Selective targeting of metastatic ovarian cancer using an engineered anthrax prodrug activated by membrane-anchored serine proteases.

Treatments for advanced and recurrent ovarian cancer remain a challenge due to a lack of potent, selective, and effective therapeutics. Here, we developed the basis for a transformative anticancer strategy based on anthrax toxin that has been engineered to be selectively activated by the catalytic power of zymogen-activating proteases on the surface of malignant tumor cells to induce cell death. Exposure to the engineered toxin is cytotoxic to ovarian tumor cell lines and ovarian tumor spheroids derived from patient ascites. Preclinical studies demonstrate that toxin treatment induces tumor regression in several in vivo ovarian cancer models, including patient-derived xenografts, without adverse side effects, supportive of progression toward clinical evaluation. These data lay the groundwork for developing therapeutics for treating women with late-stage and recurrent ovarian cancers, utilizing a mechanism distinct from current anticancer therapies.

Microtubule-Targeting Agents: Disruption of the Cellular Cytoskeleton as a Backbone of Ovarian Cancer Therapy.

Microtubules are dynamic polymers composed of α- and ß-tubulin heterodimers. Microtubules are universally conserved among eukaryotes and participate in nearly every cellular process, including intracellular trafficking, replication, polarity, cytoskeletal shape, and motility. Due to their fundamental role in mitosis, they represent a classic target of anti-cancer therapy. Microtubule-stabilizing agents currently constitute a component of the most effective regimens for ovarian cancer therapy in both primary and recurrent settings. Unfortunately, the development of resistance continues to present a therapeutic challenge. An understanding of the underlying mechanisms of resistance to microtubule-active agents may facilitate the development of novel and improved approaches to this disease.

Randomised phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum-resistant or refractory ovarian/fallopian tube/primary peritoneal cancer.

BACKGROUND: This multi-center RP2 study assessed activity/safety of ixabepilone + bevacizumab compared to ixabepilone in platinum-resistant/refractory ovarian/fallopian tube/primary peritoneal cancer. Additional objectives were to examine the role of prior bevacizumab and taxanes, and explore class III-ß-tubulin (TUBB3) as a predictive biomarker. METHODS: Participants were randomised to receive ixabepilone 20 mg/m2 days 1, 8, 15 with (IXA + BEV) or without (IXA) bevacizumab 10 mg/kg days 1, 15 every 28 days. Patients were stratified by prior BEV. The primary endpoint was PFS. OS, safety, and ORR served as secondary endpoints. RESULTS: Among 76 evaluable patients who received IXA + BEV (n = 39) compared to IXA (n = 37), the ORR was 33% (n = 13) versus 8% (n = 3)(P = 0.004), durable at 6 months in 37% (n = 14) and 3% (n = 1) (P < 0.001). BEV significantly improved PFS (median:5.5 vs 2.2 months, HR = 0.33, 95%CI 0.19-0.55, P < 0.001) and OS (median:10.0 vs 6.0 months, HR = 0.52, 95%CI 0.31-0.87, P = 0.006). Both regimens were well-tolerated. TUBB3 expression did not predict response. Subgroup analyses revealed minimal effect of prior BEV or taxane resistant/refractory status on response to IXA + BEV. CONCLUSIONS: IXA + BEV is a well-tolerated, effective combination for platinum/taxane-resistant ovarian cancer that extends PFS and likely OS relative to IXA monotherapy. Prior receipt of BEV should not preclude the use of IXA + BEV. TUBB3 is not a predictive biomarker. CLINICAL TRIAL REGISTRATION: NCT3093155.

Congenital Heart Diseases Associated With Cleft Lip and Palate and Its Impact on Surgical Treatment Planning of Patients With Cleft Lip and Palate-A Cross-Sectional Study.

