Patient perspectives on treatment and prevention of recurrent urinary tract infections: a focus group study.

INTRODUCTION AND HYPOTHESIS: We sought to understand factors that are important to patients for the management of recurrent urinary tract infections (UTI) during both an acute episode and for the prevention of future episodes. METHODS: This was a qualitative study with focus groups in women with recurrent UTIs. Participants filled out information about prior recurrent UTI treatment and the Belief about Medicines Questionnaire (BMQ). Each 90-minute focus group was moderated by a nonphysician psychologist. Line-by-line coding of each transcript by three independent physicians was used to develop emergent concepts and themes using Grounded Theory methodology. RESULTS: Twenty-six women participated in six focus groups. The average age of participants was 62 years and 77% were post-menopausal. All women had already tried multiple prevention strategies for their recurrent UTIs. The average BMQ-specific scores indicated a net positive attitude toward medicines specifically prescribed for recurrent UTI prevention. Several themes emerged from the focus groups. First, patients wanted providers to acknowledge the high burden imposed by frequent interactions with the health care system for the management of recurrent UTI. Second, patients wanted earlier access to providers knowledgeable in the management of this condition. Third, patients wanted to self-manage their condition through a structured treatment plan with support from their providers. Finally, patients wanted greater emphasis on education and prevention strategies to reduce their antibiotic intake. CONCLUSIONS: Patients with recurrent UTI want more efficient workflows, a framework that promotes self-management in partnership with their providers, and a greater emphasis on prevention.

Variation in diagnosis of urinary incontinence in women by provider and patient demographic factors.

INTRODUCTION: Urinary incontinence (UI) among women is under-recognized in primary care setting. We hypothesized that UI is, therefore, more commonly diagnosed by specialists. Our aim was to determine the rate of UI diagnosis by provider and patient demographics, and whether these factors affect the likelihood of UI diagnosis. METHODS: Retrospective study using electronic medical records from 2010 to 2019. Ambulatory patient encounters by adult females were identified. Encounters with new diagnosis of UI (stress, urgency, mixed, or unspecified) were identified using ICD 9 and 10 codes. The following data were extracted: diagnosing provider specialty and sex, patient age, BMI, race, estimated household income, insurance coverage and type, and primary care provider (PCP). Rate of UI diagnosis was calculated using proportions. Univariable comparison and multivariable logistic regression were performed. RESULTS: 576,110 patient encounters were captured. 14,378 patient encounters had UI diagnosis (2.5%). UI population had the following characteristics: Mean age of 60.1 ± 15.5 years, 65.6% identified as white, 75.7% had a PCP, and 87.9% had insurance. UI diagnosis rate was < 1% for PCPs. Multivariable logistic regression showed that urogynecologists and female providers were more likely to diagnose UI; patient demographics associated with UI diagnosis included older age, elevated BMI, white race, commercial insurance, and having a PCP. Estimated household income did not have a significant effect. CONCLUSION: Diagnosis of UI is seldom made by PCPs. Race, insurance, and having a PCP may affect the likelihood of receiving UI diagnosis. Continued efforts to promote equity in recognizing UI may be warranted.

Serum Lactate Level as a Predictor for Blood Transfusion in Postpartum Hemorrhage.

OBJECTIVE: Postpartum hemorrhage (PPH) is the leading cause of maternal morbidity and mortality. At present, there are no reliable clinical or laboratory indicators to identify which patients might require blood transfusions during a PPH. Serum lactate has long been used as an early biomarker of tissue hypoperfusion in trauma settings. The aim of this study is to understand serum lactate's role in the management of obstetric hemorrhage. STUDY DESIGN: A retrospective chart review was performed of women who delivered between 2016 and 2019 at our institution and experienced a PPH. The patients were divided into two groups: those with a normal serum lactate level, defined as ≤2 mmol/L, and those with an abnormal serum lactate level, defined as >2 mmol/L. Need for packed red blood cell transfusion, as part of the resuscitation, was assessed for both groups. RESULTS: During the study period, 938 women experienced PPH. Of these, 108 (11.5%) had a normal serum lactate, ≤2 mmol/L, and 830 (88.5%) had an abnormal lactate, >2 mmol/L. Women with elevated lactate levels were more likely to receive a blood transfusion versus those with a normal lactate level (57.0 vs. 46.3%, p = 0.035, respectively). Additionally, the average number of blood transfusions administered was significantly higher in the abnormal lactate group versus in the normal lactate group (1.34 vs. 0.97, respectively, p = 0.004). In a multivariable linear regression model, increasing serum lactate levels were found to be predictive of requiring more than 1 unit of blood (p < 0.001). CONCLUSION: Women with elevated serum lactate levels were more likely to require blood transfusions during a PPH versus those with a normal serum lactate level. Thus, serum lactate levels are useful as an early indicator of requirement for blood transfusion in the management of obstetric hemorrhage. KEY POINTS: · Lactate is a biomarker for blood transfusion in trauma.. · Lactate's role in PPH is unknown.. · Elevated lactate predicts receiving more blood transfusions..

