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Objective: The choice of treatment modality for optic pathway gliomas (OPGs) is controversial. Chemotherapy is widely regarded as first-line therapy; however, subtotal resections have been reported for decompression or salvage therapy as first- and second-line treatment. The goal of this study was to further investigate the role and efficacy of resection for OPGs., Methods: A retrospective chart review was performed on 83 children who underwent surgical treatment for OPGs between 1986 and 2014. Pathology was reviewed by a neuropathologist. Clinical outcomes, including progression-free survival (PFS), overall survival (OS), and complications, were analyzed., Results: The 5- and 10-year PFS rates were 55% and 46%, respectively. The 5- and 10-year OS rates were 87% and 78%, respectively. The median extent of resection was 80% (range 30%-98%). Age less than 2 years at surgery and pilomyxoid features of the tumor were found to be associated with significantly lower 5-year OS. No difference was seen in PFS or OS of children treated with surgery as a first-line treatment compared with children with surgery as a second- or third-line treatment. Severe complications included new disabling visual deficit in 5%, focal neurological deficit in 8%, and infection in 2%. New hormone deficiency occurred in 22% of the children., Conclusions: Approximately half of all children experience a long-term benefit from resection both as primary treatment and as a second-line therapy after failure of primary treatment. Primary surgery does not appear to have a significant benefit for children younger than 2 years or tumors with pilomyxoid features. Given the risks associated with surgery, an interdisciplinary approach is needed to tailor the treatment plan to the individual characteristics of each child.

Optic gliomas are brain tumors characterized by slow growth, progressive loss of vision, and limited therapeutic options. Optic gliomas contain various amounts of myxoid matrix, which can represent most of the tumor mass. We sought to investigate biological function and protein structure of the myxoid matrix in optic gliomas to identify novel therapeutic targets. We reviewed histological features and clinical imaging properties, analyzed vasculature by immunohistochemistry and electron microscopy, and performed liquid chromatography-mass spectrometry on optic gliomas, which varied in the amount of myxoid matrix. We found that although subtypes of optic gliomas are indistinguishable on imaging, the microvascular network of pilomyxoid astrocytoma, a subtype of optic glioma with abundant myxoid matrix, is characterized by the presence of endothelium-free channels in the myxoid matrix. These tumors show normal perfusion by clinical imaging and lack histological evidence of hemorrhage organization or thrombosis. The myxoid matrix is composed predominantly of the proteoglycan versican and its linking protein, a vertebrate hyaluronan and proteoglycan link protein 1. We propose that pediatric optic gliomas can maintain blood supply without endothelial cells by using invertebrate-like channels, which we termed primitive myxoid vascularization. Enzymatic targeting of the proteoglycan versican/hyaluronan and proteoglycan link protein 1 rich myxoid matrix, which is in direct contact with circulating blood, can provide novel therapeutic avenues for optic gliomas of childhood., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

In a single-institution retrospective cohort study, 230 patients were treated for stage III primary ovarian cancer and 175 became eligible for second-look operations by virtue of a complete clinical response after primary surgical cytoreduction and platinum-based combination chemotherapy. Of these, 109 underwent a second-look operation. Optimal primary cytoreduction was defined as residual disease < or =1 cm. Median follow-up was 68.3 months. Five-year survival for all the 230 stage III ovarian cancers was 43.4%. Among all eligible patients (n = 175), there was no survival difference (P = 0.67) in those having second look (57.3%, 5-year survival) versus no second look (48.7%). In those patients with optimal primary cytoreduction (n = 118), there was no survival advantage to second look (69% versus 61%, P = 0.7). However, in those with suboptimal primary cytoreduction (n = 47), 5-year survival was 36% in those having second look versus only 13% in those refusing second look (P < 0.05). Multivariate analysis identified second-look surgery as the only significant independent prognostic variable affecting survival (RR = 0.321, P < 0.04). Patients with suboptimal debulking at primary surgery for stage III ovarian cancer appear to achieve a survival benefit from second-look surgical procedures, presumably from the early identification and treatment of residual disease.

A case of clear cell ovarian cancer and endometriosis in a postmenopausal patient following adjuvant tamoxifen for breast cancer is presented. Immunohistochemistry demonstrated the tumor to be positive for progesterone receptor protein but not estrogen receptor protein; the endometriosis was positive for both proteins. Literature review reveals this to be the first report of both clear cell ovarian cancer and endometriosis following tamoxifen use, and the third report of epithelial ovarian cancer associated with tamoxifen.

Objective: To evaluate the impact of integration of operative laparoscopy on length of stay (LOS) and complication rates on an academic gynecologic oncology service., Methods: Retrospective analysis of all admissions to our gynecologic oncology service was performed for the academic years 1990/1991 and 1993/1994. Primary endpoints were frequency of complications and LOS., Results: In 1990/1991, there were 785 total admissions, of which 287 were surgical and 3% were approached laparoscopically. In 1993/1994, there were 973 admissions of which 436 were surgical and 23% were approached laparoscopically. Operative laparoscopy was applied equally regardless of age and reproductive status; the utilization of laparoscopy was increased by 14-fold for patients with cancer, 4. 5-fold for patients with benign disease, and 12-fold for patients with adnexal masses. No change in the mean LOS of nonsurgical admissions was noted, yet overall LOS for all patients decreased from 6.3 to 4.8 days (P < 0.0001). Mean LOS in surgical patients decreased from 9.4 to 6.0 days (P < 0.0001). After correction for complications, decreases in LOS only occurred in procedures for which laparoscopy was significantly integrated. No reductions in LOS were noted with like surgical approaches; i.e., there was no change in the LOS of patients undergoing laparotomy in both years. Surgical complications were not increased by laparoscopy., Conclusions: Aggressive utilization of operative laparoscopy, even only for selected patients, into the surgical practice of a gynecologic oncology service demonstrates significant improvements in LOS without adversely affecting surgical complication rates., (Copyright 1998 Academic Press.)

