Chemoradiation versus radiation alone in stage IIIB cervical cancer patients with or without human immunodeficiency virus.

OBJECTIVE: Cervical cancer remains the most common cancer among women in sub-Saharan Africa and is also a leading cause of cancer related deaths among these women. The benefit of chemoradiation in comparison with radiation alone for patients with stage IIIB disease has not been evaluated prospectively in women living with human immunodeficiency virus (HIV). We assessed the survival of chemoradiation versus radiation alone among stage IIIB cervical cancer patients based on HIV status. METHODS: Between February 2013 and June 2018, patients with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IIIB cervical cancer with or without HIV and treated with chemoradiation or radiation alone, were prospectively enrolled in an observational cohort study. Overall survival was evaluated using the Kaplan-Meier method. Cox proportional hazards modeling was used to analyze associations with survival. RESULTS: Among 187 patients, 63% (n=118) of women had co-infection with HIV, and 48% (n=69) received chemoradiation. Regardless of HIV status, patients who received chemoradiation had improved 2 year overall survival compared with those receiving radiation alone (59% vs 41%, p<0.01), even among women living with HIV (60% vs 38%, p=0.02). On multivariable Cox regression analysis, including all patients regardless of HIV status, 2 year overall survival was associated with receipt of chemoradiation (hazard ratio (HR) 0.63, p=0.04) and total radiation dose ≥80 Gy (HR 0.57, p=0.02). Among patients who received an adequate radiation dose of ≥80 Gy, adjusted overall survival rates were similar between chemoradiation versus radiation alone groups (HR 1.07; p=0.90). However, patients who received an inadequate radiation dose of <80 Gy, adjusted survival was significantly higher in chemoradiation versus radiation alone group (HR 0.45, p=0.01). CONCLUSIONS: Addition of chemotherapy to standard radiation improved overall survival, regardless of HIV status, and is even more essential in women who cannot receive full doses of radiation.

BRCA Mutations in Prostate Cancer: Assessment, Implications and Treatment Considerations.

Prostate cancer ranks fifth in cancer-related mortality in men worldwide. DNA damage is implicated in cancer and DNA damage response (DDR) pathways are in place against this to maintain genomic stability. Impaired DDR pathways play a role in prostate carcinogenesis and germline or somatic mutations in DDR genes have been found in both primary and metastatic prostate cancer. Among these, BRCA mutations have been found to be especially clinically relevant with a role for germline or somatic testing. Prostate cancer with DDR defects may be sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors which target proteins in a process called PARylation. Initially they were used to target BRCA-mutated tumor cells in a process of synthetic lethality. However, recent studies have found potential for PARP inhibitors in a variety of other genetic settings. In this review, we explore the mechanisms of DNA repair, potential for genomic analysis of prostate cancer and therapeutics of PARP inhibitors along with their safety profile.

Angiogenesis and Anti-Angiogenic Treatment in Prostate Cancer: Mechanisms of Action and Molecular Targets.

Prostate cancer (PC) is the most common cancer in men and the second leading cause of cancer-related death worldwide. Many therapeutic advances over the last two decades have led to an improvement in the survival of patients with metastatic PC, yet the majority of these patients still succumb to their disease. Antiagiogenic therapies have shown substantial benefits for many types of cancer but only a marginal benefit for PC. Ongoing clinical trials investigate antiangiogenic monotherapies or combination therapies. Despite the important role of angiogenesis in PC, clinical trials in refractory castration-resistant PC (CRPC) have demonstrated increased toxicity with no clinical benefit. A better understanding of the mechanism of angiogenesis may help to understand the failure of trials, possibly leading to the development of new targeted anti-angiogenic therapies in PC. These could include the identification of specific subsets of patients who might benefit from these therapeutic strategies. This paper provides a comprehensive review of the pathways involved in the angiogenesis, the chemotherapeutic agents with antiangiogenic activity, the available studies on anti-angiogenic agents and the potential mechanisms of resistance.

Epithelial Ovarian Cancer: Providing Evidence of Predisposition Genes.

Epithelial ovarian cancer (EOC) is one of the cancers most influenced by hereditary factors. A fourth to a fifth of unselected EOC patients carry pathogenic variants (PVs) in a number of genes, the majority of which encode for proteins involved in DNA mismatch repair (MMR) pathways. PVs in BRCA1 and BRCA2 genes are responsible for a substantial fraction of hereditary EOC. In addition, PV genes involved in the MMR pathway account for 10-15% of hereditary EOC. The identification of women with homologous recombination (HR)-deficient EOCs has significant clinical implications, concerning chemotherapy regimen planning and development as well as the use of targeted therapies such as poly(ADP-ribose) polymerase (PARP) inhibitors. With several genes involved, the complexity of genetic testing increases. In this context, next-generation sequencing (NGS) allows testing for multiple genes simultaneously with a rapid turnaround time. In this review, we discuss the EOC risk assessment in the era of NGS.

Non-Epithelial Ovarian Cancers: How Much Do We Really Know?

