Diagnostic biomarkers in ovarian cancer: advances beyond CA125 and HE4.

Ovarian cancer (OC) is the most lethal gynaecologic malignancy, attributed to its insidious growth, non-specific symptoms and late presentation. Unfortunately, current screening modalities are inadequate at detecting OC and many lack the appropriate specificity and sensitivity that is desired from a screening test. Nearly 70% of cases are diagnosed at stage III or IV with poor 5-year overall survival. Therefore, the development of a sensitive and specific biomarker for early diagnosis and screening for OC is of utmost importance. Currently, diagnosis is guided by CA125, the patient's menopausal status and imaging features on ultrasound scan. However, emerging evidence suggests that a combination of CA125 and HE4 (another serum biomarker) and patient characteristics in a multivariate index assay may provide a higher specificity and sensitivity than either CA125 and HE4 alone in the early detection of OC. Other attempts at combining various serum biomarkers into one multivariate index assay such as OVA1, ROMA and Overa have all shown promise. However, significant barriers exist before these biomarkers can be implemented in clinical practice. This article aims to provide an up-to-date review of potential biomarkers for screening and early diagnosis of OC which may have the potential to transform its diagnostic landscape.

The Role of Multiparametric MRI and MRI-targeted Biopsy in the Diagnosis of Radiorecurrent Prostate Cancer: An Analysis from the FORECAST Trial.

BACKGROUND: The role of multiparametric magnetic resonance imaging (MRI) for detecting recurrent prostate cancer after radiotherapy is unclear. OBJECTIVE: To evaluate MRI and MRI-targeted biopsies for detecting intraprostatic cancer recurrence and planning for salvage focal ablation. DESIGN, SETTING, AND PARTICIPANTS: FOcal RECurrent Assessment and Salvage Treatment (FORECAST; NCT01883128) was a prospective cohort diagnostic study that recruited 181 patients with suspected radiorecurrence at six UK centres (2014 to 2018); 144 were included here. INTERVENTION: All patients underwent MRI with 5 mm transperineal template mapping biopsies; 84 had additional MRI-targeted biopsies. MRI scans with Likert scores of 3 to 5 were deemed suspicious. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: First, the diagnostic accuracy of MRI was calculated. Second, the pathological characteristics of MRI-detected and MRI-undetected tumours were compared using the Wilcoxon rank sum test and chi-square test for trend. Third, four biopsy strategies involving an MRI-targeted biopsy alone and with systematic biopsies of one to two other quadrants were studied. Fisher's exact test was used to compare MRI-targeted biopsy alone with the best other strategy for the number of patients with missed cancer and the number of patients with cancer harbouring additional tumours in unsampled quadrants. Analyses focused primarily on detecting cancer of any grade or length. Last, eligibility for focal therapy was evaluated for men with localised (≤T3bN0M0) radiorecurrent disease. RESULTS AND LIMITATIONS: Of 144 patients, 111 (77%) had cancer detected on biopsy. MRI sensitivity and specificity at the patient level were 0.95 (95% confidence interval [CI] 0.92 to 0.99) and 0.21 (95% CI 0.07 to 0.35), respectively. At the prostate quadrant level, 258/576 (45%) quadrants had cancer detected on biopsy. Sensitivity and specificity were 0.66 (95% CI 0.59 to 0.73) and 0.54 (95% CI 0.46 to 0.62), respectively. At the quadrant level, compared with MRI-undetected tumours, MRI-detected tumours had longer maximum cancer core length (median difference 3 mm [7 vs 4 mm]; 95% CI 1 to 4 mm, p < 0.001) and a higher grade group (p = 0.002). Of the 84 men who also underwent an MRI-targeted biopsy, 73 (87%) had recurrent cancer diagnosed. Performing an MRI-targeted biopsy alone missed cancer in 5/73 patients (7%; 95% CI 3 to 15%); with additional systematic sampling of the other ipsilateral and contralateral posterior quadrants (strategy 4), 2/73 patients (3%; 95% CI 0 to 10%) would have had cancer missed (difference 4%; 95% CI -3 to 11%, p = 0.4). If an MRI-targeted biopsy alone was performed, 43/73 (59%; 95% CI 47 to 69%) patients with cancer would have harboured undetected additional tumours in unsampled quadrants. This reduced but only to 7/73 patients (10%; 95% CI 4 to 19%) with strategy 4 (difference 49%; 95% CI 36 to 62%, p < 0.0001). Of 73 patients, 43 (59%; 95% CI 47 to 69%) had localised radiorecurrent cancer suitable for a form of focal ablation. CONCLUSIONS: For patients with recurrent prostate cancer after radiotherapy, MRI and MRI-targeted biopsy, with or without perilesional sampling, will diagnose cancer in the majority where present. MRI-undetected cancers, defined as Likert scores of 1 to 2, were found to be smaller and of lower grade. However, if salvage focal ablation is planned, an MRI-targeted biopsy alone is insufficient for prostate mapping; approximately three of five patients with recurrent cancer found on an MRI-targeted biopsy alone harboured further tumours in unsampled quadrants. Systematic sampling of the whole gland should be considered in addition to an MRI-targeted biopsy to capture both MRI-detected and MRI-undetected disease. PATIENT SUMMARY: After radiotherapy, magnetic resonance imaging (MRI) is accurate for detecting recurrent prostate cancer, with missed cancer being smaller and of lower grade. Targeting a biopsy to suspicious areas on MRI results in a diagnosis of cancer in most patients. However, for every five men who have recurrent cancer, this targeted approach would miss cancers elsewhere in the prostate in three of these men. If further focal treatment of the prostate is planned, random biopsies covering the whole prostate in addition to targeted biopsies should be considered so that tumours are not missed.