Purpose: To evaluate the efficacy and toxicity of interferon-alpha-2b (IFN-alpha) and cisplatin given concomitantly with radiation therapy (RT) in the treatment of locally advanced cervical carcinoma., Materials and Methods: Twenty-one patients with stage bulky Ib-IIIb (Ib, 2; IIa, 2; IIb, 8; IIIb, 9) cervical carcinoma were treated with combined IFN-alpha (5 million IU) subcutaneously three times per week and cisplatin (25 mg/m2) i.v. infusion over 2 h weekly for 7 weeks, given concomitantly with RT (4500 cGy of external beam plus 2 brachytherapy procedures). Total radiation doses delivered ranged from 7500 to 9960 cGy (median, 9300 cGy). Follow-up ranged from 16 to 33 months (median, 25 months)., Results: The 2-year local control rate was 100%. The only sites of disease recurrence were distant. Freedom from distant metastases, disease-free survival, and overall survival at 2 years was 76%. Late complication rates were high. Grade 4 rectosigmoid, bladder, and small bowel complication rates were 49, 18, and 23% at 2 years. Late toxicity was seen earlier than expected with rectosigmoid complications observed 5 to 11.5 months (median, 8 months) after completion of treatment., Conclusion: Combination IFN-alpha and cisplatin produced a marked effect of enhanced radiosensitization as evidenced by 100% local tumor control and high late normal tissue complication rates. Due to the unacceptable late toxicity, its routine clinical use cannot be recommended. Further investigation is needed to determine whether a therapeutic window exists such that the use of lower doses of IFN-alpha, cisplatin, or RT can increase tumor control with more acceptable normal tissue toxicity.

Objective: This report evaluates the acceptance, results, and predictors of human immunodeficiency virus (HIV) infection in inner city women referred to a colposcopy clinic for abnormal cervical cytology., Methods: HIV testing results of 1,908 inner city women referred for abnormal cervical cytology were analyzed retrospectively with respect to acceptance, race, ethnicity, Pap smear results, sexually transmitted diseases (STDs), HIV exposures, and final histologic findings., Results: HIV testing was accepted by 50.4% of patients. Women who agreed to screening were significantly more likely to admit exposure to HIV or to be Hispanic, foreign-born, or have a history of multiple STDs. Of those screened, 3.3% were found to be HIV seropositive. Although higher grades of referral Pap smears were noted in the women found to be HIV seropositive, final histologic findings were not different. The only predictors of unknown HIV seropositivity were admitted HIV exposure and external condyloma., Conclusions: Fifty percent of inner city women of unknown HIV status referred for abnormal cervical cytology will accept HIV serotesting and 3.3% are found to be positive. Most HIV-seropositive women can be detected based on either a history of exposure to HIV or the presence of external condyloma.

Thirty-nine patients underwent pelvic exenteration for gynecologic malignancies at The Mount Sinai Medical Center between 1975 and 1992. Surgical techniques, morbidity, survival, and other variables for patients so treated in two periods, 1975-1984 and 1985-1992, were compared. The primary cancer included squamous cell carcinoma of the cervix, 27; adenocarcinoma of the cervix, 1; squamous cell carcinoma of the vagina, 4; adenocarcinoma of the endometrium, 4; squamous cell carcinoma of the vulva, 2; and adenocarcinoma of the rectum, 1. Median survival was 23.1 months, with a median follow-up of 18 months. Survival was significantly related to status of the lymph nodes (p 0.0004) and surgical margins (p 0.0038). There were two postoperative mortalities, one due to pulmonary embolus and another to myocardial infarction. The ability in the second period analyzed, 1985-1992, to integrate a continent urinary reservoir and supralevator exenteration without colostomy yet not induce increased morbidity or decreased survival, has not been previously reported.

Cefepime is a potent, broad-spectrum, fourth-generation cephalosporin with enhanced activity against most gram-positive aerobic bacterial pathogens and many gram-negative aerobic bacteria that are resistant to other cephalosporins. The drug's zwitterionic structure contributes to more rapid penetration of gram-negative bacterial cell membranes, and its low affinity for most type I beta-lactamases leads to significantly reduced enzymatic degradation compared with other cephalosporins. Cefepime has a good toxicity profile, with minor gastrointestinal and central nervous system symptoms being most prevalent. At dosages ranging from 1-2 g every 8-12 hours, it is an alternative option for infections of the lower respiratory tract, urinary tract, and skin and skin structures, as well as febrile episodes in neutropenic patients with cancer, and bacteremia or septicemia in critically ill patients.

Total cystectomy at the time of radical pelvic surgery for gynecologic malignancies is not uncommon. Many techniques have been developed for urinary diversion including the continent ileocecal urinary reservoir. Twenty-nine patients underwent construction of a continent ileocecal urinary reservoir during the reconstructive phase of an exenterative procedure or for the relief of urinary tract fistula between 1990 and 1993. All procedures were performed using the mechanical stapling devices using metal staples. The right and proximal transverse colon were mobilized to a length of 24 cm. The ileum was divided 8 cm proximal to the ileocecal valve and plicated using the stapling technique. The colonic segment was opened on its antimesenteric border and the reservoir was created by stapling in a fashion to reapproximate the distal ends to each other. The ureters were stented and implanted without tunneling. A large Malecot drain was placed in all the pouches for irrigation of the colonic mucosa in the postoperative period. The ileal stoma was fixed to the anterior abdominal wall as was the anterior surface of the pouch. Operative time ranged from 50 to 150 min for the pouch construction. All patients underwent retrograde contrast study of the pouch 7-10 days postoperatively to verify lack of anastomatic leaks. After recovery, all patients successfully self-catheterized the pouch three to five times daily without difficulty. Of the 29 patients, 17 (59%) had received prior radiation as part of therapy. All patients remained continent at the end of observation. One developed a fistula to the perineum after intraoperative placement of 125I seeds on the pelvic wall. One patient developed pouch stones; endoscopic evaluation of this pouch revealed no evidence of stones at the staple lines and metabolic workup demonstrated hypocitremia as the etiology for the stones. Mean reservoir volume was 550 ml. Mean follow-up is 15.8 months; 5 have expired due to recurrent disease and 19 (83%) remain alive. Only two patients have been admitted for urosepsis due to reflux pyelonephritis. The stapled continent ileocecal reservoir offers benefits to patients undergoing total cystectomy. Using the mechanical stapling devices decreases the operative time and has not resulted in stone formation or pouch leakage. The complications of the procedure are acceptable.