Venous thromboembolism prophylaxis in vaginal surgery for pelvic organ prolapse: Predictors of high risk in a low-risk population.

AIM: Venous thromboembolism (VTE) rates in vaginal pelvic organ prolapse (POP) repair are low. Our aim is to evaluate specific risk factors for VTE in patients undergoing vaginal POP repair. METHODS: This is a cross-sectional study using the American College of Surgeons NSQIP database. Using CPT codes, cases of vaginal POP repair between 2014 and 2017 were identified. Patient and operative characteristics were collected. VTE was defined as pulmonary embolism (PE) or deep vein thrombosis (DVT) within 30 days from surgery. Univariate analyses were performed using the Student t test for continuous and χ2  tests for categorical variables. Multivariate logistic regression was performed to identify factors independently associated with VTE. RESULTS: Of 44 207 women who underwent vaginal POP repair, there were 69 cases of VTE (0.16%). VTE rates for obliterative (0.15%) and functional (0.16%) vaginal POP repair, as well as for repairs with hysterectomy (0.17%) and without hysterectomy (0.12%) were not significantly different (p = .616 and .216, respectively). Multivariate analysis demonstrated predictors for postoperative VTE to be ASA physical status classification ≥ 3 (aOR, 1.99; p = .014), length of stay >75th percentile (aOR, 2.01; p = .007), operative time >3 h (aOR, 2.24; p = .007), and dyspnea (aOR, 3.26, p = .004). CONCLUSION: Despite the low incidence of VTE after vaginal POP repair, patients with ASA physical status classification ≥ 3, length of stay >75th percentile, operative time >3 h, and dyspnea were at higher risk for VTE. Vaginal POP repair may have independent VTE risk factors not captured in standard risk assessment tools.

The impact of concomitant mid-urethral sling surgery on patients undergoing vaginal prolapse repair.

INTRODUCTION AND HYPOTHESIS: The aim of this study was to assess whether mid-urethral sling (MUS) placement at the time of vaginal prolapse repair compared to vaginal prolapse repair alone is associated with an increase in 30-day postoperative complications. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Database, Current Procedural Terminology codes were used to identify cases of vaginal prolapse repair with and without concomitant MUS from 2012 to 2017. Student's t-test and chi-square test were used to compare differences between the groups. RESULTS: A total of 1469 cases of vaginal prolapse repair with sling were compared to 4566 cases without sling. There was no difference between prolapse repair with sling compared to without sling in mean hospital length of stay (LOS) (1.42 versus 1.32 days, p = 0.65), postoperative urinary tract infection (UTI) (6.1% versus 5.8%, p = 0.670), perioperative blood transfusion (1.1% versus 1.2%, p = 0.673), readmission (2.7% versus 2.6%, p = 0.884) and postoperative wound infection (0.5% versus 0.7%, p = 0.51). There was a higher rate of reoperation (2.2% versus 1.5%, p = 0.049) and venous thromboembolism (VTE) (0.4% versus 0.1%, p = 0.030) in patients undergoing concomitant MUS compared to those undergoing prolapse repair alone. CONCLUSIONS: Compared to prolapse repair alone, the addition of a sling did not increase hospital LOS, UTI, perioperative blood transfusions, readmission or postoperative wound infections. However, concomitant sling was found to be associated with a higher risk of reoperation and VTE.

Identifying modifiable and non-modifiable risk factors associated with prolonged length of stay after hysterectomy for uterine cancer.

