystic renal masses using the Bosniak classification

Purpose

Our purpose was to determine whether quantitative diffusion-weighted MR imaging (DWI) could be used in discrimination of benign and malignant primary solid and cystic renal tumors.

Materials and methods

A total of 105 consecutive patients with renal masses and 30 healthy controls were enrolled in this prospective study. Dynamic contrast enhanced routin renal images and DWI (with b factors of 0, 500 and 1000 s/mm²) was performed at 1.5 T unit. Renal masses were divided into two groups as cystic or solid and all cystic lesions were prospectively assigned to a Bosniak classification number. The median apparent diffusion coefficient (ADC) values along with b 500 and 1000 signal intensities of normal kidneys, solid components of mixed renal masses and total of cystic lesions were calculated.

Results

The mean ADC value of normal renal parenchyma in control group was 2.18 ± 0.13 × 10⁻³ mm²/s. Solid renal tumors had significant lower ADC values (median: 1.16 ± 0.27 × 10⁻³ mm²/s), in contrast to cystic tumors (median: 2.73 ± 0.44 × 10⁻³ mm²/s). The mean ADC value of the Bosniak Category I cysts was significantly higher (3.09 ± 0.14 × 10⁻³ mm²/s) than normal renal parenchyma (p < 0.01). A statistical significance was achieved between the signal intensity of Bosniak Category I and Category II–III cysts with b 1000 (p < 0.05). Among the different histologic subtypes of renal cell carcinoma, the mean ADC value of chromophobe cell carcinoma (1.41 ± 0.09 × 10⁻³ mm²/s) was significantly higher than that of papillary cell carcinoma (0.90 ± 0.16 × 10⁻³ mm²/s) and clear cell carcinoma (1.23 ± 0.13 × 10⁻³ mm²/s).

Conclusion

Accurate assessment of renal masses is important for establishing whether tumors require surgical intervention or not. While MRI is a useful modality as an investigative tool for diagnosing, characterizing and staging renal masses, DWI contributes additional value by promising differentiation benign from malignant renal tumors, even histologically subtyping of renal cell cancer.     

Psychodramatic group psychotherapy as a parental intervention in attention deficit hyperactivity disorder: A preliminary study

It is already known that clinical attention deficit hyperactivity disorder (ADHD) is affected by some negative parenting variables. The aim of this study was to investigate the effects of psychodramatic group psychotherapy (PGP) on parenting variables. The study group included seven mothers whose children had been diagnosed with ADHD and were attending a special education and rehabilitation center. Twelve PGP sessions, one per week, were conducted with these mothers. Participants’ statements were recorded at each session, and these statements were evaluated to indicate basic parental variables, namely: parental psychopathology, negative parental cognitions, negative parental attitudes, family functionality–marital conflict, and parental stress. The statistical study revealed that statements indicating parental psychopathology and negative parental attitudes showed a statistically significant negative correlation with time. Qualitative data indicate mothers stigmatization, self-stigmatization and harsh punishment toward the children. Parental psychopathology and negative parental attitudes are two parental factors that are known to have a negative impact on the clinical status of ADHD, and PGP might be effective in improving these two factors.     