Both epidermal growth factor receptor (EGFR) and HER-2/neu (neu) have been found to be of prognostic importance in epithelial ovarian and endometrial carcinoma, but alterations in proto-oncogene expression of normal tissues of patients with gynecologic malignancies are unknown. Patients (118) undergoing laparotomy for gynecologic indications (78 ovarian cancer, 11 endometrial cancer, 19 benign gynecologic disease, 10 other cancers) had biopsies of normal peritoneum for quantitative assessment of neu and EGFR concentrations. Patients undergoing exploration for gynecologic malignancy were found to have significantly higher median neu expression in the peritoneal biopsies than patients with benign gynecologic disease (P = 0.002). Most patients in this study were found to have ovarian cancer, and median peritoneal neu expression was found to be significantly higher in patients with ovarian cancer versus benign ovarian masses (P = 0.0008) or any benign gynecologic disease (P = 0.004). No significant alteration of unbound EGFR was found in peritoneal biopsies of any of the groups of patients. No associations were found for a history of breast cancer, presence of ascites, or menopausal status with alteration of neu or EGFR expression in normal peritoneum. These findings of altered expression of neu in normal tissues of patients with ovarian cancer are suggestive of the presence of proto-oncogene alterations in loco-regional tissues of the peritoneum, such as might be seen if a paracrine influence existed between tumor and peritoneal cells. Alternatively, the alterations may represent subtle alterations of proto-oncogene expression of germ-line tissues.

In spite of diagnostic and therapeutic improvements the Surveillance Epidemiology and End Results Program data suggest that the overall cure rate for patients with ovarian cancer is 39%. Because of the dramatic difference in cure between patients with local disease (80% to 90%) and those with distant disease (15% to 25%), screening to find early ovarian cancer or its precursors is desirable. Transvaginal ultrasonography is the most efficient, accurate, and least expensive of the imaging modalities (transabdominal ultrasonography, computed tomography, magnetic resonance imaging, radioimmunoscintigraphy) for this purpose. To date, 10,000 women have been screened in three large programs; 11 cancers were detected (10 stage I, one occult stage IIIB) and all have apparently been cured. Doppler flow imaging and morphology index values improve the accuracy of transvaginal ultrasonography. A cost analysis suggests that screening costs are not yet less than treatment costs if there is to be universal screening of 27 million women at risk in the United States. However, for a population with a lifetime risk for ovarian cancer of 1%, screening will save five lives per 2000 patients screened.

The application of operative laparoscopy to patients with gynecologic malignancy is in its infancy, but promising findings have been demonstrated for surgical end staging after cytotoxic therapy for ovarian cancer, laparoscopic lymph node sampling for cervical cancer, and laparoscopic staging, vaginal hysterectomy and adnexectomy for corpus cancer. The most significant difficulty in integrating operative laparoscopy with gynecologic oncology, at this time, is the lack of controlled studies to demonstrate the ability of endoscopy to improve the contemporary management of these diseases. Further study will be necessary by subspecialists in gynecologic oncology to demonstrate the proper application of these new techniques.

Objective: To review the role of itraconazole as oral therapy for the major infections caused by Aspergillus spp.: allergic bronchopulmonary aspergillosis, aspergilloma, and invasive aspergillosis., Data Sources: A MEDLINE search of articles published in the English language between 1986 and 1993 was used to identify relevant citations, including review articles. In addition, a search of the published abstracts of the past two Interscience Conferences on Antimicrobial Agents and Chemotherapy (ICAAC) was performed., Study Selection: Clinical trials that evaluated itraconazole therapy in either allergic bronchopulmonary aspergillosis, aspergilloma, or invasive aspergillosis were critically reviewed. Trials were evaluated based upon entry criteria for the diagnosis of each type of aspergillosis, risk factors for the development of aspergillosis (neutropenia, transplant recipient, hematologic malignancy), prior antifungal chemotherapy, and dose and duration of itraconazole therapy., Data Synthesis: Overall, the clinical trials of itraconazole therapy for aspergillosis are limited and of variable quality. In the treatment of allergic bronchopulmonary aspergillosis, itraconazole has been reported to prompt a reduction in corticosteroid dosage in selected patients. There have been no controlled trials of itraconazole as treatment for aspergilloma, but data from several open-label trials suggest that this agent may be of clinical benefit in aspergilloma, primarily as an alternative to surgery. The use of itraconazole for invasive aspergillosis has been evaluated in several trials, most often in patients who were intolerant to amphotericin B treatment. Response to oral itraconazole has generally been promising., Conclusions: Although itraconazole offers promise for oral therapy against infections caused by Aspergillus spp., it should not presently be regarded as primary therapy for any of these diseases. Amphotericin B, in doses ranging from 1 to 1.5 mg/kg to a total dose of 1.5-4.0 g, should remain the treatment of choice in both aspergilloma and invasive aspergillosis. Itraconazole use should be restricted to patients who experience severe toxicity with amphotericin B therapy. Corticosteroids continue to be first-line therapy for allergic bronchopulmonary aspergillosis, with the use of itraconazole reserved for those patients who would benefit from a reduction in corticosteroid dose.

This investigation examined whether or not a gender-related effect on theophylline pharmacokinetics and metabolism exists in smoking and nonsmoking subjects with and without the concurrent administration of cimetidine. With a crossover design, 28 healthy men and premenopausal women (14 in each group) were administered intravenous aminophylline before (phase 1) and during (phase 2) a 10-day course of cimetidine, 300 mg four times a day. Statistically significant gender- and smoking-related effects were seen for theophylline half-life and clearance in phase 1, but only the smoking effect was statistically significant for these pharmacokinetic parameters in phase 2. Urinary metabolite excretion patterns demonstrated a greater percentage of excretion of 3-methylxanthine in female smokers than in male smokers in phase 1. Time-averaged urinary clearance of 1,3-dimethyluric acid was greater in female smokers than in male smokers. In phase 2, a significant reduction in the clearance of 1,3-dimethyluric acid was noted in female smokers but not in any other group. The results of our investigation suggest that a significant difference in the pharmacokinetics of theophylline exists that is related to gender and smoking status. Theophylline metabolism also seems to vary according to these factors. Administration of cimetidine results in a significant reduction in clearance of theophylline and abolishes the gender differences but not the smoking differences.