Non-epithelial ovarian cancers (NEOC) are a group of uncommon malignancies that mainly includes germ cell tumours (GCT), sex cord-stromal tumours (SCST), and some extremely rare tumours, such as small cell carcinomas and sarcomas. Each of these classifications encompasses multiple histologic subtypes. The aetiology and molecular origins of each sub-group of NEOC require further investigation, and our understanding on the genetic changes should be optimised. In this article, we provide an update on the clinical presentation, pathology, genetics, treatment and survival of the main histological subtypes of the GCT and the SCST, as well as of ovarian small cell carcinomas. We also discuss miRNA expression profiles of NEOC and report the currently active clinical trials that include NEOC.

Epilepsy and Diagnostic Dilemmas: The Role of Language and Speech-Related Seizures.

Although the impact of epilepsy on expressive language is heavily discussed, researched, and scientifically grounded, a limited volume of research points in the opposite direction. What about the causal relationship between disorder-related language activities and epileptic seizures? What are the possible diagnostic dilemmas that experts in the field of speech-language pathology, neurology, and related fields face? How far has research gone in investigating psychogenic nonepileptic seizures, the misdiagnosis of which can be a thorny issue for clinicians and a detrimental factor for the patients' health? In order to address these questions, the study at hand focuses on a common, ever-intensified (by the COVID-19 pandemic) speech disorder-stuttering, and explores the pathophysiological and psychogenic background of the phenomenon. It also looks at the role of stuttering as a contributing factor to the appearance of epileptic seizures, in the hope of drawing attention to the complexity and importance of precise detection of stuttering-induced epilepsy, as a specific subcategory of language-induced epilepsy.

The Utility of Breast Cancer Index (BCI) Over Clinical Prognostic Tools for Predicting the Need for Extended Endocrine Therapy: A Safety Net Hospital Experience.

INTRODUCTION: Extended endocrine therapy (EET) benefits select patients with early-stage hormone-receptor positive (HR+) breast cancer (BC) but also incurs side effects and cost. The Clinical Treatment Score at Five Years (CTS5) is a free tool that estimates risks of late relapse in estrogen-receptor positive (ER+) BC using clinicopathologic factors. The Breast Cancer Index (BCI) incorporates 2 genomic assays to estimate late relapse risk and likelihood of benefit from EET. This retrospective study assesses the utility of BCI in selecting EET candidates in a safety net hospital. MATERIALS AND METHODS: We performed a retrospective chart review on 69 women with early-stage HR+, HER2- BC diagnosed at our institution from December 2009 to February 2016 on whom BCI was submitted. The CTS5 score was also calculated to assess clinical risk of late relapse. RESULTS: Median age was 53 years. All patients included in our analysis had early ER+ HER2-negative BC. Roughly half of the patients (55%) were postmenopausal and 61% were of Hispanic origin. A total of 34 patients (49%) were deemed high-risk (>5%) for late relapse by CTS5, compared to 42 (61%) by BCI. BCI identified 31 (45%) patients that would benefit from EET and of those, 74%% were advised EET. 16 (47%) clinical high-risk patients were advised against EET due to low benefit predicted by BCI. In the clinical low risk group, 9 (26%) were recommended EET based on high benefit predicted by BCI. CONCLUSION: BCI is reasonable to consider in early-stage HR+ BC and offered clinically relevant information over clinical pathologic information alone.

Differences in Outcomes of Chemoradiation in Women With Invasive Cervical Cancer by Human Immunodeficiency Virus Status: A Systematic Review.

PURPOSE: Cervical cancer is one of the leading causes of cancer death among women worldwide, and women living with human immunodeficiency virus (HIV) carry the highest burden of disease. Chemoradiation (CRT) is the current standard treatment for locally advanced cervical cancer, without specific treatment modifications based on HIV status. This systematic review evaluates existing literature reporting differences in outcomes between HIV+ and HIV- women with invasive cervical cancer treated with CRT. METHODS AND MATERIALS: Searches were conducted through Pubmed, Ovid MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library. Two researchers independently conducted article selection; articles were selected by title, then abstract, and then by full text content. Data were extracted using a structured form. RESULTS: Thirteen articles were included in the analysis, all of which were either retrospective or prospective cohort studies published between 2012 and 2018, and most of which were conducted in Sub-Saharan Africa. Treatment outcomes included treatment response, survival, toxicities, and quality of life. The majority of studies (8 of 13) reported no differences in treatment outcomes by HIV status. Out of 8 studies that assessed survival, 6 reported no significant difference based on HIV status. All 4 studies assessing treatment response found no significant differences based on HIV status. Among 6 studies primarily assessing treatment toxicity, 3 showed no differences based on HIV status. Factors affecting treatment outcomes, such as treatment selection bias, pretreatment hemoglobin levels, and antiretroviral therapy administration, were not systematically accounted for. CONCLUSIONS: The majority of studies analyzed showed no differences in treatment outcomes, including overall toxicity, treatment response, or mortality, on the basis of HIV infection status. These results suggest CRT should continue to be the treatment of choice for locally invasive cervical cancer regardless of HIV status. Further study is required to more precisely account for other variables that influence treatment outcome.

