Cisplatin induces BDNF downregulation in middle-aged female rat model while BDNF enhancement attenuates cisplatin neurotoxicity.

Cancer-related cognitive impairments (CRCI) are neurological complications associated with cancer treatment, and greatly affect cancer survivors' quality of life. Brain-derived neurotrophic factor (BDNF) plays an essential role in neurogenesis, learning and memory. The reduction of BDNF is associated with the decrease in cognitive function in various neurological disorders. Few pre-clinical studies have reported on the effects of chemotherapy and medical stress on BDNF levels and cognition. The present study aimed to compare the effects of medical stress and cisplatin on serum BDNF levels and cognitive function in 9-month-old female Sprague Dawley rats to age-matched controls. Serum BDNF levels were collected longitudinally during cisplatin treatment, and cognitive function was assessed by novel object recognition (NOR) 14 weeks post-cisplatin initiation. Terminal BDNF levels were collected 24 weeks after cisplatin initiation. In cultured hippocampal neurons, we screened three neuroprotective agents, riluzole (an approved treatment for amyotrophic lateral sclerosis), as well as the ampakines CX546 and CX1739. We assessed dendritic arborization by Sholl analysis and dendritic spine density by quantifying postsynaptic density-95 (PSD-95) puncta. Cisplatin and exposure to medical stress reduced serum BDNF levels and impaired object discrimination in NOR compared to age-matched controls. Pharmacological BDNF augmentation protected neurons against cisplatin-induced reductions in dendritic branching and PSD-95. Ampakines (CX546 and CX1739) and riluzole did not affect the antitumor efficacy of cisplatin in vitro. In conclusion, we established the first middle-aged rat model of cisplatin-induced CRCI, assessing the contribution of medical stress and longitudinal changes in BDNF levels on cognitive function, although future studies are warranted to assess the efficacy of BDNF enhancement in vivo on synaptic plasticity. Collectively, our results indicate that cancer treatment exerts long-lasting changes in BDNF levels, and support BDNF enhancement as a potential preventative approach to target CRCI with therapeutics that are FDA approved and/or in clinical study for other indications.

Cisplatin Induces BDNF Downregulation in Middle-Aged Female Rat Model while BDNF Enhancement Attenuates Cisplatin Neurotoxicity.

Cancer-related cognitive impairments (CRCI) are debilitating consequences of cancer treatment with platinum agents (e.g., cisplatin) that greatly alter cancer survivors' health-related quality of life. Brain-derived neurotrophic factor (BDNF) plays an essential role in neurogenesis, learning, and memory, and the reduction of BDNF is associated with the development of cognitive impairment in various neurological disorders, including CRCI. Our previous CRCI rodent studies have shown that cisplatin reduces hippocampal neurogenesis and BDNF expression and increases hippocampal apoptosis, which is associated with cognitive impairments. Few studies have reported on the effects of chemotherapy and medical stress on serum BDNF levels and cognition in middle-aged female rat models. The present study aimed to compare the effects of medical stress and cisplatin on serum BDNF levels and cognitive performance in 9-month-old female Sprague Dawley rats to age-matched controls. Serum BDNF levels were collected longitudinally during cisplatin treatment, and cognitive function was assessed by novel object recognition (NOR) 14 weeks post-cisplatin initiation. Terminal BDNF levels were collected ten weeks after cisplatin completion. We also screened three BDNF-augmenting compounds, riluzole, ampakine CX546, and CX1739, for their neuroprotective effects on hippocampal neurons, in vitro . We assessed dendritic arborization by Sholl analysis and dendritic spine density by quantifying postsynaptic density-95 (PSD95) puncta. Cisplatin and exposure to medical stress reduced serum BDNF levels and impaired object discrimination in NOR compared to age-matched controls. Pharmacological BDNF augmentation protected neurons against cisplatin-induced reductions in dendritic branching and PSD95. Ampakines (CX546 and CX1739) but not riluzole altered the antitumor efficacy of cisplatin in two human ovarian cancer cell lines, OVCAR8 and SKOV3.ip1, in vitro. In conclusion, we established the first middle-aged rat model of cisplatin-induced CRCI, assessing the contribution of medical stress and longitudinal changes in BDNF levels with cognitive function. We conducted an in vitro screening of BDNF-enhancing agents to evaluate their potential neuroprotective effects against cisplatin-induced neurotoxicity and their effect on ovarian cancer cell viability.

Rapid progression of cervical squamous cell carcinoma with delayed treatment in pregnancy.

•Delayed treatment of cervical cancer in pregnancy can result in progression.•Surveillance of cervical cancer in pregnancy with pelvic MRIs every 6 weeks.•Comprehensive multidisciplinary care is essential in setting of treatment delays.

