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.

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.

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.

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.

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.

Informing sleep policy through field experiments.

Evidence is particularly needed from poorer communities.

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.

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.

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.

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.

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.

The Role of Eicosanoids in Gynecological Malignancies.

Eicosanoids, bio-active lipid molecules, evoke a multitude of biological effects that directly affect cancer cells and indirectly affect tumor microenvironment. An emerging role has been shown for eicosanoids in the pathogenesis of gynecological malignancies which include cancers of the vulva, vagina, cervix, uterine, and ovary. Eicosanoid biosynthesis pathways start at the metabolism of phospholipids by phospholipase A2 then proceeding to one of three pathways: the cyclooxygenase (COX), lipoxygenase (LOX), or P450 epoxygenase pathways. The most studied eicosanoid pathways include COX and LOX; however, more evidence is appearing to support further study of the P450 epoxygenase pathway in gynecologic cancers. In this review, we present the current knowledge of the role of COX, LOX and P450 pathways in the pathogenesis of gynecologic malignancies. Vulvar and vaginal cancer, the rarest subtypes, there is association of COX-2 expression with poor disease specific survival in vulvar cancer and, in vaginal cancer, COX-2 expression has been found to play a role in mucosal inflammation leading to disease susceptibility and transmission. Cervical cancer is associated with COX-2 levels 7.4 times higher than in healthy tissues. Additionally, HPV elevates COX-2 levels through the EGFR pathway and HIV promotes elevated COX-2 levels in cervical tissue as well as increases PGE2 levels eliciting inflammation and progression of cancer. Evidence supports significant roles for both the LOX and COX pathways in uterine cancer. In endometrial cancer, there is increased expression of 5-LOX which is associated with adverse outcomes. Prostanoids in the COX pathway PGE2 and PGF2α have been shown to play a significant role in uterine cancer including alteration of proliferation, adhesion, migration, invasion, angiogenesis, and the inflammatory microenvironment. The most studied gynecological malignancy in regard to the potential role of eicosanoids in tumorigenesis is ovarian cancer in which all three pathways have shown to be associated or play a role in ovarian tumorigenesis directly on the tumor cell or through modulation of the tumor microenvironment. By identifying the gaps in knowledge, additional pathways and targets could be identified in order to obtain a better understanding of eicosanoid signaling in gynecological malignancies and identify potential new therapeutic approaches.

Novel Titanium Cages for Minimally Invasive Lateral Lumbar Interbody Fusion: First Assessment of Subsidence.

INTRODUCTION: Implant subsidence is a potential complication of spinal interbody fusion and may negatively affect patients subjected to procedures relying on indirect decompression such as minimally invasive transpsoas lateral lumbar interbody fusion (LLIF). The porous architecture of a recently developed titanium intervertebral cage maximizes bone-to-implant contact and minimizes stress shielding in laboratory experiments; however, its subsidence rate in patients has not yet been evaluated. The goal of this current study was to evaluate implant subsidence in patients subjected to LLIF. METHODS: Our institutional review board-approved single-center experience included 29 patients who underwent 30 minimally invasive LLIF from July 2017 to September 2018 utilizing the novel 3D-printed porous titanium implants. Radiographs, obtained during routine postoperative follow-up visits, were reviewed for signs of implant subsidence, defined as any appreciable compromise of the vertebral endplates. RESULTS: Radiographic subsidence occurred in 2 cases (6.7%), involving 2 out of 59 porous titanium interbody cages (3.4%). Both cases of subsidence occurred in four-level stand-alone constructs. The patients remained asymptomatic and did not require surgical revision. Ten surgeries were stand-alone constructs, and 20 surgeries included supplemental posterior fixation. CONCLUSIONS: In our patient cohort, subsidence of the porous titanium intervertebral cage occurred in 6.7% of all cases and in 3.4% of all lumbar levels. This subsidence rate is lower compared to previously reported subsidence rates in patients subjected to LLIF using polyetheretherketone implants.

Histone Deacetylase SIRT1 Mediates C5b-9-Induced Cell Cycle in Oligodendrocytes.

Sublytic levels of C5b-9 increase the survival of oligodendrocytes (OLGs) and induce the cell cycle. We have previously observed that SIRT1 co-localizes with surviving OLGs in multiple sclerosis (MS) plaques, but it is not yet known whether SIRT1 is involved in OLGs survival after exposure to sublytic C5b-9. We have now investigated the role of SIRT1 in OLGs differentiation and the effect of sublytic levels of C5b-9 on SIRT1 and phosphorylated-SIRT1 (Ser27) expression. We also examined the downstream effects of SIRT1 by measuring histone H3 lysine 9 trimethylation (H3K9me3) and the expression of cyclin D1 as a marker of cell cycle activation. OLG progenitor cells (OPCs) purified from the brain of rat pups were differentiated in vitro and treated with sublytic C5b-9 or C5b6. To investigate the signaling pathway activated by C5b-9 and required for SIRT1 expression, we pretreated OLGs with a c-jun antisense oligonucleotide, a phosphoinositide 3-kinase (PI3K) inhibitor (LY294002), and a protein kinase C (PKC) inhibitor (H7). Our data show a significant reduction in phospho-SIRT1 and SIRT1 expression during OPCs differentiation, associated with a decrease in H3K9me3 and a peak of cyclin D1 expression in the first 24 h. Stimulation of OLGs with sublytic C5b-9 resulted in an increase in the expression of SIRT1 and phospho-SIRT1, H3K9me3, cyclin D1 and decreased expression of myelin-specific genes. C5b-9-stimulated SIRT1 expression was significantly reduced after pretreatment with c-jun antisense oligonucleotide, H7 or LY294002. Inhibition of SIRT1 with sirtinol also abolished C5b-9-induced DNA synthesis. Taken together, these data show that induction of SIRT1 expression by C5b-9 is required for cell cycle activation and is mediated through multiple signaling pathways.