OBJECTIVE: We examined the influence of modifiable (intraoperative factors and complications) and non-modifiable (clinical and demographic characteristics) factors on length of stay (LOS) for women who underwent hysterectomy for uterine cancer. METHODS: The National Surgical Quality Improvement Program database was used to identify women who underwent hysterectomy for uterine cancer from 2006 to 2015. The association between demographic, preoperative, intraoperative, and postoperative factors and LOS was examined. The primary outcome was prolonged LOS (>75th an3 >90th percentiles). Model fit statistics were used to assess the importance of each group of characteristics. RESULTS: Of 19,084 women identified, 6082 (31.9%) underwent abdominal and 13,002 (68.1%) underwent minimally invasive hysterectomy. In the abdominal hysterectomy group, the 75th and 90th percentiles for LOS were 5 and 8days, respectively. All risk factors combined accounted for 23.6% of the variation in LOS >75th percentile. Demographic characteristics explained 4.0%, preoperative factors 7.0%, intraoperative factors 7.9%, and postoperative characteristics 9.7% of variation in prolonged LOS. In the minimally invasive group, the 75th and 90th percentiles for LOS were 1 and 2days, respectively. The combined risk factors explained 16.2% of the variation in prolonged LOS. Demographic characteristics accounted for 6.2%, preoperative factors 4.1%, intraoperative factors 6.9%, and postoperative characteristics 1.3% of variation in prolonged LOS. Similar patterns were seen when prolonged LOS was defined as >90th percentile. CONCLUSION: Perioperative risk factors account for approximately one quarter of the variation in prolonged LOS. Overall, a substantial proportion of the variation in LOS remains unexplained by measurable patient and hospital factors which may limit the utility of LOS as a quality metric for endometrial cancer.

Characteristics associated with prolonged length of stay after hysterectomy for benign gynecologic conditions.

BACKGROUND: Length of stay after surgery has become an important quality measure for many common surgical procedures and is now also tied to reimbursement. Currently, little is known about the perioperative factors that contribute to prolonged hospital length of stay in women who undergo hysterectomy for benign conditions. OBJECTIVE: We performed a population-based analysis to investigate the association between perioperative factors and prolonged length of stay in women who undergo minimally invasive, abdominal, and vaginal hysterectomy. STUDY DESIGN: We used the National Surgical Quality Improvement Program database to identify women from 2006-2015 who underwent benign hysterectomy. The primary outcome was length of stay >75th percentile. Demographic, preoperative, intraoperative, and postoperative factors were analyzed to determine individual predictors of prolonged length of stay. Model fit statistics were used to assess the importance of each group of perioperative factors on prolonged length of stay. RESULTS: We identified a total of 157,589 women, including 83,172 (52.8%) of whom underwent minimally invasive hysterectomy, 45,149 (28.6%) of whom underwent abdominal hysterectomy, and 29,268 (18.6%) of whom underwent vaginal hysterectomy. The 75th percentile for length of stay was 1 day for minimally invasive, 3 days for abdominal, and 2 days for vaginal hysterectomy. The measured factors accounted for 11.0% of the ability to predict a prolonged length of stay for minimally invasive, 20.3% for abdominal, and 16.2% for vaginal hysterectomy. Intraoperative factors were the most important contributors to length of stay for minimally invasive and abdominal hysterectomy; demographic factors dominated for vaginal hysterectomy. CONCLUSION: The most important perioperative factors that contributed to prolonged length of stay for hysterectomy were, in large part, not modifiable and suggest that targeted interventions to reduce length of stay will be challenging.

Survival trends in patients with tracheal carcinoma from 1973 to 2011.

PURPOSE: The prognosis for primary tracheal cancer is dismal. We investigated whether there has been improvement in survival in tracheal cancer patients and how treatment modality affected overall and cancer-specific survival. MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results database, 1144 patients with tracheal cancer were identified between 1973 and 2011. Patients were stratified by age group, gender, race, tumor histology, and treatment modality. Radical surgery and survival rates based upon these stratifications were determined. Longitudinal analyses of survival and the percentage of patients undergoing surgery and radiation were conducted. RESULTS: In the final cohort, 327 tracheal cancer patients (34%) underwent radical surgery. Patients of younger age, female gender, and who presented with non-squamous cell tumors were statistically more likely to undergo surgery. Over time, utilization of radiation has declined while use of radical surgery has increased. Concomitantly, 5-year survival has increased from approximately 25% in 1973 to 30% by 2006. Those who did not have surgery were 2.50 times more likely to die of tracheal cancer (95% Confidence Interval 2.00-3.11, p<0.001) than those who did have surgery. Additionally, patients who underwent radical surgery alone (without adjuvant radiation therapy) were 50% or 19% less likely to die of tracheal cancer than those who underwent no treatment or combination therapy, respectively (both p<0.001). CONCLUSIONS: Survival in patients with tracheal cancer is improving over time. The utilization of radical surgery is increasing and confers the highest survival advantage to patients who are candidates.