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.

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.

Unraveling the Wide Spectrum of Melanoma Biomarkers.

The use of biomarkers in medicine has become essential in clinical practice in order to help with diagnosis, prognostication and prediction of treatment response. Since Alexander Breslow's original report on "melanoma and prognostic values of thickness", providing the first biomarker for melanoma, many promising new biomarkers have followed. These include serum markers, such as lactate dehydrogenase and S100 calcium-binding protein B. However, as our understanding of the DNA mutational profile progresses, new gene targets and proteins have been identified. These include point mutations, such as mutations of the BRAF gene and tumour suppressor gene tP53. At present, only a small number of the available biomarkers are being utilised, but this may soon change as more studies are published. The aim of this article is to provide a comprehensive review of melanoma biomarkers and their utility for current and, potentially, future clinical practice.

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.

Development and Usability of a Smartphone Application for Tracking Oncology Patients in Gaborone, Botswana.

BACKGROUND: The majority of new cancer cases are expected to be diagnosed in low- and middle-income countries (LMICs) by 2025, and 65% of cancer deaths currently occur in LMICs. Treatment adherence, patient monitoring, and follow-up are essential to cancer care but are often not possible in these settings. Out Patient (OP) Care, a smartphone application (app) developed to fill this gap, texts appointment reminders to patients and electronically stores medical records confidentially. OBJECTIVES: This study aims to present the development of this app and evaluate its usability and feasibility as defined by provider and patient experiences in the context of a multidisciplinary cancer clinic in Gaborone, Botswana. METHODS: OP Care was piloted at a multidisciplinary team gynecologic oncology clinic in Gaborone, Botswana. The app was developed through an iterative process with feedback from clinic staff and physicians. The usability was evaluated using a cross-sectional survey. All staff members in the gynecologic oncology clinic, which typically consists of one doctor and four nurses, as well as a portion of the staff in the (Princess Marina Hospital general) oncology ward used the app. All providers using the app were surveyed, along with all patients who attended the gynecologic oncology clinic during the 3-week survey period. Staff demographics, reactions, and opinions on usability, as well as patients' reactions to the appointment reminders were collected. Agreement to the ease-of-usability statements was recorded on a 1 (not at all) to 7 (extremely so) scale. Primary outcomes were the app's usability and the feasibility of text reminders from the patient's perspective. RESULTS: Nine staff and 15 patients were surveyed. Staff included three doctors and six nurses and encompassed all of the staff in the gynecologic oncology clinic as well as a portion of the general oncology ward. All surveyed staff owned a smartphone and used a computer at home. Most (78%) staff did not feel that OP Care would increase their work burden and were willing to use the app if implemented permanently (median: 6; interquartile range [IQR]: 1). Seventeen out of the nineteen usability questions, such as "I feel comfortable using this system," scored a median of 6, corresponding to "very much so." Patients reported that the reminder text messages were helpful (median: 6; IQR: 1) and preferred the text reminders to be in Setswana (median: 7; IQR: 1). CONCLUSION: High usability scores indicate that the app can be scaled up to usage in this clinic and others. Although patients appreciate OP Care, the option for call and text reminders in Setswana is indicated.

Association Between CD4 Count and Chemoradiation Therapy Outcomes Among Cervical Cancer Patients With HIV.

BACKGROUND: In Botswana, nearly two-thirds of cervical cancer patients are HIV-positive. This study examined the relationship between CD4 count and chemoradiation therapy outcomes among cervical cancer patients with HIV. SETTING: A prospective cohort study of 231 HIV-positive women with locally invasive cervical cancer was conducted in Gaborone, Botswana from January 2015 to February 2018. METHODS: Primary outcome was survival, defined as time from scheduled end of chemoradiation therapy to death or last contact with patient. Nadir CD4 count was defined as lowest CD4 available before cancer diagnosis. Delta CD4 count was defined as improvement from nadir CD4 to CD4 at cancer diagnosis. Hazard ratio (HR) analyses were adjusted for presenting variables (age, baseline hemoglobin, cancer stage, and performance status) and treatment variables (chemotherapy cycles and radiation dose). RESULTS: Two hundred thirty-one patients were included in nadir CD4 analysis; 139 were included in delta CD4 analysis. Higher delta CD4 was significantly associated with reduced mortality after adjusting for presenting and treatment variables (CD4 100-249: HR 0.45, 95% CI: 0.21 to 0.95; CD4 ≥250: HR 0.45, 95% CI: 0.20 to 1.02). Higher nadir CD4 showed a trend toward reduced mortality after adjusting for presenting and treatment variables (HR 0.94, 95% CI: 0.84 to 1.06). CONCLUSIONS: Higher delta CD4 (greater improvement from nadir CD4 to CD4 at cervical cancer diagnosis) is significantly associated with lower mortality. Although not statistically significant, data suggest that higher nadir CD4 may reduce mortality. These results reinforce the importance of early HIV diagnosis and antiretroviral therapy initiation, as their effects influence cervical cancer outcomes years later.