In order to assess the acute effects of the intraoperative administration of intraperitoneal (IP) carboplatin with and without intravenous (IV) doxorubicin in patients with gynecologic malignancies, 25 patients were treated at the conclusion of their surgical procedure. Twenty-three had epithelial ovarian cancer and 2 had advanced endometrial cancer. Twelve patients received IP carboplatin and IV doxorubicin at the conclusion of their primary cytoreduction. The remaining 13 received IP carboplatin alone and consisted of 4 reassessment laparotomies for ovarian cancer, 7 secondary cytoreductions, 1 minilaparotomy for the placement of an IP catheter, and 1 second-look laparoscopy. The median age of the 25 patients was 59 years. Eight patients underwent bowel resections with anastomoses; 2 had ureteral resections and ureteroneocystostomies, 1 required a splenectomy, and 1 underwent a partial hepatic resection. There were no mortalities. Three of the 13 patients who received the IP carboplatin alone had postoperative fevers with no infectious source, which did not delay discharge. No other morbidity was noted in this group. However, 7 patients who received IV doxorubicin along with the IP carboplatin developed severe leukopenia requiring antimicrobial and colony-stimulating factor support. One patient required reexploration for postoperative hemorrhage and also developed a pulmonary embolus. One woman developed postoperative pneumonia. The median hospital stay for the 25 patients was 9 days. Intraoperative chemotherapy can be administered with tolerable immediate adverse effects.

Objective: The surgical treatment of optic pathway gliomas (OPG) remains controversial, with visual outcomes often unpredictable. The present study explored surgical and clinical factors influencing visual acuity (VA) after OPG treatment and developed anatomical subtypes correlated with clinical symptoms., Methods: Children with OPG who underwent initial partial tumor resection at Beijing Tiantan Hospital from January 2011 to December 2022 were retrospectively analyzed. Multivariate logistic regression and random forest analyses were performed to identify risk factors for post-treatment VA deterioration and a decision tree model was created based on significant factors., Results: A total of 140 patients were enrolled. Multivariate logistic regression analysis identified surgical approach and initial VA as independent predictors of post-treatment VA deterioration (P < 0.05). Surgical approach, initial VA, and extent of tumor resection were the most significant factors for risk assessment and were included in the decision tree model, with surgical approach as the most important "root" node. The model demonstrated good predictive performance, with area under the curve values of 0.75 and 0.66 for the training and test datasets, respectively. A simple anatomical classification was developed, which revealed clinical characteristic differences among OPG types. Meanwhile, a correlation analysis of post-treatment visual deterioration was performed for each of the three anatomical types., Conclusion: This study offers a predictive model for visual outcomes following initial tumor-reduction surgery in OPG patients, which may help in visual outcomes risk stratification. Additionally, the anatomical classification effectively indicates OPG growth direction, offering potential insights into clinical symptoms., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Patients with advanced epithelial ovarian cancer who undergo incomplete surgery followed by six cycles of chemotherapy could benefit from second-look or consolidation cytoreductive surgery (CCRS). The primary goal of this study was to evaluate the overall survival (OS) in patients undergoing complete CCRS and the factors affecting survival. The secondary goal was to study the benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in these patients. Methods: This was a retrospective analysis of 173 patients with CCRS with (n = 118) or without (n = 55) HIPEC treated at 12 French centers. Only patients having a completeness of cytoreduction (CC) 0/1 resection and a minimum of 5 years of follow-up were included. HIPEC was performed systematically for all patients except those treated at the four centers that did not perform HIPEC. Results: The median Peritoneal Cancer Index was 6 (range 0–33). Closed HIPEC was performed in 59 (34.1%) patients and open HIPEC was performed in 56 (32.3%) patients. Grade 3–4 complications occurred in 64 (36.9%) patients. The median OS was 35.67 months (95% confidence interval [CI] 29.8–46.1) and was significantly longer for CCRS + HIPEC (31.4 months without HIPEC and 42.5 months with HIPEC; p = 0.022). On multivariate analysis, closed HIPEC (hazard ratio [HR] 0.46, 95% CI 0.29–0.73; p < 0.001) resulted in a longer OS, and age > 65 years (HR 2.17, 95% CI 1.14–4.11; p = 0.018) and bowel resection (HR 1.98, 95% CI 1.27–3.08; p = 0.020) led to a shorter OS. On multivariate logistic regression analysis, closed HIPEC (odds ratio 0.18; p = 0.001) was associated with a lower risk of dying at 5 years. Conclusions: CCRS was performed with an acceptable morbidity and resulted in good overall survival. The role of HIPEC in addition to CCRS should be evaluated in prospective, randomized studies and the closed technique prospectively compared with the open technique. [ABSTRACT FROM AUTHOR]

Smoking drug interaction studies represent a common approach for the clinical investigation of CYP1A2 induction. Despite this important role, they remain an "orphan topic" in the existing regulatory framework of drug interaction studies, and important methodological aspects remain unaddressed. The University of Washington Drug Interaction Database (DIDB) was used to systematically review the published literature on dedicated smoking pharmacokinetic interaction studies in healthy subjects (1990 to 2021, inclusive). Various methodological aspects of identified studies were reviewed. A total of 51 studies met all inclusion criteria and were included in the analysis. Our review revealed that methods applied in smoking interaction studies are heterogeneous and often fall short of established methodological standards of other interaction trials. Methodological deficiencies included incomplete description of study populations, poor definition and lack of objective confirmation of smoker and nonsmoker characteristics, under‐representation of female subjects, small sample sizes, frequent lack of statistical sample size planning, frequent lack of use of existing markers of nicotine exposure and CYP1A2 activity measurements, and frequent lack of control of extrinsic CYP1A2 inducing or inhibiting factors. The frequent quality issues in the assessment and reporting of smoking interaction trials identified in this review call for a concerted effort in this area, if the results of these studies are meant to be followed by actionable decisions on dose optimization, when needed, for the effects of smoking on CYP1A2 victim drugs in smokers. [ABSTRACT FROM AUTHOR]