Poisoning of mitochondrial topoisomerase I by lamellarin D.

Lamellarin D (Lam-D) is a hexacyclic pyrole alkaloid isolated from marine invertebrates, whose biologic properties have been attributed to mitochondrial targeting. Mitochondria contain their own DNA (mtDNA), and the only specific mitochondrial topoisomerase in vertebrates is mitochondrial topoisomerase I (Top1mt). Here, we show that Top1mt is a direct mitochondrial target of Lam-D. In vitro Lam-D traps Top1mt and induces Top1mt cleavage complexes (Top1mtcc). Using single-molecule analyses, we also show that Lam-D slows down supercoil relaxation of Top1mt and strongly inhibits Top1mt religation in contrast to the inefficacy of camptothecin on Top1mt. In living cells, we show that Lam-D accumulates rapidly inside mitochondria, induces cellular Top1mtcc, and leads to mtDNA damage. This study provides evidence that Top1mt is a direct mitochondrial target of Lam-D and suggests that developing Top1mt inhibitors represents a novel strategy for targeting mitochondrial DNA.

A Hospital-Based Case-Control Study on Raised Homocysteine Level in Vitiligo Patients and Its Association With Disease Severity.

Introduction Vitiligo is an acquired pigmentary disorder clinically manifested by circumscribed depigmented macules and often associated with leucotrichia. Not much is known about the biochemical abnormality occurring in vitiligo. Our study aims to determine whether serum homocysteine is raised in vitiligo patients and whether it can be used as a prognostic marker for vitiligo. Material and methods This study is a hospital-based, case-control, analytical study conducted on 70 patients of vitiligo patients. A total of 30 staff of the hospital served as control. Venous blood was withdrawn from the antecubital vein from all study participants using all aseptic precautions. Investigation of blood homocysteine levels was done in all the study participants. Scoring of vitiligo was done based on Vitiligo European Task Force (VETF) criteria which take into account body surface area, stage, and spread. Results Mean serum homocysteine level among vitiligo patients was 14.40± 5.80 micromoles/lit as compared to 10.33± 5.05 micromole/lit in control groups, and this difference was statistically significant (t-value = 3.19and p-value = 0.002). The correlation coefficient was statistically significant (correlation coefficient = 0.25 and p-value = 0.03) in between homocysteine level and stage of the disease. On multiple comparisons difference in serum homocysteine level of progressing category is significantly raised as compared to control, stable, and regressing categories. Conclusion The mean serum homocysteine level among all vitiligo patients was higher as compared to control groups. Moreover, the serum homocysteine level of active cases is significantly higher as compared to control, stable, and regressing categories. Also, serum homocysteine levels showed a positive correlation with the degree of depigmentation, i.e., stage of the disease.

Reactivation of Herpes Zoster Virus After COVID-19 Vaccination: Is There Any Association?

SARS-CoV-2 disease, COVID-19 infection, is a multi-system illness that has afflicted people all over the world. A number of vaccines have been produced to combat the current COVID-19 pandemic, and a variety of side effects have been recorded following the vaccination. However, there are limited data on the negative effects of immunological reactivation following vaccination. We report 10 incidences of herpes zoster reactivation within 7-21 days of getting the COVID-19 vaccination. Transient immunomodulation following vaccination, similar to that seen in COVID-19 illness, could be one explanation for this reactivation. These cases highlight the significance of continuing to examine vaccine safety during the COVID-19 pandemic's ongoing mass vaccination campaign. We also underline the importance of peripheral health professionals in the management and reporting of any vaccination-associated adverse event.

Pattern of Papulosquamous Disorders in Children: A Clinico-Epidemiological Study.