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a “DFG-out” covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.Receptor tyrosine kinases (RTKs) serve as critical sensors of extracellular cues that activate a myriad of intracellular signaling pathways to regulate cell state. There are 58 receptor tyrosine kinases in the human genome, and many have been demonstrated to be constitutively activated through amplification or mutation in particular cancers. The signals emanating from these RTKs, such as epidermal growth factor receptor (EGFR), FGF receptor (FGFR), platelet-derived growth factor receptor (PDGFR), protein kinase Kit (KIT), and protein kinase c-Met (MET), have been pharmacologically proven to be essential to the survival of cancers expressing mutant forms of these proteins. However, rapid resistance to monotherapy with first-generation RTK inhibitors has been universally observed. Resistance typically arises from the emergence of cancer cells expressing mutant forms of RTKs that are impervious to the action of first-generation drugs or from the activation of by-pass signaling mechanisms. Resistance can be overcome by developing new inhibitors that target the mutant RTK directly or target bypass signaling mechanisms. Indeed this approach has been deployed successfully in the case of resistance to first-generation inhibitors of EGFR in nonsmall cell lung cancer (NSCLC) and of Abelson tyrosine-protein kinase (ABL) in chronic myelogenous leukemia (CML) (1–4).Human FGFRs are a family of four RTKs (FGFR1–4) which are sensors of a diverse family of 18 FGF ligands. FGFRs are key regulators of fibrogenesis, embryogenesis, angiogenesis, metabolism, and many other processes of proliferation and differentiation (5, 6). The fundamental importance of FGFR to development is well proven by gain-of-function mutations that result in dwarfism in model organisms and in humans (7–10). Deregulation of FGFR signaling through mutation, chromosomal translocation, and gene amplification or overexpression has been documented abundantly in numerous cancers (11). Activation of FGFR-dependent signaling pathways can stimulate tumor initiation, progression, and resistance to therapy. Translocation events implicating the FGFR1 gene and various fusions of FGFR1 are found in myeloproliferative syndromes (12); chromosomal translocations of FGFR1 or FGFR3 and the transforming acidic coiled-coil genes (TACC1 or TACC3) are oncogenic in glioblastoma multiforme, bladder cancer, head and neck cancer, and lung cancer (13–16); oncogenic mutations of FGFR2 and FGFR3 are observed in lung squamous cell carcinoma; FGFR2 N549K is observed in 25% of endometrial cancers; FGFR3 t(4;14) alterations are reported in 15–20% of multiple myeloma (17–19); FGFR4 Y367C mutation in the transmembrane domain drives constitutive activation and enhanced tumorigenic phenotypes in a breast carcinoma cell line (20–22); and K535 and E550 mutants are reported to activate FGFR4 in rhabdomyosarcoma (23). FGFR amplification is reported in various cancers (24, 25): FGFR1 is amplified in colorectal, lung, and renal cell cancers (26, 27); FGFR2 is amplified in gastric cancer and colorectal cancer (28, 29); FGFR3 is commonly amplified in bladder cancer and also is reported for cervical, oral, and hematological cancers (30–32); and FGFR4 is amplified in hepatocellular carcinoma, gastric cancer, pancreatic cancer, and ovarian cancer (33–37). FGFR also is involved in autocrine activation of STAT3 as a positive feedback in many drug-treated cancer cells which are driven by diverse oncogenes such as EGFR, ALK, MET, and KRAS (38).Currently known inhibitors of kinases can target a variety of conformational states and binding pockets and can be either reversible or covalent. Several potent and selective ATP-competitive, small-molecule FGFR inhibitors have been reported, with BGJ398 and AZD4547 being the clinically most advanced compounds (Fig. 1A) (39–42). We previously reported the first (to our knowledge) covalent FGFR irreversible inhibitor (FIIN-1), which targets a cysteine residue conserved in all four FGFR kinases and which inhibits the proliferation of Ba/F3 cells engineered to be dependent on FGFR1, FGFR2, or FGFR3 with EC₅₀s in the 10-nM range, a potency comparable to that exhibited by BGJ398 and AZD4547 (43). All FGFR kinases have a valine at the gatekeeper position, in contrast to ABL, EGFR, KIT, and PDGFR, which all possess a threonine gatekeeper in which resistance can be conferred by mutation of the threonine to a larger hydrophobic valine, isoleucine, or methionine residue in response to first-generation inhibitors of these kinases (44–46). The FGFR V561M mutation was reported to induce strong resistance to PD173074 and FIIN-1 (43, 47); later the gatekeeper mutant FGFR3 V555M emerged as a mechanism of resistance to AZ8010 in KMS-11 myeloma cells and also was demonstrated to confer resistance to other FGFR inhibitors, including PD173074 and AZD4547 (48). The FGFR2 V564I gatekeeper mutant was isolated as a resistant clone in a FGFR2 Ba/F3 screen of dovitinib and also was reported to confer resistance to the multitargeted drug ponatinib (19). In humans the FGFR4 V550L gatekeeper mutation was detected in 9% (4/43) of embryonal rhabdomyosarcoma tumors (49), and the FGFR4 V550M mutation was detected in 13% (2/15) of neuroendocrine breast carcinomas (50). To overcome gatekeeper mutations found in primary FGFR-driven cancers and those that likely will arise in FGFR inhibitor-treated tumors in the future, we developed next-generation covalent FGFR inhibitors. Here we describe the identification and characterization of the covalent FGFR inhibitors FIIN-2 and FIIN-3, which to our knowledge are the first FGFR inhibitors that are capable of potently inhibiting the gatekeeper mutants of FGFRs. We also demonstrate that FIIN-3 is capable of covalently inhibiting both FGFR and EGFR by using distinct binding modes to target different cysteine residues.Open in a separate windowFig. 1.(A) Chemical structures of clinical-stage FGFR inhibitors. (B) Evolution of FIIN-2 and FIIN-3 from FIIN-1. Structures of the reversible counterparts FRIN-2 and FRIN-3 are shown also.     

Prognostic value of 18F-FDG PET/CT parameters and histopathologic variables in head and neck cancer

Introduction¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography parameters such as; maximum standardized uptake values, standard metabolic tumor volume and otal lesion glycosis are important prognostic biomarkers in cancers.ObjectiveTo investigate the prognostic value of these parameters in patients with head and neck cancers.MethodsWe performed a retrospective study including 47 patients with head and neck cancer who underwent¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography prior to treatment. Standard metabolic tumor volume, otal lesion glycosis and standardized uptake were measured for each patient. The prognostic value of quantitative ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography parameters and clinicopathologic variables on disease free survival and overall survival were analyzed.ResultsThe median (range) standard metabolic tumor volume and otal lesion glycosis and standardized uptake were 7.63 cm³ (0.6–34.3), 68.9 g (2.58–524.5 g), 13.89 (4.89–33.03 g/mL), respectively. Lymph node metastases and tumour differentiation were significant variables for disease free survival and overall survival, however, all ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography parameters were not associated with disease- free survival and overall survival.ConclusionPretreatment quantities positron emission tomography parameters did not predict survival in head and neck cancer.