EP4 and Class III ß-Tubulin Expression in Uterine Smooth Muscle Tumors: Implications for Prognosis and Treatment.

The microtubule-stabilizing agent docetaxel in combination with gemcitabine represents one of the most effective regimens against the aggressive gynecologic tumor leiomyosarcoma (LMS). Upregulation of class III ß-tubulin has previously been shown to confer taxane resistance in a variety of human cancers. Prostaglandin E2 receptor EP4 is linked to progression of a variety of human cancers and may represent a novel target for tumor inhibition in LMS. We evaluated the hypotheses that EP4 and class III ß-tubulin have increased expression in LMS in comparison to normal myometrium or benign tumors and that expression of class III ß-tubulin correlates with resistance to taxanes and poor clinical outcome. Gene expression was examined using TCGA data and correlated with clinicopathologic outcome which demonstrated that class III ß-tubulin is more highly expressed in more aggressive sarcomas with EP4 being widely expressed in all subtypes of sarcoma. Immunohistochemistry for EP4 and class III ß-tubulin was performed on patients with LMS, leiomyomatosis/STUMP, leiomyoma, and normal myometrium. Expression of EP4 and class III ß-tubulin were characterized for cell lines SK-UT-1, SK-UT-1B, and PHM-41 and these cell lines were treated with docetaxel alone and in combination with EP4 inhibitors. In taxane-resistant cell lines that overexpress class III ß-tubulin and EP4, treatment with EP4 inhibitor resulted in at least 2-fold sensitization to docetaxel. Expression of class III ß-tubulin and EP4 in LMS may identify patients at risk of resistance to standard chemotherapies and candidates for augmentation of therapy through EP4 inhibition.

Indications and Safety of the Zygomatic Osteotomy in Middle Cranial Fossa Surgery: A Retrospective Cohort Review.

Background Zygomatic osteotomy, an adjunct to middle cranial fossa (MCF) surgical approaches, improves the superior-inferior angle of approach and minimizes temporal lobe retraction. However, a decision-making algorithm for selective use of the zygomatic osteotomy and the impact of the zygomatic osteotomy on surgical complications have not been well documented. Objective We described an algorithm for deciding whether to use a zygomatic osteotomy in MCF surgery and evaluated complications associated with a zygomatic osteotomy. Methods A retrospective review of MCF cases over 11 years at our academic tertiary referral center was conducted. Demographic variables, tumor characteristics, surgical details, and postoperative complications were extracted. Results Of the 87 patients included, 15 (17%) received a zygomatic osteotomy. Surgical trajectory oriented from anterior to posterior (A-P) was significantly correlated with the use of the zygomatic osteotomy. Among the cases approached from A-P, we found (receiver-operating characteristic curve) that the cut-off tumor size that predicted a zygomatic osteotomy was 30 mm. Of the 87 cases included, 15 patients had a complication. The multivariate logistic regression model failed to reveal any significant correlation between complications and zygomatic osteotomies. Conclusions We found that the most important factor determining the use of a zygomatic osteotomy was anticipated trajectory. A-P approaches were most highly correlated with zygomatic osteotomy. Within those cases, a lesion size cut-off of 30 mm was the secondary predicting factor of zygomatic osteotomy use. The odds of suffering a surgical complication were not significantly increased by use of zygomatic osteotomy.

Unusual case of anti-N-methyl-D-aspartic acid-receptor (NMDA-R) encephalitis and autoimmune polyglandular syndrome (APS).

Anti-N-methyl-D-aspartic acid-receptor (NMDA-R) encephalitis is a novel disease discovered within the past 10 years. It is an autoimmune disease (AD) that has been associated with other ADs, such as Graves' disease. However, association with autoimmune polyglandular syndromes (APS) has not been previously described. A 58-year-old woman presented with altered mental status and an 8-month history of weight loss, apathy and somnolence. Laboratory evaluation confirmed Graves' disease with thyrotoxicosis and type 1 diabetes mellitus. Despite treatment, she continued to have a fluctuating mental status. Further diagnostic evaluation included an abdominal MRI that showed a cystic lobular left adnexal mass. Serum anti-NMDA-R antibodies were positive, raising concern for NMDA-R encephalitis. Bilateral salpingo-oophorectomy was performed, with pathology consistent with cystadenofibroma. She had a favourable recovery with marked clinical improvement. Anti-NMDA-R antibodies were negative 2 months following surgery. The concomitant occurrence of APS and anti-NMDA-R encephalitis suggests a shared mechanism of autoimmune pathophysiology.