Introduction Skin disorders are a major health problem in the pediatric age group and are associated with significant morbidity. Papulosquamous disorders, forming a major part of the skin diseases in children, present in a variety of clinical pattern. This study is conducted in order to study the hospital-based prevalence of papulosquamous disorders in the pediatric age group (2-14 years) and to determine the morphology and clinical patterns with respect to their age and sex distribution. Methodology An analytical cross-sectional study was conducted from December 1, 2019, to May 30, 2021, in the outpatient department of the Department of Dermatology, Venereology, and Leprology, JK Hospital and LN Medical College, Bhopal, India. Ninety-five consecutive patients belonging to the age group of 2-14 years, attending the Dermatology OPD and also referred cases from the Pediatrics Department were enrolled in the study. A detailed history of illness, regarding age, duration, onset, symptoms, recurrence, family history of the disease, pre-existing medical conditions, and drug intake history was taken. Information regarding the history of fever, sore throat, and vaccination was noted. Clinical and dermatological examination including hair, nail, and mucosal examination was done for all the cases. Necessary investigations were ordered for relevant cases and the data was recorded in a form specially designed for the study. Results In the present study, papulosquamous disorders constituted 2.9% of all pediatric (2-14 years) dermatosis. Of the various papulosquamous disorders found, psoriasis was the most common disease that was found (in 31.6%) followed by Gianotti-Crosti syndrome (18.9%), and lichen planus (18.9%). Males outnumbered females with a ratio of 1.48:1. The incidence of papulosquamous disorders was highest in 11-14 years of age in the present study. Conclusion Papulosquamous disorders account for a large number of the overall dermatoses, belonging to both the adult and pediatric populations. Due to significant changes in clinical presentation, geographical and environmental influences, treatment, and prognosis; the papulosquamous group of disorders in children require a varying approach than adult dermatoses. More studies are required in this field to appropriately diagnose and manage pediatric papulosquamous disorders in order to reduce the disease burden and as a key to better patient care.

Evaluation of the Efficacy and Safety Profile of Long-Pulsed 1064 Neodymium:Yttrium-Aluminum-Garnet (Nd:YAG) Laser in Hemangioma and Vascular Malformation in Darker Skin Types.

Introduction A prospective, interventional study was conducted to evaluate the efficacy and safety profile of long-pulsed neodymium:yttrium-aluminum-garnet (Nd:YAG) laser in the treatment of vascular lesions in the darker skin patients of Fitzpatrick skin type IV and V. Materials and method The study was conducted at a tertiary care hospital. Institutional ethical committee permission was obtained before starting the study. Twenty-nine patients presenting with vascular lesions were enrolled in the study. The patients were called once a month for sessions for six months. Clinician Global Impression (CGI) scores were used for evaluation. We followed a "per protocol" analysis. Results Of the 29 patients we enrolled, three dropped out for various logistic reasons, and 26 patients completed their treatment. After six months of follow-up of the 26 patients who completed their treatment, 12 (46.15%) had shown complete healing (CGI = 4, 70%-100% improvement in lesions). The rest of the 14 (53.84%) patients showed good improvement (CG1 = 3, reduction of 50%-70% of lesions). No permanent side effects were noted. Conclusion Long-pulsed 1064 Nd:YAG laser proves to be an effective treatment for hemangioma and vascular malformation in darker skin patients with its major advantages of being a safe, well-tolerated, cost-effective procedure with minimal downtime and minimal side effects.

The Masquerading Retinopathy of Revesz Syndrome.

Revesz syndrome is a rare telomeropathy characterized by bone marrow failure and exudative retinopathy. We report the case of a 2-year-old male child, initially treated with bilateral laser photocoagulation for retinopathy of prematurity. He developed exudative changes in the right eye, presumed to be Coats disease. Later, the left eye developed a total vitreous hemorrhage. Proliferative retinopathy was noted intraoperatively. Systemic features of bone marrow failure, growth retardation, and nail pigmentation were present. Genetic testing confirmed the diagnosis of Revesz syndrome. We describe our approach to diagnosis and surgical management of the case. [Ophthalmic Surg Lasers Imaging Retina 2022;53(6): 346-348.].

Systematic Identification and Critical Appraisal of Pediatric COVID-19 Guidelines Applicable in India.

OBJECTIVE: To systematically identify and critically appraise the methodological quality of pediatric guidelines applicable to management of COVID-19 in India. METHODS: Pediatric COVID-19 guidelines applicable to India, published until 30 April 2021, were identified through a systematic search across ten databases. Each was critically appraised for methodological quality using the AGREE-II tool, by at least two appraisers. Median (interquartile range) of the total score and domain-wise scores were calculated, and compared for Indian vs. foreign guidelines, updated vs. original versions of guidelines, and those developed earlier vs. later in the pandemic. RESULTS: A total of 62 guidelines was identified. Only 8 (12.9%) were published in India. The overall AGREE-II score ranged from 4.7% to 72.8%; with median (IQR) 37.9% (29.4, 48.6). This suggested overall low(er) methodological quality. The median (IQR) domain-wise scores were as follows: Scope and Purpose 66.7% (58.3, 83.3), Stakeholder Involvement 41.7% (30.6, 83.3), Rigor of Development 23.4% (14.8, 37.5), Clarity of Presentation 59.7% (50.0, 75.0), Applicability 27.1% (18.8, 33.3), and Editorial Independence 8.3% (0.0, 45.8). This suggested diversity in quality of different aspects of the guidelines, with very low quality in the critical domain of methodological rigor. There were no statistically significant differences in the overall scores of Indian vs. foreign guidelines, updated versions vs. original versions, and those developed earlier vs. later in the pandemic. CONCLUSION: The currently available pediatric COVID-19 guidelines have low methodological quality, adversely affecting their credibility, validity, and applicability. Urgent corrective strategies are presented for consideration.