A trustworthy high‐performance liquid chromatography approach for the simultaneous measurement of cefepime and sulbactam was created using quality by design. Finding reliable chromatographic settings for quality peaks and suitable component separation within a manageable run time was the key objective. Critical quality attributes for risk measurement were evaluated. To create an analytical design space and create a control strategy, the quantitative link between critical material attributes and critical quality attributes was built. Acetonitrile volume, trimethylamine volume, and flow rate were the three independent parameters considered in the mathematical models. Acetonitrile:high‐performance liquid chromatography water:triethylamine and pH 6.0, adjusted with orthophosphoric acid (50.0:50:0.15, v/v/v) as the mobile phase at 1.1 ml/min, were the ideal and anticipated conditions. We obtained appropriate baseline separation of both medications in about 10 min using these ideal conditions. The main determinant of the perturbation plot responses was found to be the quantity of acetonitrile. At all three levels, the percent recoveries for both medications ranged from 99% to 99.68%. Relative standard deviations were less than 2% for both drugs' intermediate accuracy and repeatability. A straightforward, precise, and repeatable high‐performance liquid chromatography method for regular quality control testing was created as a consequence. [ABSTRACT FROM AUTHOR]

Endometrial cancer is the most common carcinoma of the female genital organs and cervical cancer is the leading cause of cancer death in women worldwide. The aim of this review is to evaluate the role of laparoscopic hysterectomy in patients with endometrial and cervical cancer in this period, and analyze the outcome of hysterectomy in terms of survival. Moreover, we present the historical background, new techniques, the anatomical features, and surgical steps of radical hysterectomy. According to new evidence, minimally invasive surgery in patients with cervical cancer is associated with higher rates of recurrence and mortality compared to the open approach. Despite the numerous explanations offered for this phenomenon, the reasons for these results are unclear. Additional large trials have been launched to reevaluate the above-mentioned data. On contrary, the laparoscopic approach provides surgical outcomes and similar survival rates as open surgery in patients with early endometrial carcinoma. Furthermore, the radicality of hysterectomy does not influence local recurrence rates or overall survival in cases with complete surgical removal of the tumor. A laparoscopic radical hysterectomy is no longer an option in patients with cervical cancer. When minimally invasive surgery is offered, the patients must be counseled in detail about the current debate. [ABSTRACT FROM AUTHOR]

Optic pathway glioma (OPG) is a rare brain tumor affecting children, with no standard treatment strategy. This study described the sporadic OPG survival outcomes after surgical treatment and analyzed the role of imaging features and resection status in children receiving different adjuvant treatments. This retrospective study included 165 OPG patients whose clinical information were obtained from the hospital record system. Tumor volume and residual tumor volume were calculated by delineating the lesion area. Kaplan–Meier method and Cox proportional hazards model were conducted to analyze the independent prognosis factor. A total of 165 patients were included in this study. Respectively, the 5-year overall survival (OS) and progression-free survival (PFS) were 87.58% and 77.87%. Residual tumor size and first adjuvant treatment (AT) after surgery were both associated with PFS. In patients with small-size residual tumors, there was no significant difference in PFS between the AT treatment groups. Moreover, age, exophytic cystic components, leptomeningeal metastases, and AT were associated with OS. In patients with exophytic cystic components and those with leptomeningeal metastases, there was no significant difference in OS. Our results revealed that OPG patients could avoid or defer AT by maximized resection. Age ≤ 2 years was a disadvantageous factor for OS. Patients with exophytic cystic components were more likely to benefit from primary surgery, and CT or RT was not beneficial for these patients. Patients with leptomeningeal metastases had a poor prognosis regardless of the treatment they received. Future prospective clinical studies are needed to develop more effective treatment regimens. [ABSTRACT FROM AUTHOR]

Background: Optic Pathway Gliomas (OPG) are the most common brain tumor in Neurofibromatosis 1 patients (NF1). They are found along the optic pathway and may involve the optic nerves, chiasm, retro-chiasmatic structures, and the optic radiations. NF1 associate OPG (NF1-OPG) have variable presentation, disease course and response to treatment. The optimal management is patient-specific and should be tailored by a multidisciplinary team. Age, sex, histology, and molecular markers may be important factors in the individualized decision-making process. Chemotherapy is the first-line treatment in cases of progressive tumors, and visual preservation is the main goal of treatment. Purpose: In this paper we will review the disease, practical management, and recent advances of NF1-OPG. [ABSTRACT FROM AUTHOR]

The efficiency of treatment of human infections with the unicellular eukaryotic pathogens such as fungi and protozoa remains deeply unsatisfactory. For example, the mortality rates from nosocomial fungemia in critically ill, immunosuppressed or post-cancer patients often exceed 50%. A set of six systemic clinical azoles [sterol 14 α -demethylase (CYP51) inhibitors] represents the first-line antifungal treatment. All these drugs were discovered empirically, by monitoring their effects on fungal cell growth, though it had been proven that they kill fungal cells by blocking the biosynthesis of ergosterol in fungi at the stage of 14 α -demethylation of the sterol nucleus. This review briefs the history of antifungal azoles, outlines the situation with the current clinical azole-based drugs, describes the attempts of their repurposing for treatment of human infections with the protozoan parasites that, similar to fungi, also produce endogenous sterols, and discusses the most recently acquired knowledge on the CYP51 structure/function and inhibition. It is our belief that this information should be helpful in shifting from the traditional phenotypic screening to the actual target-driven drug discovery paradigm, which will rationalize and substantially accelerate the development of new, more efficient and pathogen-oriented CYP51 inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: Endometrioma is known to be an occurrence site of ovarian cancer, but there is no evidence on how to reduce the risk of canceration. Here, we report three cases of ovarian cancer arising from endometrioma during hormone therapies of GnRH analogue and tamoxifen, low‐dose estrogen‐progestin (LEP) and dienogest. In all cases, each hormonal treatment was effective in shrinking the size of the endometrioma. During hormonal treatments, solid parts inside endometrioma were observed, which was followed by surgery. The histology of the solid parts was clear‐cell adenocarcinoma in all cases. An immunohistochemistry study demonstrated that the estrogen receptor (ER) and progesterone receptor (PR) were positive in the endometriosis part but negative in the cancer part, while the human EGF receptor (HER) 2 was negative or very weak in the benign part and positive in the malignant part in all three cases. Even though hormonal treatments seem to be effective to regulate endometrioma, careful observation is needed to follow‐up patients with endometrioma. [ABSTRACT FROM AUTHOR]

