Prognostic Factors in Patients with Metastatic Spinal Cord Compression Secondary to Lung Cancer-A Retrospective UK Single-Centre Study.

PURPOSE: Metastatic spinal cord compression (MSCC) is a severe complication of cancer that can lead to irreversible neurological impairment, necessitating prompt recognition and intervention. This retrospective, single-centre study aimed to determine the prognostic factors and survival rates among patients presenting with MSCC secondary to lung cancer. METHODS AND MATERIALS: We identified 74 patients with epidural metastases-related spinal cord compression and a history of lung cancer through the electronic database of Medway Maritime Hospital in the United Kingdom (UK), spanning the period from April 2016 to September 2021. Among them, 39 were below 55 years old, while 35 were aged 55 years or older; 24 patients were diagnosed with small cell lung cancer (SCLC), and 50 patients had non-small cell lung cancer (NSCLC). RESULTS: The median overall survival (OS) was 5.5 months, with 52 out of 74 patients dying within 6 months of diagnosis with MSCC. For the entire cohort, the statistically significant variables on multi-variate analysis were cancer type (NSCLC had improved OS), the number of involved vertebrae (one to two vertebrae involvement had improved OS), and the time taken to develop motor deficits (≤10 days to develop motor deficits had worsened OS). For the NSCLC cohort, the statistically significant variables on multivariate analysis were molecular alterations (patients with epidermal growth factor receptor (EGFR) mutation), pre-treatment ambulatory status, Eastern Cooperative Oncology Group (ECOG) performance status, and the time taken to develop motor deficits. CONCLUSIONS: Within the entire cohort, patients diagnosed with NSCLC and spinal metastases affecting one to two vertebrae exhibited enhanced OS. Within the NSCLC subgroup, those with EGFR mutations who were ambulatory and possessed an ECOG performance status of 1-2 demonstrated improved OS. In both the entire cohort and the NSCLC subgroup, the development of motor deficits within a period of ≤10 days was associated with poor OS.

The Experience of a Single NHS England Trust on the Impact of the COVID-19 Pandemic on Junior and Middle-Grade Doctors: What Is Next?

The COVID-19 pandemic has undoubtedly affected all national healthcare systems at different levels. In countries heavily hit by the pandemic, it was reported that healthcare workers were asked to work long hours, had increased workload, were faced with difficult decisions, and that the resources were stretched. As such, the COVID-19 pandemic would create the perfect storm for burnout in healthcare workers. Within this context, we conducted a survey in a district general hospital in Southeast England. We focused on doctors in training, in different specialties. This survey included parts of the Maslach Burnout Inventory for healthcare professionals, along with other relevant questions, such as the financial impact and seeking of psychological support. The results showed moderate levels of emotional exhaustion, but high levels of personal satisfaction, a positive impact on doctors finances and very low levels of seeking support.

Cancer-Associated Thrombosis: A New Light on an Old Story.

Cancer-associated thrombosis (CAT) is a rising and significant phenomenon, becoming the second leading cause of death in cancer patients. Pathophysiology of CAT differs from thrombosis in the non-cancer population. There are additional risk factors for thrombosis specific to cancer including cancer type, histology, and treatment, such as chemotherapy. Recently developed scoring systems use these risk factors to stratify the degree of risk and encourage thromboprophylaxis in intermediate- to high-risk patients. Anticoagulation is safely used for prophylaxis and treatment of CAT. Both of these have largely been with low-molecular-weight heparin (LMWH), rather than the vitamin K antagonist (VKA); however, there has been increasing evidence for direct oral anticoagulant (DOAC) use. Consequently, international guidelines have also adapted to recommend the role of DOACs in CAT. Using DOACs is a turning point for CAT, but further research is warranted for their long-term risk profile. This review will discuss mechanisms, risk factors, prophylaxis and management of CAT, including both LMWH and DOACs. There will also be a comparison of current international guidelines and how they reflect the growing evidence base.