Visual inspection with acetic acid screening for cervical cancer among women receiving anti-retroviral therapy for human immunodeficiency virus infection in northern Tanzania.

AIM: To evaluate visual inspection with acetic acid (VIA) screening for cervical cancer among human immunodeficiency virus (HIV)-positive patients in an East African community. METHODS: During a July 2018 cervical cancer screen-and-treat in Mwanza, Tanzania, participants were offered free cervical VIA screening, cryotherapy when indicated, and HIV testing. Acetowhite lesions and/or abnormal vascularity were designated VIA positive in accordance with current guidelines. The association between VIA results and HIV status was compared using Chi-square and Fisher exact tests. RESULTS: Eight hundred and twenty-four of 921 consented participants underwent VIA screening and 25.0% (n = 206) were VIA positive. VIA-positive nonpregnant women (n = 147) received cryotherapy and 15 (1.8%) with cancerous-appearing lesions were referred to Bugando Hospital. Sixty-six women were HIV-positive and included 25 diagnosed with HIV at the cervical cancer VIA screening and 41 with a prior diagnosis of HIV who were receiving antiretroviral therapy (ART) at the time of cervical cancer VIA screening. Sixty-four of these 66 patients, were screened with VIA. HIV infection was not associated with VIA findings. Abnormal VIA positive screening was observed in 20.3% (n = 13) of HIV-positive patients and in 24.4% (n = 145) of HIV-negative patients (p = 0.508). A nonsignificant trend of higher VIA positive screens among newly diagnosed HIV patients of 26.1% (n = 6) versus patients with preexisting HIV on ART of 17.1% (n = 7) was observed (p = 0.580). CONCLUSION: The unexpected lack of correlation between HIV infection and VIA positivity in a community with access to ART warrants additional research regarding the previously described role of ART in attenuating HPV-mediated neoplasia.

Lung cancer diagnosed on pap smear: A case report and review of the literature.

•Pap smear test can detect metastases of extragenital malignancies.•Metastases of extragenital cancers to the cervix are predominantly adenocarcinomas.•Immunostaining is critical in determining the primary cancer site.

Implementation of human papillomavirus video education for women participating in mass cervical cancer screening in Tanzania.

BACKGROUND: Because the global disease burden of cervical cancer is greatest in Africa, the World Health Organization has endorsed visual inspection with acetic acid screening with cryotherapy triage for the screen-and-treat approach. With the lowest doctor-to-patient ratio worldwide (1:50,000), Tanzania has nearly 10,000 new cases of cervical cancer and 7000 deaths annually. OBJECTIVE: We report on the feasibility of visual inspection with acetic acid in the severely resource-limited Mwanza district and on the impact of intervening education on baseline human papillomavirus and cervical cancer knowledge. STUDY DESIGN: Two 5-day free visual inspection with acetic acid (VIA) clinics in urban Buzuruga and rural Sangabuye on the shores of Lake Victoria were approved by our university institutional review board and local Tanzanian health authorities. Participants completed a demographic survey and a 6-question (1 point per question) multiple choice test written in Kiswahili to assess baseline knowledge. A 15-minute educational video in Kiswahili (MedicalAidFilms: Understanding screening, treatment, and prevention of cervical cancer) was followed by repeated assessment using the same test, visual inspection with acetic acid screening, and optional HIV testing. Pre- and postvideo scores and change of score were analyzed via t test, analysis of variance, and multivariate regression. Significance was considered at P<.05. RESULTS: From July 2, 2018 to July 6, 2018, 825 women were screened, and 207 women (25.1%) were VIA positive (VIA+). One hundred forty-seven VIA+ nonpregnant women received same-day cryotherapy. Seven hundred sixty women participated in an educational intervention-61.6% of whom were from an urban site and 38.2% from a rural site. The mean age was 36.4 (standard deviation, 11.1). Primary languages were Kiswahili (62.2%) and Kisukuma (30.6%). Literacy was approximately 73%, and average education level was equivalent to the seventh grade (United States). Less than 20% of urban and rural women reported access to healthcare providers. Mean score of the participants before watching the video was 2.22 (standard deviation, 1.76) and was not different between VIA+ and VIA negative groups. Mean score of the participants after watching the video was 3.86 (standard deviation, 1.78). Postvideo scores significantly improved regardless of age group, clinic site, primary language, education level, literacy, or access to healthcare provider (P<.0001). Change of score after watching the video was significantly greater in participants from urban areas (1.99±2.07) than in those from rural areas (1.07±1.95) (P<.0001). Multivariate analysis identified urban site as an independent factor in change of score (P=.0211). CONCLUSION: Visual inspection with acetic acid screening for cervical cancer is feasible and accepted in northern Tanzania. Short video-based educational intervention improved baseline knowledge on the consequences of human papillomavirus infection in the studied populations. The impact was greater in the urban setting than in the rural setting.