OBJECTIVES: The aim of this study is to know the prevalence, type of congenital heart diseases (CHDs), and its association with cleft lip and/or palate and to know the impact of CHDs on surgical treatment planning of cleft lip and palate from a craniofacial hospital specializing in orofacial clefts, head and neck cancer, and trauma management. DESIGN: A total of 1381 patients with nonsyndromic cleft lip and palate were included in the study. This is a hospital-based retro-prospective case record analysis. The data were collected from clinical records of the patients which included clinical, chest radiographic and 2D echocardiographic findings. Total incidence of CHDs and its impact on treatment planning was evaluated using κ statistics and χ2 test. RESULTS: There were 32 (2.32%) cleft lip and palate patients with CHDs. In 2 patients, cleft surgery was delayed by 6 to 9 months to allow the defect to decrease in size. Subacute bacterial endocarditis prophylaxis was administered in 7 patients before cleft surgery. Cardiac surgery was advised prior to cleft surgery in 3 patients. Sixteen patients with CHDs were not taken for cleft surgery considering the potential risk to the patient's life as they had multiple cardiac anomalies. There were no intraoperative and postoperative complications in these patients. CONCLUSION: The results emphasize the association between clefting and CHD. The collected data suggest that there should be careful examination of children with cleft lip and palate for signs of heart disease. This could significantly reduce the morbidity/mortality of cleft lip and palate surgery making it more predictable and safer.

Pelvic floor disorders in women with gynecologic malignancies: a systematic review.

INTRODUCTION AND HYPOTHESIS: Pelvic floor disorders (PFDs) negatively affect quality of life in the general population, and their prevalence in gynecologic cancer survivors has not been systematically described. This study aimed to determine the prevalence of PFDs in cancer survivors. We hypothesized that the prevalence of PFDs in the gynecologic cancer population would be higher than in the general female population. METHODS: We searched PubMed (1809 to present), EMBASE (1974 to present), and the Cochrane Central Register of Controlled Trials (CENTRAL) through May 2017. The search combined subject headings, title, and abstract words for gynecologic cancer, PFDs, and prevalence. Any studies evaluating the prevalence of PFDs in gynecologic malignancies were included. RESULTS: A total of 550 articles met the designated search criteria and 31 articles were included in this review. In cervical cancer survivors, before treatment the prevalences of stress urinary incontinence (SUI), urgency urinary incontinence (UUI) and fecal incontinence (FI) were 24-29%, 8-18% and 6%, respectively, and after treatment the prevalences of SUI, UUI, urinary retention, FI, fecal urge, dyspareunia and vaginal dryness were 4-76%, 4-59%, 0.4-39%, 2-34%, 3-49%, 12-58% and 15-47%, respectively. In uterine cancer survivors, before treatment the prevalences of SUI, UUI and FI were 29-36%, 15-25% and 3%, respectively, and after treatment the prevalences of urinary incontinence (UI) and dyspareunia were 2-44% and 7-39%, respectively. In vulvar cancer survivors, after treatment the prevalences of UI, SUI and FI were 4-32%, 6-20% and 1-20%, respectively. In ovarian cancer survivors, the prevalences of SUI, UUI, prolapse and sexual dysfunction were 32-42%, 15-39%, 17% and 62-75%, respectively. CONCLUSIONS: PFDs are prevalent in gynecologic cancer survivors and this is an important area of clinical concern and future research.

SIRT1 as a potential biomarker of response to treatment with glatiramer acetate in multiple sclerosis.

SIRT1, a NAD dependent histone and protein deacetylase, is a member of the histone deacetylase class III family. We previously showed that SIRT1 mRNA expression is significantly lower in peripheral blood mononuclear cells (PBMCs) of multiple sclerosis (MS) patients during relapses than in stable patients. We have now investigated SIRT1 as a possible biomarker to predict relapse as well as responsiveness to glatiramer acetate (GA) treatment in relapsing-remitting MS (RRMS) patients. Over the course of 2years, a cohort of 15 GA-treated RRMS patients were clinically monitored using the Expanded Disability Status Scale and assessed for MS relapses. Blood samples collected from MS patients were analyzed for levels of SIRT1 and histone H3 lysine 9 (H3K9) acetylation and dimethylation. During relapses, MS patients had a lower expression of SIRT1 mRNA than did stable MS patients. In addition, there was a significant decrease in H3K9 dimethylation (H3K9me2) during relapses in MS patients when compared to stable patients (p=0.01). Responders to GA treatment had significantly higher SIRT1 mRNA (p=0.01) and H3K9me2 levels than did non-responders (p=0.018). Receiver operating characteristic analysis was used to assess the predictive power of SIRT1 and H3K9me2 as putative biomarkers: for SIRT1 mRNA, the predictive value for responsiveness to GA treatment was 70% (p=0.04) and for H3K9me2 was 71% (p=0.03). Our data suggest that SIRT1 and H3K9me2 could serve as potential biomarkers for evaluating patients' responsiveness to GA therapy in order to help guide treatment decisions in MS.