Management of Metastatic Spinal Cord Compression in Secondary Care: A Practice Reflection from Medway Maritime Hospital, Kent, UK.

INTRODUCTION: Malignant spinal cord compression (MSCC) is one of the most devastating complications of cancer. This event requires rapid decision-making on the part of several specialists, given the risk of permanent spinal cord injury or death. The goals of treatment in spinal metastases are pain control and improvement of neurological function. There can be challenges in delivering prompt diagnosis and treatment in a secondary care setting. We have reflected on the experience of managing MSCC in a district general setting. AIM: Our retrospective audit identified 53 patients with suspected MSCC who entered the relevant pathway from April 2017 to March 2018 at Medway, United Kingdom (UK). Our audit standards were set out by Medway Maritime Hospital and Maidstone and Tunbridge Wells NHS Trust MSCC working group members, using a combination of published evidence and best practice. RESULTS: The patients with suspected MSCC were 53 and 29 of them (54.7%) had confirmed MSCC. The most common malignancies within the confirmed MSCC were lung (11 patients, 37.9%), breast (5 patients 17.2%), and renal (3 patients, 10.3%), followed by prostate, myeloma and carcinoma of unknown primary (2 patients (6.9%) each), as well as pancreatic, colorectal, lymphoma and, bladder (1 patient (3.4%) each). A magnetic resonance imaging (MRI) scan was performed in 48 patients (90.5%); the majority (31 patients, 64.6%) underwent the MRI within the first 24 h, whereas 3 patients had the investigation between 24 and 72 h from the admission. Among the 29 patients with confirmed MSCC, 6 (20.6%) were treated with surgical decompression, while 20 (69%) received radiotherapy (RT) and 3 (10.3%) best supportive care, respectively. Median time to surgery was 5 days (ranged between 2 and 8 days), whereas for RT 44.4 h (ranged between 24 and 72 h). Finally, all 3 patients that decided on symptom control were referred to a palliative care team within the first 24 h following the MRI scan. CONCLUSIONS: MSCC is frequently presented outside tertiary care. This may cause subsequent delays in investigation, diagnosis, and treatment, which can be improved by following a fast track referral pathway.

Langerhans cell histiocytosis with spinal, pulmonary and pituitary involvement: What about ACTH deficiency without diabetes insipidus? A propos of a case.

Langerhans cell histiocytosis (LCH) is disease process characterized by clonal proliferation of CD1a+ dendritic cells within an inflammatory infiltrate of hematopoietic derived cells. LCH can manifest with a broad spectrum of symptoms and can involve single organs or have a multisystem distribution. Central nervous system (CNS) involvement of LCH can manifest as granulomatous parenchymal or pituitary mass lesions. Focal, space-occupying lesions, such as masses in the meninges, choroid plexus, and brain parenchyma may contain CD1a+ LCH cells, lymphocytes, and macrophages with histology similar to that of extracranial lesions. Here, we describe a rare case of multisystem LCH in an adult patient presenting with spinal lesions and isolated adrenocorticotropic (ACTH) deficiency without diabetes insipidus (DI). In addition, we review the literature summarizing the few reports of hypopituitarism in LCH in the absence of DI.

Wise Management of Ovarian Cancer: On the Cutting Edge.

