Therapies in Cervical Cancer-Editorial.

George Papanikolaou is famously quoted as saying "the first observation of cancer cells in the smear of the uterine cervix gave me one of the greatest thrills I ever experienced during my scientific career" [...].

A single centre evaluation of the 2019 UK SABR consortium guidelines for primary lung cancer: correlation between Prescription Dose Spillage and inverse Paddick Conformity Index.

Background: The aim of the study was to determine level of agreement between RTOG Conformity Index (RTOG-CI), Paddick Conformity Index (PCI) and Prescription Dose Spillage (PDS) in describing lung stereotactic ablative radiotherapy (SABR) plan conformity; to elucidate any limitations, in practice, of PCI and PDS. International Commission on Radiation Units and Measurements report 91 (ICRU 91) aimed to reduce inconsistencies in dose prescription and normalisation between centres by specifying SABR reporting rules, and suggested using PCI. UK SABR Consortium 2019 guidelines adopted PDS to measure plan quality, but not the PCI. Materials and methods: 51 consecutive lung SABR plans received 54 Gy in 3 fractions (54 Gy/3 Fr), 55 Gy/5 Fr or 60 Gy/8 Fr. Plans were developed according to 2016 UK SABR consortium guidelines, which did not specify PCI or PDS; these values were retrospectively calculated. As PCI varies from 0 to an optimum of 1, inverse PCI (invPCI) was used for calculations. Results: PTV-adjusted PDS tolerances were met in 80.4% of studied plans. A near-perfect positive correlation between invPCI and PDS (R2 = 0.978) was found - stronger than between invPCI and the previously-used RTOG-CI (R2 = 0.915). Conclusions: The strong invPCI-PDS correlation is likely dependent on adequate PTV coverage, present in our cohort. This supports the UK SABR Consortium's adoption of PDS provided PTV coverage is ensured. Plan conformity should be confirmed by visual slice-by-slice review.

British Gynaecological Cancer Society recommendations for women with gynecological cancer who received non-standard care during the COVID-19 pandemic.

During the COVID-19 pandemic, pressures on clinical services required adaptation to how care was prioritised and delivered for women with gynecological cancer. This document discusses potential 'salvage' measures when treatment has deviated from the usual standard of care. The British Gynaecological Cancer Society convened a multidisciplinary working group to develop recommendations for the onward management and follow-up of women with gynecological cancer who have been impacted by a change in treatment during the pandemic. These recommendations are presented for each tumor type and for healthcare systems, and the impact on gynecological services are discussed. It will be important that patient concerns about the impact of COVID-19 on their cancer pathway are acknowledged and addressed for their ongoing care.

Niraparib as maintenance therapy in a patient with ovarian cancer and brain metastases.

Ovarian cancer is the second the most common gynaecological malignancy in developed countries. 70% of patients relapse in the first 3 years following debulking surgery and first-line chemotherapy. Niraparib is a poly adenosine diphosphate ribose polymerase inhibitor which uses the concept of synthetic lethality in the presence of a mutation in the breast cancer susceptibility gene (BRCA), and is now recommended as maintenance treatment in patients with platinum-sensitive relapse of ovarian cancer. It has been shown to increase progression-free survival. We present a case of a 68-year-old woman with brain metastases from high-grade serous ovarian cancer who has remained free of disease progression for longer than 17 months with niraparib use as maintenance treatment after second-line chemotherapy.

Linking genotoxicity and cytotoxicity with membrane fluidity: A comparative study in ovarian cancer cell lines following exposure to auranofin.

Auranofin, an organogold compound classified as an anti-rheumatic agent is under phase 2 clinical trials for re-purposing to treat recurrent epithelial ovarian cancer. We have reported earlier that Breast cancer 1, early onset (BRCA1) mutant ovarian cancer cells exhibit increased sensitivity to auranofin. BRCA1 is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer. Apart from DNA repair capability of cancer cells, membrane fluidity is also implicated in modulating resistance to chemotherapeutics. We report here that membrane fluidity influences the sensitivity of ovarian cancer cell lines, OVCAR5 and IGROV1, to auranofin. Electron spin resonance (ESR) analysis revealed a more fluidized membrane in IGROV1 compared to OVCAR5. Interestingly, IGROV1 cells were more sensitive to auranofin induced cytotoxicity than OVCAR5. In comparison to OVCAR5, IGROV1 cells also exhibited an increased number of DNA double strand breaks (DSBs) upon auranofin treatment as assessed by 53BP1 immunostaining. Furthermore, correlation analysis demonstrated a strong positive correlation (r=0.856) between membrane fluidity and auranofin sensitivity in these cell lines. Auranofin-treated IGROV1 cells also exhibited increased cellular oxidation and apoptosis. Anti-oxidant, N-acetyl cysteine (NAC) inhibited the cellular oxidation and apoptosis in auranofin-treated ovarian cancer cells suggesting reactive oxygen species (ROS) mediate the anti-cancer properties of auranofin. Overall, our study suggests that auranofin mediates its cytotoxicity via ROS production in ovarian cancer cells which correlates positively with membrane fluidity.

BRCA1 deficiency increases the sensitivity of ovarian cancer cells to auranofin.