ACR Appropriateness Criteria® Adjuvant Management of Early-Stage Endometrial Cancer.

These consensus guidelines on adjuvant radiotherapy for early-stage endometrial cancer were developed from an expert panel convened by the American College of Radiology. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method; and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. After a review of the published literature, the panel voted on three variants to establish best practices for the utilization of imaging, radiotherapy, and chemotherapy after primary surgery for early-stage endometrial cancer.

RGC-32 as a potential biomarker of relapse and response to treatment with glatiramer acetate in multiple sclerosis.

Currently there is critical need for the identification of reliable biomarkers to help guide clinical management of multiple sclerosis (MS) patients. We investigated the combined roles of Response Gene to Complement 32 (RGC-32), FasL, CDC2, AKT, and IL-21 as possible biomarkers of relapse and response to glatiramer acetate (GA) treatment in relapsing-remitting MS (RRMS) patients. Over the course of 2 years, a cohort of 15 GA-treated RRMS patients was clinically monitored and peripheral blood mononuclear cells (PBMCs) were collected at 0, 3, 6, and 12 months. Target gene mRNA expression was measured in patients' isolated PBMCs by real-time qRT-PCR. Compared to stable MS patients, those with acute relapses exhibited decreased expression of RGC-32 (p<0.0001) and FasL (p<0.0001), increased expression of IL-21 (p=0.04), but no change in CDC2 or AKT. Compared to non-responders, responders to GA treatment showed increased expression of RGC-32 (p<0.0001) and FasL (p<0.0001), and decreased expression of IL-21 (p=0.02). Receiver operating characteristic (ROC) analysis was used to assess the predictive accuracy of each putative biomarker. The probability of accurately detecting relapse was 90% for RGC-32, 88% for FasL, and 75% for IL-21. The probability of accurately detecting response to GA was 85% for RGC-32, 90% for FasL, and 85% for IL-21. Our data suggest that RGC-32, FasL, and IL-21 could serve as potential biomarkers for the detection of MS relapse and response to GA therapy.

ACR Appropriateness Criteria® Adjuvant Therapy in Vulvar Cancer.

These American College of Radiology consensus guidelines were formed from an expert panel on the appropriate use of adjuvant therapy in vulvar cancer after primary treatment with surgery. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. The panel reviewed the pertinent literature in vulvar cancer and voted on three variants to establish appropriate use of imaging, adjuvant radiation, including dose, fields, and technique, as well as adjuvant chemotherapy. This report will aid clinicians in selecting appropriate patients for adjuvant treatment and will provide guidelines for the optimal delivery of adjuvant radiation therapy and chemotherapy.

Acr appropriateness Criteria management of vaginal cancer.

Due to its rarity, treatment guidelines for vaginal cancer are extrapolated from institutional reports and prospective studies of cervical and anal cancer. An expert panel was convened to reach consensus on the selection of imaging and therapeutic modalities. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) used by the panel to rate the appropriateness of imaging and treatment procedures. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Four variants were developed to represent clinical scenarios in vaginal cancer management. Group members reached consensus on the appropriateness of the pretreatment evaluation and therapeutic interventions. This article represents the consensus opinion of an expert panel and may be used to inform clinical recommendations in vaginal cancer management.

Clinical Outcomes of Intensity Modulated Proton Therapy Reirradiation for Gynecologic Malignancies.

Purpose: Pelvic reirradiation (re-RT) for patients with gynecologic cancers remains a challenge because of toxicity concerns. Given the dosimetric advantages of proton therapy, we aimed to assess oncologic and toxicity outcomes of patients with re-RT to the pelvis/abdomen with intensity modulated proton therapy (IMPT) for gynecologic cancers. Methods and Materials: We performed a retrospective analysis of all patients with gynecologic cancer treated at a single institution between 2015 and 2021 with IMPT re-RT. Patients were included for analysis if the IMPT plan had at least partial overlap with the treated volume of a previous radiation treatment. Results: A total of 29 patients were included for analysis, with 30 total courses of re-RT. The majority of patients had been treated previously with conventional fractionation to a median dose of 49.2 Gy (30-61.6 Gy). With a median follow-up of 23 months, 1-year local control was 83.5% and overall survival was 65.7%. Three patients (10%) developed acute and late grade 3 toxicity. One-year freedom from late grade 3+ toxicity was 96.3%. Conclusions: This is the first complete analysis of clinical outcomes for re-RT with IMPT for gynecologic malignancies. We demonstrate excellent local control and acceptable acute and late toxicity. IMPT should strongly be considered for treatments requiring re-RT for gynecologic malignancies.