The insufficient basic and clinical knowledge about invasive mold infections necessitated to review aspergillosis rodent models. The scope of this review has two major aspects. (1) It briefly summarizes Aspergillus toxicoses, the adverse effects of Aspergillus mycotoxins, the virulence factors of Aspergillus fumigatus, and how mild Aspergillus infections can turn to immunosuppressive diseases, ultimately to lethal invasive pulmonary aspergillosis. (2) The second major aspect of the review deals with earlier and recent murine models of pulmonary aspergillosis. Particular attention will be paid to the development of unified and generally applicable methods to detect, follow, and combat aspergillosis by medical treatments. Additionally, the review raises the question of responsibility regarding the application of immunosuppressive agents that initiate, contribute, and aggravate aspergillosis. Future studies of immunosuppression by chemical agents impacting aspergillosis deserve more studies. [ABSTRACT FROM AUTHOR]

Background: Peritoneal carcinomatosis is common after curative resection of gastric cancer. Intraperitoneal administration of paclitaxel (PTX) is known to control ovarian peritoneal metastases. Patients and methods: Patients with either linitis plastica or T4 cancer with high risk of peritoneal metastasis or recurrence but whose cancer was considered resectable were preregistered. After their cancer had been confirmed intraoperatively as resectable, the patients were randomized into either group A (PTX at 60 mg/m intraperitoneally on the day of surgery and on days 14, 21, 28, 42, 49, and 56) or group B (PTX at 80 mg/m administered intravenously by the identical schedule) before being treated by evidence-based chemotherapy. The primary end point was the 2-year survival rate. Safety, the secondary end point, was also analyzed. The study has been registered as UMIN000002957. Results: Of 177 preregistered patients, 83 underwent treatment (39 by intraperitoneal administration and 44 by intravenous administration). There was no difference in patient demographics between the two groups. The incidences of surgical complications were similar between the groups, except for transient bowel obstruction observed exclusively in group A. The relative dose intensity of PTX was 81.4 % for group A and 76.3 % for group B. There was one death due to pulmonary thrombosis and a case of anaphylaxis that led to termination of the protocol treatment (group B). Other adverse events were mild and manageable. Conclusions: Intraperitoneal administration of PTX from the day of gastrectomy did not result in a higher incidence of surgical complications and adverse reactions when compared with intravenous administration of PTX. [ABSTRACT FROM AUTHOR]

The efficacy, safety, and tolerability of drugs are dependent on numerous factors that influence their disposition. A dose that is efficacious and safe for one individual may result in sub-therapeutic or toxic blood concentrations in others. A significant source of this variability in drug response is drug metabolism, where differences in presystemic and systemic biotransformation efficiency result in variable degrees of systemic exposure (e.g., AUC, C max , and/or C min ) following administration of a fixed dose.Interindividual differences in drug biotransformation have been studied extensively. It is recognized that both intrinsic factors (e.g., genetics, age, sex, and disease states) and extrinsic factors (e.g., diet , chemical exposures from the environment, and the microbiome) play a significant role. For drug-metabolizing enzymes, genetic variation can result in the complete absence or enhanced expression of a functional enzyme. In addition, upregulation and downregulation of gene expression, in response to an altered cellular environment, can achieve the same range of metabolic function (phenotype), but often in a less predictable and time-dependent manner. Understanding the mechanistic basis for variability in drug disposition and response is essential if we are to move beyond the era of empirical, trial-and-error dose selection and into an age of personalized medicine that will improve outcomes in maintaining health and treating disease., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Intraperitoneal chemotherapy preceded by cytoreductive surgery should be the standard of care in the treatment of advanced epithelial ovarian cancer. This combination has been extensively examined in both the clinical and preclinical settings with favourable oncologic outcomes. Unfortunately, despite the existence of these evidence-based data, this management strategy remains underutilised. Materials and methods: We review and discuss the role of intraperitoneal chemotherapy with particular emphasis about the pharmacokinetics and pharmacodynamics aspects, the mode of administration, the reported side effects, the compliance of the patients and the clinical ongoing studies. Conclusions: Further studies investigating the pharmacokinetics and pharmacodynamics aspect of IP route may help to reduce toxicity pending more effective treatments. [ABSTRACT FROM AUTHOR]

Objective: To review the outcomes of pelvic exenterative surgery done with a palliative intent and evaluate its role in relapsed gynaecology malignancies. Method: This is a retrospective cohort study between April 2009 and May 2012 in Oxford Gynaecological Cancer Centre. Patients were identified from the oncology surgical database. Results: 18 patients were identified with a mean age 54 (26-79) years, who underwent surgery for symptomatic recurrent cancer. All except one patient had radiotherapy prior to surgery. 12 patients had cervical cancer, five had vulval cancer and one had endometrial cancer. About half of the patients had major surgical complications; however, majority was patients satisfied with the outcome. Conclusion: Pelvic exenteration in this context carries considerable morbidity and in this series achieved good symptom control with a mean overall survival of 11 months. Careful patient selection, adequate counselling and ongoing support are imperative of successful outcome. [ABSTRACT FROM AUTHOR]