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women. Two-thirds of patients present at advanced stage at diagnosis, and the estimated 5 year survival rate is 20-40%. This heterogeneous group of malignancies has distinguishable etiology and molecular biology. Initially, single-gene sequencing was performed to identify germline DNA variations associated with EOC. However, hereditary EOC syndrome can be explained by germline pathogenic variants (gPVs) in several genes. In this regard, next-generation sequencing (NGS) changed clinical diagnostic testing, allowing assessment of multiple genes simultaneously in a faster and cheaper manner than sequential single gene analysis. As we move into the era of personalized medicine, there is evidence that poly (ADP-ribose) polymerase (PARP) inhibitors exploit homologous recombination (HR) deficiency, especially in breast cancer gene 1 and 2 (BRCA1/2) mutation carriers. Furthermore, extensive preclinical data supported the development of aurora kinase (AURK) inhibitors in specific tumor types, including EOC. Their efficacy may be optimized in combination with chemotherapeutic or other molecular agents. The efficacy of metformin in ovarian cancer prevention is under investigation. Certain mutations, such as ARID1A mutations, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which are specific in ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC), may offer additional therapeutic targets in these clinical entities. Malignant ovarian germ cell tumors (MOGCTs) are rare and randomized trials are extremely challenging for the improvement of the existing management and development of novel strategies. This review attempts to offer an overview of the main aspects of ovarian cancer, catapulted from the molecular mechanisms to therapeutic considerations.

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond.

Genetic complexity and DNA damage repair defects are common in different cancer types and can induce tumor-specific vulnerabilities. Poly(ADP-ribose) polymerase (PARP) inhibitors exploit defects in the DNA repair pathway through synthetic lethality and have emerged as promising anticancer therapies, especially in tumors harboring deleterious germline or somatic breast cancer susceptibility gene (BRCA) mutations. However, the utility of PARP inhibitors could be expanded beyond germline BRCA1/2 mutated cancers by causing DNA damage with cytotoxic agents in the presence of a DNA repair inhibitor. US Food and Drug Administration (FDA)-approved PARP inhibitors include olaparib, rucaparib, and niraparib, while veliparib is in the late stage of clinical development. Talazoparib inhibits PARP catalytic activity, trapping PARP1/2 on damaged DNA, and it has been approved by the US FDA for the treatment of metastatic germline BRCA1/2 mutated breast cancers in October 2018. The talazoparib side effect profile more closely resembles traditional chemotherapeutics rather than other clinically approved PARP inhibitors. In this review, we discuss the scientific evidence that has emerged from both experimental and clinical studies in the development of talazoparib. Future directions will include optimizing combination therapy with chemotherapy, immunotherapies and targeted therapies, and in developing and validating biomarkers for patient selection and stratification, particularly in malignancies with 'BRCAness'.

Development of new poly(ADP-ribose) polymerase (PARP) inhibitors in ovarian cancer: Quo Vadis?

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women, potentially due to ineffectiveness of screening tests for early detection. Patients typically present with advanced disease at diagnosis, whereas, up to 80% relapse and the estimated median progression-free survival (PFS) is approximately 12-18 months. Increased knowledge on the molecular biology of EOC resulted in the development of several targeted therapies, including poly(ADP-ribose) polymerase (PARP) inhibitors. These agents have changed the therapeutic approach of the EOC and exploit homologous recombination (HR) deficiency through synthetic lethality, especially in breast cancer genes 1 and 2 (BRCA1/2) mutation carriers. Furthermore, BRCA wild-type patients with other defects in the HR repair pathway, or those with platinum-resistant tumors may obtain benefit from this treatment. While PARP inhibitors as a class display many similarities, several differences in structure can translate into differences in tolerability and antitumor activity. Currently, olaparib, rucaparib, and niraparib have been approved by Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) for the treatment of EOC, while veliparib is in the late stage of clinical development. Finally, since October 2018 talazoparib is FDA and EMA approved for BRCA carriers with metastatic breast cancers. In this article, we explore the mechanisms of DNA repair, synthetic lethality, efficiency of PARP inhibition, and provide an overview of early and ongoing clinical investigations of the novel PARP inhibitors veliparib and talazoparib.

Veliparib in ovarian cancer: a new synthetically lethal therapeutic approach.