Mitochondrial-associated impairments of temozolomide on neural stem/progenitor cells and hippocampal neurons.

Primary brain tumor patients often experience neurological, cognitive, and depressive symptoms that profoundly affect quality of life. The DNA alkylating agent, temozolomide (TMZ), along with radiation therapy forms the standard of care for glioblastoma (GBM) - the most common and aggressive of all brain cancers. Numerous studies have reported that TMZ disrupts hippocampal neurogenesis and causes spatial learning deficits in rodents; however, the effect of TMZ on mature hippocampal neurons has not been addressed. In this study, we examined the mitochondrial-mediated mechanisms involving TMZ-induced neural damage in primary rat neural stem/progenitor cells (NSC) and hippocampal neurons. TMZ inhibited mtDNA replication and transcription of mitochondrial genes (ND1 and Cyt b) in NSC by 24 h, whereas the effect of TMZ on neuronal mtDNA transcription was less pronounced. Transmission electron microscopy imaging revealed mitochondrial degradation in TMZ-treated NSC. Acute TMZ exposure (4 h) caused a rapid reduction in dendritic branching and loss of postsynaptic density-95 (PSD95) puncta on dendrites. Longer TMZ exposure impaired mitochondrial respiratory activity, increased oxidative stress, and induced apoptosis in hippocampal neurons. The presented findings suggest that NSC may be more vulnerable to TMZ than hippocampal neurons upon acute exposure; however long-term TMZ exposure results in neuronal mitochondrial respiratory dysfunction and dendritic damage, which may be associated with delayed cognitive impairments.

Targeted treatment of advanced ovarian cancer: spotlight on rucaparib.

The last 2 years have ushered in a new era in ovarian cancer therapy with the US Food and Drug Administration's (FDA) approval of poly-ADP ribose polymerase (PARP) inhibitors (PARPi). One of the deadliest cancers that women experience, ovarian cancer, is most often diagnosed in advanced stages. Although cytoreductive surgery and (platinum/taxane-based) chemotherapy can place the majority of patients into remission, most will experience a relapse of their disease in their lifetime. This has led to studies exploring the benefits and efficacy of maintenance treatment. This review will briefly discuss the history of maintenance therapy as well as focus on the FDA's approval of rucaparib and its companion tumor profiling test, in the US. It will describe how women with deleterious mutations in the BRCA gene, through their inherent deficiency in homologous recombination, presented scientists with a target to exploit through a concept known as synthetic lethality. Not only did this lead to a targeted treatment for BRCA mutation carriers but for other patients with deficiencies in homologous recombination and, more broadly, also in platinum-sensitive patients. The focus of this review will be on rucaparib in the US, approved for both maintenance of platinum-sensitive recurrent ovarian cancer and treatment in the third-line setting and beyond. It has the broadest indication amongst the three PARPi in ovarian cancer. Furthermore, the ongoing trials using rucaparib in ovarian cancer and other disease types will be discussed.

Chemotherapy-related cognitive dysfunction and effects on quality of life in gynecologic cancer patients.

INTRODUCTION: chemotherapy-related cognitive dysfunction (CRCD) is a growing problem due to rising cancer rates and increasing numbers of cancer survivors. upwards of 70% of ovarian cancer patients report cognitive-changes following treatment for their cancer. AREAS COVERED: the underlying mechanisms of CRCD are a subject of active research and debate. the initial insult may start with the diagnosis of cancer itself, both in the number of peripheral cytokines it produces but also in the psychological changes caused by stress and anxiety associated with the diagnosis. chemotherapy, in its ability to alter dna in the replication cycle, has been shown to damage neurons and their stem cell precursors. EXPERT COMMENTARY: based on proposed mechanisms and advancements in other neuropsychological diseases, various pharmacologic and behavioral interventions have been demonstrated to show improvements in patient's quality of life and in their perceived cognitive abilities and memory. further research is necessary to be able to determine when and how these cognitive changes occur, and if their multiple potential biological underpinnings can synergize toward deleterious cognitive effects. future therapies will include prevention strategies to avert CRCD's effects on patients.

Solitary fibrous tumor of the vulva resulting in spinal metastasis: A case report.

•Solitary fibrous tumors are typically indolent tumors of the pleura.•Primary origin in the female reproductive organs is rare, as are aggressive forms.•We report a case of a vulvar solitary fibrous tumor, notable for extensive spinal metastasis.