ACR Appropriateness Criteria® role of adjuvant therapy in the management of early stage cervical cancer.

OBJECTIVE: The use of adjuvant treatment(s) following initial hysterectomy and retroperitoneal nodal harvesting of patients with clinical stage I and II cervical carcinoma is (are) presently based on the pathological assessment of surgical specimens. This report sought to delineate further the clinical application of potential therapeutic interventions and associated follow-up investigations of this patient cohort. METHODS: The American College of Radiology (ACR) Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journal and the application of a well-established consensus methodology (modified Delphi) to rate appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. RESULTS: From this process, 5 unique clinical variants were developed. These scenarios pertained to options of adjuvant radiation therapy and chemotherapy, methods of delivery of radiotherapy to optimize target volume coverage while simultaneously minimizing radiation exposure of adjacent healthy organs, and recommendations for patient follow-up care. Group members reached consensus of topic ratings in descending order of importance. A risk assessment breakdown was established to highlight the most likely indications for adjuvant treatment(s). CONCLUSION: This assembly by the ACR of physicians involved in the management of patients with early stage cervical cancer was able to describe appropriateness criteria to aid other practitioners in selecting reasonable implementation of postoperative therapies and subsequent surveillance studies. These guidelines await further validation and refinement by both current and future prospectively randomized clinical studies regarding this patient population.

Microtentacle Formation in Ovarian Carcinoma.

BACKGROUND: The development of chemoresistance to paclitaxel and carboplatin represents a major therapeutic challenge in ovarian cancer, a disease frequently characterized by malignant ascites and extrapelvic metastasis. Microtentacles (McTNs) are tubulin-based projections observed in detached breast cancer cells. In this study, we investigated whether ovarian cancers exhibit McTNs and characterized McTN biology. METHODS: We used an established lipid-tethering mechanism to suspend and image individual cancer cells. We queried a panel of immortalized serous (OSC) and clear cell (OCCC) cell lines as well as freshly procured ascites and human ovarian surface epithelium (HOSE). We assessed by Western blot ß-tubulin isotype, α-tubulin post-translational modifications and actin regulatory proteins in attached/detached states. We studied clustering in suspended conditions. Effects of treatment with microtubule depolymerizing and stabilizing drugs were described. RESULTS: Among cell lines, up to 30% of cells expressed McTNs. Four McTN morphologies (absent, symmetric-short, symmetric-long, tufted) were observed in immortalized cultures as well as ascites. McTN number/length varied with histology according to metastatic potential. Most OCCC overexpressed class III ß-tubulin. OCCC/OSC cell lines exhibited a trend towards more microtubule-stabilizing post-translational modifications of α-tubulin relative to HOSE. Microtubule depolymerizing drugs decreased the number/length of McTNs, confirming that McTNs are composed of tubulin. Cells that failed to form McTNs demonstrated differential expression of α-tubulin- and actin-regulating proteins relative to cells that form McTNs. Cluster formation is more susceptible to microtubule targeting agents in cells that form McTNs, suggesting a role for McTNs in aggregation. CONCLUSIONS: McTNs likely participate in key aspects of ovarian cancer metastasis. McTNs represent a new therapeutic target for this disease that could refine therapies, including intraperitoneal drug delivery.

Effect of normal variations on disease classification of Raman spectra from cervical tissue.

In this paper, we examine how variations in normal tissue can influence disease classification of Raman spectra. Raman spectra from normal areas may be affected by previous disease or proximity to areas of dysplasia. Spectra were acquired in vivo from 172 patients and classified into five tissue categories: true normal (no history of disease), previous disease normal (history of disease, current normal diagnosis), adjacent normal (disease on cervix, spectra acquired from visually normal area), low grade, and high grade. Taking into account the various "normal" states of the tissue before statistical analysis led to a disease classification accuracy of 97%. These results indicate that abnormal changes significantly affect Raman spectra, even when areas are histopathologically normal. The sensitivity of Raman spectroscopy to subtle biochemical differences must be considered in order to successfully implement it in a clinical setting for diagnosing cervical dysplasia and cancer.