Epithelial ovarian cancer (EOC) accounts for nearly 90% of all ovarian malignancies. The standard therapeutic strategy includes cytoreductive surgery and neo (adjuvant) platinum-based chemotherapy. Relapse of advanced high grade serous ovarian cancer (HGSOC) is related to the development of drug resistance. A defective DNA damage response is a defining hallmark of HGSOC. Poly (ADP-ribose) polymerase (PARP) inhibitors exploit this deficiency through synthetic lethality and have emerged as promising anticancer therapies, especially in breast cancer gene (BRCA1 or BRCA2) mutation carriers. Apart from inducing synthetic lethality, PARP inhibitors have also been shown to trap PARP1 and PARP2 on DNA, leading to PARP-DNA complexes. This "PARP trapping" potentiates synergism between PARP inhibition and both alkylating agents and platinum-based chemotherapy. However, there are remarkable differences in the ability of PARP inhibitors to trap PARP, based on the size and structure of each separate molecule. Since monotherapy with PARP inhibitors is unlikely to induce cancer cell death in BRCA-proficient tumors, the efficacy of PARP inhibitors could be potentially optimized when combined with DNA-damaging agents, or with molecular targeted agents that also impair mechanisms of DNA repair. Olaparib, rucaparib, and niraparib have all obtained US Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) approval in ovarian cancer in different settings. Veliparib does not yet have an approved label; nevertheless, there are currently promising results available in preclinical and early clinical settings. This comprehensive review summarizes the mechanism of action of veliparib and provides an overview of its early and ongoing clinical investigations.

Combined Strategies with Poly (ADP-Ribose) Polymerase (PARP) Inhibitors for the Treatment of Ovarian Cancer: A Literature Review.

Poly (ADP-ribose) polymerase (PARP) inhibitors are the first clinically approved drugs designed to exploit synthetic lethality, and were first introduced as a cancer-targeting strategy in 2005. They have led to a major change in the treatment of advanced ovarian cancer, and altered the natural history of a disease with extreme genetic complexity and defective DNA repair via homologous recombination (HR) pathway. Furthermore, additional mechanisms apart from breast related cancer antigens 1 and 2 (BRCA1/2) mutations can also result in HR pathway alterations and consequently lead to a clinical benefit from PARP inhibitors. Novel combinations of PARP inhibitors with other anticancer therapies are challenging, and better understanding of PARP biology, DNA repair mechanisms, and PARP inhibitor mechanisms of action is crucial. It seems that PARP inhibitor and biologic agent combinations appear well tolerated and clinically effective in both BRCA-mutated and wild-type cancers. They target differing aberrant and exploitable pathways in ovarian cancer, and may induce greater DNA damage and HR deficiency. The input of immunotherapy in ovarian cancer is based on the observation that immunosuppressive microenvironments can affect tumour growth, metastasis, and even treatment resistance. Several biologic agents have been studied in combination with PARP inhibitors, including inhibitors of vascular endothelial growth factor (VEGF; bevacizumab, cediranib), and PD-1 or PD-L1 (durvalumab, pembrolizumab, nivolumab), anti-CTLA4 monoclonal antibodies (tremelimumab), mTOR-(vistusertib), AKT-(capivasertib), and PI3K inhibitors (buparlisib, alpelisib), as well as MEK 1/2, and WEE1 inhibitors (selumetinib and adavosertib, respectively). Olaparib and veliparib have also been combined with chemotherapy with the rationale of disrupting base excision repair via PARP inhibition. Olaparib has been investigated with carboplatin and paclitaxel, whereas veliparib has been tested additionally in combination with temozolomide vs. pegylated liposomal doxorubicin, as well as with oral cyclophosphamide, and topoisomerase inhibitors. However, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations requires further investigation with dose escalation studies. In this review, we discuss multiple clinical trials that are underway examining the antitumor activity of such combination strategies.

PARP Inhibitors in Ovarian Cancer: The Route to "Ithaca".

Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Early studies have shown significant efficacy for PARP inhibitors in patients with germline breast related cancer antigens 1 and 2 (BRCA1/2) mutations. It has also become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this treatment. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The choice of which PARP inhibitor is mainly based upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of patients most likely to benefit from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The aim of this review is to describe the current evidence for PARP inhibitors in ovarian cancer, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolution of resistance.

The Developing Story of Predictive Biomarkers in Colorectal Cancer.

Colorectal cancer (CRC) is the third most common malignancy worldwide. Surgery remains the most important treatment for non-metastatic CRC, and the administration of adjuvant chemotherapy depends mainly on the disease stage, which is still the strongest prognostic factor. A refined understanding of the genomics of CRC has recently been achieved thanks to the widespread use of next generation sequencing with potential future therapeutic implications. Microsatellite instability (MSI) has been suggested as a predictive marker for response to anti-programmed-cell-death protein 1 (PD-1) therapy in solid tumors, including CRC. It should be noted that not all cancers with MSI phenotype respond to anti-PD-1 immunotherapy, highlighting the urgent need for even better predictive biomarkers. Mitogen-Activated Protein Kinase (MAPK) pathway genes KRAS, NRAS, and BRAF represent important molecular targets and could serve as independent prognostic biomarkers in CRC, and identify those who potentially benefit from anti-epidermal growth factor receptor (EGFR) treatment. Emerging evidence has attributed a significant role to inflammatory markers including blood cell ratios in the prognosis and survival of CRC patients; these biomarkers can be easily assessed in routine blood exams and be used to identify high-risk patients or those more likely to benefit from chemotherapy, targeted therapies and potentially immunotherapy. Analysis of cell-free DNA (cfDNA), circulating tumor cells (CTC) and/or micro RNAs (miRNAs) could provide useful information for the early diagnosis of CRC, the identification of minimal residual disease and, the evaluation of the risk of recurrence in early CRC patients. Even the selection of patients suitable for the new targeted therapy is becoming possible with the use of predictive miRNA biomarkers. Finally, the development of treatment resistance with the emergence of chemo-resistance clones after treatment remains the most important challenge in the clinical practice. In this context it is crucial to identify potential biomarkers and therapeutic targets which could lead to development of new and more effective treatments.

Ovarian carcinosarcoma: Current developments and future perspectives.

Ovarian carcinosarcoma (OCS) constitute uncommon malignancies accounting for only 1-4% of ovarian cancers. Patients more often present with advanced stage disease and symptoms similar to those of epithelial ovarian cancers (EOC). Optimal tumor cytoreduction appears to be an important determinant of survival. Platinum-based chemotherapy remains the most commonly employed adjuvant treatment. The uncertain origin and poor prognosis of OCS motivate determination of the molecular basis of carcinosarcomas aggressive behavior in the hope of developing novel and effective treatment modalities. The present review summarizes the current knowledge on the epidemiology, pathology, prognostic factors, clinical presentation, and therapeutic interventions including future potential therapeutic targets.

Malignant peritoneal mesothelioma: clinical aspects, and therapeutic perspectives.

Malignant peritoneal mesothelioma (MPM) is a rare disease with a wide clinical spectrum. It arises from the peritoneal lining and commonly presents with diffuse, extensive spread throughout the abdomen and, more rarely, metastatic spread beyond the abdominal cavity. Computed tomography, magnetic resonance imaging and positron-emission tomography are important diagnostic tools used for the preoperative staging of MPM. The definitive diagnosis is based on histopathological analysis, mainly via immunohistochemistry. In this regard, paired-box gene 8 negativity represents a useful diagnostic biomarker for differentiating MPM from ovarian carcinoma. In addition, BRCA1-associated protein-1 (BAP1) loss is specific to MPM and allows it to be distinguished from both benign mesothelial lesions and ovarian serous tumors. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has become an increasingly important therapeutic approach, while systemic therapies are still being developed. Histology, Ki-67, completeness of cytoreduction, age, sex, and baseline thrombocytosis are commonly used to optimize patient selection for CRS with HIPEC. Additionally, it is well recognized that, compared to other subtypes, an epithelial morphology is associated with a favorable prognosis, whereas baseline thrombocytosis predicts an aggressive biologicalbehavior. Platelets and other immunologic cytokines have been evaluated as potential novel therapeutic targets. Epigenetic modifiers, including BAP1, SETD2 and DDX3X, are crucial in mesothelial tumorigenesis and provide opportunities for targeted treatment. Overexpression of the closely interacting phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways appears crucial in regulation of the malignant phenotype. The use of targeted therapies with PI3K-mTOR-based inhibitors requires further clinical assessment as a novel approach.