Auranofin, a thioredoxin reductase inhibitor and an anti-rheumatic drug is currently undergoing phase 2 clinical studies for repurposing to treat recurrent epithelial ovarian cancer. Previous studies have established that auranofin exerts its cytotoxic activity by increasing the production of reactive oxygen species (ROS). Breast cancer 1, early onset (BRCA1) is a DNA repair protein whose functional status is critical in the prognosis of ovarian cancer. Apart from its key role in DNA repair, BRCA1 is also known to modulate cellular redox homeostasis by regulating the stability of anti-oxidant transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) via direct protein-protein interaction. However, it is currently unknown whether BRCA1 modulates the sensitivity of ovarian cancer cells to auranofin. Here we report that BRCA1-depleted cells exhibited increased DNA double strand breaks (DSBs) and decreased clonogenic cell survival upon auranofin treatment. Interestingly, auranofin induced the expression of Nrf2 in BRCA1-depleted cells suggesting its regulation independent of BRCA1. Furthermore, anti-oxidant agent, N-acetyl cysteine (NAC) protected BRCA1-depleted cells from DNA damage and apoptosis induced by auranofin. Our study suggests that accumulated lethal DSBs resulting from the oxidative damage render BRCA1 deficient cells more sensitive to auranofin despite the activation of Nrf2.

Unilateral Optic Disc Papilloedema following Administration of Carboplatin Chemotherapy for Ovarian Carcinoma.

A 48-year-old woman with a positive BRCA1 gene mutation was diagnosed with stage 3b high-grade ovarian endometrioid carcinoma. She was treated with adjuvant carboplatin at a dose of 740 mg (AUC 6) in 3-weekly cycles. Five days after her fifth cycle of carboplatin, she awoke with new-onset blurred vision in her left eye. An ophthalmology review showed left-sided disc oedema with normal optic nerve function tests and 6/24 visual acuity. A CT scan of the head and orbits was performed which showed no evidence of metastasis or raised intracranial pressure. An autoimmune screen was performed which did not reveal any explanation for her visual symptoms. Fundus fluorescein angiography showed bilateral intense late disc leakage with no evidence of vasculitis. Her chemotherapy was stopped in view of a radiological and biochemical remission and her visual symptoms were monitored. She was also started on a tapering dose of prednisolone 40 mg daily. Five months after the initial review, she has developed left optic disc atrophy with 6/18 visual acuity, while the right eye remains asymptomatic. The diagnosis was felt to be that of carboplatin-induced unilateral disc oedema, a very rare side effect of this chemotherapy.

Occupational exposure to anti-cancer drugs: A review of effects of new technology.

Because anti-cancer drugs are non-selective, they affect both cancerous and non-cancerous cells. Being carcinogenic and mutagenic, many anticancer drugs therefore present a major health risk to healthcare staff working with them. This paper reviews the means by which exposure to anti-cancer drugs in the workplace may be monitored, assessed and reduced. Both biological monitoring, using non-selective methods or compound-selective methods, and environmental monitoring have provided information on the nature and degree of exposure in the workplace. Pharmaceutical isolators, used for the compounding of cytotoxic IV infusions and the preparation of injectable drugs, provide a physical barrier between pharmacists and cytotoxic drugs and reduce direct exposure. However, the interior of isolators and the contents thereof (e.g. infusion bags and syringes) are readily contaminated by aerosols and spillages and afford a secondary source of exposure to pharmacists, nurses and cleaning staff. Closed system transfer devices (CSTDs), designed to prohibit the transfer of contaminants into the working environment during drug transfer between the vial and syringe, have been successful in further reducing, but not eliminating surface contamination. Given that the number of patients requiring treatment with chemotherapeutic agents is predicted to increase, further efforts to reduce occupational exposure to anti-cancer drugs, including the refinement and wider use of CTSDs, are recommended.

Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC).

BACKGROUND: NSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy and similar heterogeneity is noted in vitro in a variety of model systems. This study has tested the hypothesis that the molecular basis of the observed in vitro chemosensitivity of NSCLC lies within the known resistance mechanisms inherent to these patients' tumors. METHODS: The chemosensitivity of a series of 49 NSCLC tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA) and compared with quantitative expression of resistance genes measured by RT-PCR in a Taqman Array following extraction of RNA from formalin-fixed paraffin-embedded (FFPE) tissue. RESULTS: There was considerable heterogeneity between tumors within the ATP-TCA, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single agents and combinations tested. For instance, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA repair enzyme expression. Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel and cisplatin. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents. CONCLUSION: Genes predicted to be involved in known mechanisms drug sensitivity and resistance correlate well with in vitro chemosensitivity and may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer.

Marked response to a cisplatin/docetaxel/temozolomide combination in a heavily pretreated patient with metastatic large cell neuroendocrine lung carcinoma.

At present, there is no clear consensus on the most appropriate treatment approach for large cell neuroendocrine carcinoma of the lung. Large cell neuroendocrine carcinoma lesions differ from other nonsmall cell lung carcinomas in that they have a particularly aggressive clinical behaviour and extremely poor prognosis. We report a 52-year-old woman large cell neuroendocrine carcinoma patient with progressive stage IV disease in the chest, liver, adrenal glands and, particularly, the brain, who achieved a marked response to a fourth-line combination of docetaxel, cisplatin and temozolomide. This regimen significantly improved her quality of life and survival. The good response obtained in this heavily pretreated patient adds to the evidence regarding the use of temozolomide in patients with lung cancer with brain metastases.