The Economic Consequences of Increasing Sleep Among the Urban Poor.

The urban poor in developing countries face challenging living environments, which may interfere with good sleep. Using actigraphy to measure sleep objectively, we find that low-income adults in Chennai, India, sleep only 5.5 hours a night on average despite spending 8 hours in bed. Their sleep is highly interrupted, with sleep efficiency-sleep per time in bed-comparable to those with disorders such as sleep apnea or insomnia. A randomized three-week treatment providing information, encouragement, and improvements to home sleep environments increased sleep duration by 27 minutes a night by inducing more time in bed. Contrary to expert predictions and a large body of sleep research, increased nighttime sleep had no detectable effects on cognition, productivity, decision making, or well being, and led to small decreases in labor supply. In contrast, short afternoon naps at the workplace improved an overall index of outcomes by 0.12 standard deviations, with significant increases in productivity, psychological well-being, and cognition, but a decrease in work time.

Informing sleep policy through field experiments.

Evidence is particularly needed from poorer communities.

The Safety and Efficacy of Stand-Alone Lateral Lumbar Interbody Fusion for Adjacent Segment Disease in a Cohort of 44 Patients.

BACKGROUND: A mainstay of treatment for symptomatic adjacent segment disease (ASD) has consisted of revision with posterior decompression and fusion. This carries significant morbidity and can be technically difficult. An alternative is stand-alone lateral lumbar interbody fusion (LLIF), which may avoid complications associated with revision surgery. We describe the largest cohort of patients treated with LLIF for ASD to our knowledge. METHODS: We conducted a retrospective cohort study on all patients who underwent transpsoas LLIF for ASD at a single academic center between 2012 and 2019. Postoperative improvement was measured using the Visual Analog Scale (VAS) and the Oswestry Disability Index (ODI). RESULTS: Forty-four patients who underwent LLIF for ASD were identified. Median age was 65 years. Median time from index surgery to ASD development was 78 months. Median levels fused via LLIF was 1. Our median follow-up was 358 days. At follow-up, the median VAS back pain score was 0 (mean, 0.884), median VAS leg pain score was 1 (mean, 0.953), and median ODI was 8. The median improvement for VAS back pain was 8, for VAS leg pain was 6, and for ODI was 40. No patients suffered new neurologic symptoms postoperatively. Of the 17 patients who initially presented with non-pain neurologic symptoms, 8 (47.1%) experienced complete resolution of symptoms, and 5 (29.4%) experienced only some improvement. CONCLUSIONS: To our knowledge, this is the largest cohort study of patients to date evaluating stand-alone LLIF for ASD. Our patient outcomes show it is safe and effective with low risk of morbidity.

Clear cell odontogenic carcinoma of maxilla: A rare case report.

Clear cell odontogenic carcinoma is a rare, infrequent, aggressive in nature, locally reoccurring odontogenic tumor with a tendency of distant metastasis, occurring during to 4th to 6th decades with a mostly female predilection. Histologically, it is characterized by sheets and islands of vacuolated/clear cells. Till date, only 74 cases have been reported in the literature. We present a case of 45-year-old woman with a tumor mass extending from the maxillary right first premolar till the third molar region measuring 4 cm × 4 cm. The diagnosis was given based on the histopathological findings. Being locally aggressive, the reported data and understanding of this infrequent tumor needs to be strengthened by reporting new cases, and it also demands to be distinguished from other primary and metastatic clear cell tumors of the head-and-neck region.

Poverty, depression, and anxiety: Causal evidence and mechanisms.

Why are people who live in poverty disproportionately affected by mental illness? We review the interdisciplinary evidence of the bidirectional causal relationship between poverty and common mental illnesses-depression and anxiety-and the underlying mechanisms. Research shows that mental illness reduces employment and therefore income, and that psychological interventions generate economic gains. Similarly, negative economic shocks cause mental illness, and antipoverty programs such as cash transfers improve mental health. A crucial step toward the design of effective policies is to better understand the mechanisms underlying these causal effects.