Spinal Ewing Sarcoma Debuting with Cord Compression: Have We Discovered the Thread of Ariadne?

Ewing's sarcoma (ES) of the spine with cord or radicular compression as an initial sign is infrequent. It is unclear, in alleviating a neurological deficit, whether decompressive laminectomy is preferred over chemotherapy. Herein, a literature review of the treatment approaches to the primary or metastatic ES of the spine has been performed. Collected data included clinical features of the patients, treatment, and outcome. There are reported 69 cases with initial presentation of cord or radicular compression of spinal cord, arising from primary or metastatic ES, treated either with initial chemotherapy and/or radiotherapy (RT) (33.33%, n=23), or decompressive surgery (66.66%, n=46). The median age at diagnosis was 17.95 years old (range=0.06-60), and 38 patients (55.07%) were male. Eighteen (78.26%) were initially treated with chemotherapy combined with RT, whereas 3 (13.04%) were managed with RT alone. One patient (4.35%) received only corticosteroids, while there are not available data for the treatment of another one (4.35%). The remaining 46 patients (66.66%) were initially treated with decompressive surgery. Among them, 40 (57.97%) received postoperative chemotherapy, RT or combined modality therapy, whereas 6 patients (8.69%) were not treated adjuvantly. Sixteen out of 23 patients (69.6%) treated with systemic therapy, and 37 from 46 (80.43%) of those managed with decompressive laminectomy were still alive at a mean follow-up period of 2.11 years (range=0.16-6) and 3.45 years (range=0.16-26.08), respectively. To summarize, spinal resection and reconstruction followed by adjuvant treatment reduce the risk of local recurrence, and improve long-term survival. However, ES of the spine is not a distinct clinical entity and can be either managed with chemotherapy and/or RT, similarly to other localization.

Metastatic Spinal Cord Compression: Unraveling the Diagnostic and Therapeutic Challenges.

Malignant spinal cord compression (MSCC) is one of the most devastating complications of cancer. Patients often present with a history of progressive pain, paralysis, sensory loss, progressive spinal deformity, and loss of sphincter control. It is an emergency that requires rapid decision making on the part of several specialists, given the risk of permanent spinal cord injury or death. The goals of treatment in spinal metastases are pain control and improvement of neurological function in order to achieve better quality of life (QoL). The standard of care in most cases is rapid initiation of corticosteroids in combination with either surgical decompression in case of an operable candidate, followed by radiation therapy (RT) or RT alone. Surgery is associated with improved outcomes, but is not appropriate for many patients presenting with advanced symptoms of MSCC, such as paralysis, or those with a poor performance status, or cachexic state, as well as altered mental conditions, co-morbidities, surgical risks, and limited life expectancy. On the other hand, aggressive surgical treatment and post-operative RT is advocated for those with more favorable prognosis, or who are expected to have higher neurological recovery potential. Many candidates may require for combined anterior and posterior approaches to effectively deal with the compressive pathology and stabilize the spine. Most patients are presently treated by primary RT, given with the aim of improving function and symptom management. However, there is still debate regarding the most appropriate RT schedule. Rehabilitation can serve to relieve symptoms, QoL, enhance functional independence, and prevent further complications. Ambulatory status has been found to be an important prognostic factor for patients with MSCC.