Purpose: To derive estimates of CYP1A2 abundance as a function of daily cigarette consumption and use these values to predict the clearances of CYP1A2 substrates in smokers. Methods: Smoking-induced changes in hepatic CYP1A2 abundance were extrapolated from reported in vivo caffeine clearance data for sub-groups of a smoking population that were categorized according to their daily cigarette consumption. These abundance values together with in vitro-in vivo extrapolation (IVIVE) within the Simcyp population-based Simulator were used to predict the clearances of caffeine, theophylline, and clozapine in smokers. The model was used subsequently to predict differences in oral clearance between smoker and non-smoker cohorts in a Phase 1 clinical trial involving PF-2400013, a drug metabolized by CYP1A2. Results: Estimated hepatic CYP1A2 abundance values were 52, 64, 79, 90, and 94 pmol/mg microsomal protein for subjects smoking 0, 1-5, 6-10, 11-20, and >20 cigarettes/day respectively. Predicted -fold increases in oral clearance of caffeine, theophylline and clozapine in smokers relative to non-smokers were consistent with observed data. The validated model was able to recover the smoking-induced increase in oral clearance of PF-2400013; predicted and observed mean (CV%) values in male nonsmokers and smokers were 90 L/h (40%) and 141 L/h (34%) respectively, and 100 L/h (58%) and 131 L/h (33%) respectively. Conclusions: This study demonstrates that it may be possible to predict the clearance of CYP1A2 substrates in smoking populations using quantitative estimates of CYP1A2 abundance based on daily cigarette consumption in conjunction with an IVIVE approach. [ABSTRACT FROM AUTHOR]

Chronic cavitary pulmonary aspergillosis (CCPA) has been associated with advanced lung diseases. Pulmonary sarcoidosis, a granulomatous inflammatory disorder, is associated with CCPA. We identified CCPA in 2% of cases in a large cohort of sarcoidosis patients. We found a lack of response to medical treatment and poor outcome in this subgroup. [ABSTRACT FROM AUTHOR]

Acute mesenteric ischemia (AMI) is a highly lethal clinical entity associated with high morbidity and mortality. Bowel necrosis often results, usually necessitating bowel resection; however, deciding on the extent of resection is problematic as accurate identification of ischemic bowel that may undergo subsequent infarction is difficult. Therefore, a second-look laparotomy after the first operation is usually recommended. While the second-look procedure is widely accepted, its optimal indications and mode are still controversial, raising questions such as “second-look or not?,” “planned relaparotomy or relaparotomy on demand?,” and “open or laparoscopic?” In this review we discuss the relevant literature and reassess the role of the second-look operation in the treatment of AMI. [ABSTRACT FROM AUTHOR]

Introduction: The coexistence of allergic bronchopulmonary aspergillosis and aspergilloma is rare.Case Presentation: We present the case of a 56-year-old Caucasian man who worked as a farmer, with infiltrates in the right lower and middle lung lobes, partial consolidation of the middle lobe and with previous diagnosis of chronic obstructive bronchitis. Evaluation of our patient led to the diagnosis of allergic bronchopulmonary aspergillosis with coexistent aspergilloma in the right lower lobe. He was treated with oral methylprednisolone and itraconazole. At the five-year follow-up he is without any sign of recurrence.Conclusion: Aspergillus infection after the inhalation of spores in the form of a hypersensitivity reaction and saprophytic colonization can be coexistent. [ABSTRACT FROM AUTHOR]

Ovarian cancer is today the most lethal female cancer with an overall survival of only 49.9%. The currently available screening modalities are disappointing in detecting highly curable early stage ovarian cancer. Natural history of ovarian cancer is unknown; it appears it can develop quickly from normal looking ovaries. Timely referral of women with non-specific symptoms (such as abdominal bloating, pelvic pain) for an ultrasound scan or blood CA125 assessments may help in the early diagnosis. Patients with Stage IA or IB disease with grade 1 tumors have a cure rate of >90%; this is likely to be compromised by laparoscopic surgery. In selected patients fertility preservation with good obstetric outcome is possible. However, the relapse rate in ‘high risk’ early stage ovarian cancers is 40–45%; adjuvant chemotherapy is needed. Only 20–25% of those with stage III and IV disease are cured. Despite a high primary response (70%) majority (70–75%) will relapse and all are likely to succumb. Optimal debulking surgery followed by adjuvant chemotherapy are needed for stages III and IV disease; the outcome is superior if managed by gynecologic oncologists. Where cost of drugs is an important consideration, an alternative is carboplatin (an affordable and equally effective drug). The role of vaccines needs further study. When relapses occur palliation will be the aim in most instances. Oral contraceptives, breast feeding, tubal sterilization and hysterectomy also have a protective effect. Risk-reducing salpingo-oopherectomy has been suggested in women with BRCA mutations. [ABSTRACT FROM AUTHOR]

Objective: Theophylline is metabolized to 1,3-dimethyluric acid (1,3-DMU), 3-methylxanthine, and 1-methylxanthine by CYP1A2 and partly by CYP2E1. Because 1,3-DMU is the major metabolite of theophylline, the 1,3-DMU/theophylline ratio is viewed as a good indicator of theophylline metabolic clearance. Here, we investigated the associations between 1,3-DMU/theophylline ratios and genetic polymorphisms of CYP2E1 and CYP1A2. Methods: Polymerase chain reaction (PCR) and direct sequencing or PCR-restriction fragment length polymorphism (RFLP) were performed to analyze CYP2E1 and CYP1A2 promoter polymorphisms in 62 Korean asthma patients. Plasma theophylline and 1,3-DMU levels were measured by liquid chromatography-tandem mass spectrometry. Results: Eleven polymorphisms including Ins96, -1566 T>A, -1515 T>G, -1414 C>T, -1295 G>C, -1055 C>T, -1027 T>C, -930 A>G, -807 T>C, -352 A>G, and -333 T>A were detected in the 5' flanking region of the CYP2E1 gene (numbering according to GenBank Accession number NT_017795). Of these, five single nucleotide polymorphisms (SNPs) (-1566 T>A, -1295 G>C, -1055 C>T, -1027 T>C, and -807 T>C) were closely linked. Another three polymorphisms (Ins96, -930 A>G, and -352 A>G) and two polymorphisms (-1515 T>G and -333 T>A) were also closely linked. The five closely linked polymorphisms were associated with significantly different 1,3-DMU/theophylline ratios between heterozygotes plus homozygotes of a rare allele (n=23, 0.0368±0.0171) and common allelic homozygotes (n=39, 0.0533±0.0343) (p=0.024 by Mann-Whitney U test). In the CYP1A2 gene, the -2964G>A polymorphisms exhibited a significant difference in 1,3-DMU/theophylline levels between heterozygotes plus homozygotes of a rare allele (n=30, 0.0406±0.0272) and homozygotes of a common allele (n=32, 0.0534± 0.0316) (p=0.032). Conclusion: We confirm that hydroxylation at the 8 position of theophylline (1,3-DMU) is significantly affected by genetic polymorphism in CYP2E1 in addition to CYP1A2. [ABSTRACT FROM AUTHOR]