Long-term real-world outcomes in retinal vein occlusions: How close are we to the trials?

Purpose: To assess and analyze the visual outcomes of patients with retinal vein occlusions in a real-world setting with a long-term follow-up of more than 5 years. Methods: Retrospective analysis of 56 patients having retinal vein occlusions from a tertiary eye center, with a mean follow-up of 7 years was performed. Primary outcome measures were mean change in best-corrected visual acuity (BCVA) from baseline at 6 months, 1 year, 2 years, 3 years, and final visit (≥5 years), proportion of patients having BCVA better than 20/40 and worse than 20/200, and mean number of injections. Secondary outcome measures were change in central macular thickness (CMT), development of subsequent retinal vein occlusion (RVO) in same eye or the other eye, and development of neovascular complications. Results: The mean change in letter score was + 11.84 in branch RVO (BRVO), +7.14 in non-ischemic central RVO (CRVO), and -9.5 in ischemic CRVO at 1 year, which changed to + 8.57, -5 and - 24, respectively, at the end of follow-up. CMT had improved from 506 ± 98.8 µm, 576.44 ± 149 µm, and 618 ± 178.27 µm, respectively, at baseline to 267 ± 94 µm, 345.20 ± 122.61 µm, and 265.50 ± 107.75 µm, respectively, in BRVO, non-ischemic, and ischemic hemi RVO (HRVO)/CRVO groups. The total mean number of injections given in BRVO, non-ischemic CRVO, and ischemic CRVO groups were 4.6, 6.6, and 4.1, respectively. None of the patients with BRVO developed neovascular glaucoma (NVG). Non-ischemic to ischemic HRVO/CRVO conversion was noted in 4/11 eyes at a mean duration of 12.6 months. NVG was noted in 7/9 eyes (77.8%) in initial ischemic CRVO/HRVO group and 3/4 (75%) converted eyes. Conclusion: Patients with BRVO have good visual outcomes with anti-VEGF, while in CRVO results may vary considerably owing to patient compliance and treatment burden on long-term follow-up in a real-world setting.

Antegrade cystoscopy - An innovative approach to managing acute urinary retention following vulvar reconstruction flap stenosis.

Vulvar reconstruction can be performed following radical vulvectomy and is known to be associated with urologic complications. We describe the use of antegrade cystoscopy to manage acute urinary retention secondary to an obliterated urethral meatus following radical vulvectomy and reconstruction for radiation dermatitis. Antegrade cystoscopy was performed by applying the surgical concepts for suprapubic catheterization and general laparoscopy. Antegrade cystoscopy is a simple and safe approach for female patients with distorted pelvic anatomy from radical surgery and reconstructions for vulvar cancer.

The structure-activity relationships of A-ring-substituted aromathecin topoisomerase I inhibitors strongly support a camptothecin-like binding mode.

Aromathecins are inhibitors of human topoisomerase I (Top1). These compounds are composites of several heteroaromatic systems, namely the camptothecins and indenoisoquinolines, and they possess notable Top1 inhibition and cytotoxicity when substituted at position 14. The SAR of these compounds overlaps with indenoisoquinolines, suggesting that they may intercalate into the Top1-DNA complex similarly. Nonetheless, the proposed binding mode for aromathecins is purely hypothetical, as an X-ray structure is unavailable. In the present communication, we have synthesized eight novel series of A-ring-substituted (positions 1-3) aromathecins, through a simple, modular route, as part of a comprehensive SAR study. Certain groups (such as 2,3-ethylenedioxy) moderately improve Top1 inhibition, and, often, antiproliferative activity, whereas other groups (2,3-dimethoxy and 3-substituents) attenuate bioactivity. Strikingly, these trends are very similar to those previously observed for the A-ring of camptothecins, and this considerable SAR overlap lends further support (in the absence of crystallographic data) to the hypothesis that aromathecins bind in the Top1 cleavage complex as interfacial inhibitors in a 'camptothecin-like' pose.