Objective: The effect of cigarette smoking on CYP2C9 activity is unknown. We conducted a study to evaluate whether there is a difference in CYP2C9 activity in smokers versus non-smokers by examining S-warfarin AUC after CYP2C9 inhibition with fluvastatin. In addition, the effect of the CYP2C9 inhibitor fluvastatin was evaluated using S-warfarin as a probe. Methods: A randomized, single dose, two-treatment crossover study of warfarin with a washout period of 21 days was performed. Eighteen healthy Caucasian smokers and non-smokers, genotyped as CYP2C9*1/*1 or CYP2C9*1/*2, received warfarin 10 mg plus vitamin K 10 mg to measure baseline CYP2C9 activity. Warfarin dosing was repeated after 18 days of fluvastatin 40 mg twice daily to evaluate CYP2C9 activity after inhibition. Results: The S-warfarin AUC0-∞ between smokers and non-smokers did not differ by >25% after inhibition. There was no difference in S-warfarin AUC0-∞ during baseline (p=0.45) or inhibition (p=0.19) periods for smokers versus non-smokers. Fluvastatin increased the AUC of S-warfarin by 42±29% and 26±18% in smokers and nonsmokers, respectively. Linear regression analyses showed significant but weak correlations between peak concentrations (Cat 1 h) or (-) 3S,5R-fluvastatin AUC0-12 h and extent of warfarin inhibition. For (+) 3R,5S-fluvastatin, a weak correlation was found between Cat 1 h and extent of warfarin inhibition. Conclusions: Cigarette smoking does not affect CYP2C9 activity as evaluated using S-warfarin as a CYP2C9 probe. Fluvastatin is a weak inhibitor of CYP2C9 activity in both smokers and non-smokers. [ABSTRACT FROM AUTHOR]

The digitalics (digoxin and digitoxin) have an estrogenic action, confirmed by the presence of gynecomastia observed in men who are users of steroids, and it is also confirmed by the increase of vaginal trophism in postmenopausal female users, although little is known about the endometrium. These effects might result from the similarity of the chemical structures between the digitalics and estrogens. This study evaluated 27 female mice. Twenty-four mice were oophorectomized and in three of them the ovaries were manipulated, but they were not extirpated. Forty days after the surgery each group of three animals received a medication with a specific drug (digoxin, digitoxin or estradiol) for 2 weeks. Twenty-four hours after the last medication, all the animals were hysterectomized and the wombs were processed, cut and put on laminae. By histomorphometry, we analysed the area of the transverse sections of the endometrium, the area of the endometrial glands and the height of the uterine epithelium. The respective averages and the standard deviations were calculated. The results showed that digoxin neither presented an estrogenic action ( p ?>?0.05) nor raised the power of the estradiol action ( p ?>?0.05). Digitoxin promoted an estrogenic action on the glandular area ( p < 0.05), and also raised the power of the estradiol action on the transverse section of the endometrium and on the glandular area ( p < 0.05). [ABSTRACT FROM AUTHOR]

The Food and Drug Administration (FDA) reviewed 300 new drug applications between 1995 and 2000. Of the 163 that included a sex analysis, 11 drugs showed a >40% difference in pharmacokinetics between males and females, which was listed on the product label, yet no dosing recommendations were made based on sex. Female sex has been shown to be a risk factor for clinically relevant adverse drug reactions. Would simply dosing females based on their different pharmacokinetics decrease the incidence of adverse events? The answer is not known. Sex-dependent pharmacodynamic effects have been identified. The role of pharmacokinetics vs. pharmacodynamics is unclear, as is the impact of pharmacogenetics on both. This review highlights a few specific examples in each area in which sex differences in pharmacokinetics and pharmacodynamics are important and provides recommendations for additional needed research. [ABSTRACT FROM AUTHOR]

There are pharmacological differences between women and men that have important clinical consequences. For several drugs, there is a higher incidence in women of drug-induced QT prolongation and a potentially fatal arrhythmia, torsades de pointes. This may be a reflection of the longer baseline QT interval in women. A difference in cardiovascular disease between women and men is that women have a higher mortality rate after myocardial infarction (MI). Women also have a higher rate of hemorrhagic stroke after receiving thrombolytic therapy for an MI. Differences in effectiveness of analgesics have been demonstrated, with kappa opioids providing pain relief for women but not men. Drugs may have different pharmacokinetics in women and men because of differences in phase I and phase II enzymes that metabolize drugs. Conflicting results about biological sex differences have been reported for the major drug metabolizing enzyme, cytochrome P450 3A4 (3A4) and may be related to a role for P-glycoprotein, a cell membrane transporter, reported as two times higher in male livers than those of females. It has been reported that boys need a higher dose of 6-mercaptopurine, which is metabolized by thiopurine methyltransferase (TPMT). TPMT is reported to be 14% higher in male human liver biopsies than those from females. Verapamil, a drug for angina and hypertension, has different clearance and side effects in men and women. Ethnic/racial variations have also been demonstrated with the drug metabolizing enzymes, CYP2C9, 2C19, and 2D6. [ABSTRACT FROM AUTHOR]