Hallmarks of the Tumour Microenvironment of Gliomas and Its Interaction with Emerging Immunotherapy Modalities.

Gliomas are aggressive, primary central nervous system tumours arising from glial cells. Glioblastomas are the most malignant. They are known for their poor prognosis or median overall survival. The current standard of care is overwhelmed by the heterogeneous, immunosuppressive tumour microenvironment promoting immune evasion and tumour proliferation. The advent of immunotherapy with its various modalities-immune checkpoint inhibitors, cancer vaccines, oncolytic viruses and chimeric antigen receptor T cells and NK cells-has shown promise. Clinical trials incorporating combination immunotherapies have overcome the microenvironment resistance and yielded promising survival and prognostic benefits. Rolling these new therapies out in the real-world scenario in a low-cost, high-throughput manner is the unmet need of the hour. These will have practice-changing implications to the glioma treatment landscape. Here, we review the immunobiological hallmarks of the TME of gliomas, how the TME evades immunotherapies and the work that is being conducted to overcome this interplay.

Predictive biomarkers for immune checkpoint inhibitor response in urothelial cancer.

Immune checkpoint inhibitors (ICIs) are commonly used to treat patients with advanced urothelial cancer. However, a significant number of patients do not respond to ICI, and the lack of validated predictive biomarkers impedes the success of the ICI strategy alone or in combination with chemotherapy or targeted therapies. In addition, some patients experience potentially severe adverse events with limited clinical benefit. Therefore, identifying biomarkers of response to ICI is crucial to guide treatment decisions. The most evaluated biomarkers to date are programmed death ligand 1 expression, microsatellite instability/defective mismatch repair phenotype, and tumor mutational burden. Other emerging biomarkers, such as circulating tumor DNA and microbiota, require evaluation in clinical trials. This review aims to examine these biomarkers for ICI response in urothelial cancer and assess their analytical and clinical validation.

Gestational Renal Cell Cancer - An Update.

Gestational renal cell carcinoma (RCC) is an uncommon occurrence and presents a diagnostic and clinical challenge for healthcare providers. The manifestation of gestational RCC often lacks overt symptoms and can mimic physiological changes and disorders associated with pregnancy. Frequently, patients are asymptomatic, and the condition is detected during routine antenatal ultrasonography. However, the options for imaging modalities and treatment are limited due to the potential risks of harm to the developing fetus and interruption of pregnancy. Throughout the management of pregnant patients with RCC, both maternal and neonatal risks must be carefully considered, while respecting the patient's autonomy. Currently, there are no internationally or nationally recognized evidence-based guidelines for managing gestational RCC, highlighting the need for a multidisciplinary approach to treatment. Advances in surgical techniques have resulted in a shift from open surgeries to laparoscopic radical or partial nephrectomy procedures, with robotic-assisted approaches also gaining popularity. In cases of metastatic gestational RCC, termination of the pregnancy may be considered, and the appropriate treatment of RCC should be the priority. This article aims to provide a comprehensive review of the epidemiology, aetiology, clinical presentation, diagnosis, prognosis, and management of gestational RCC.

Melanoma-the therapeutic considerations in the clinical practice.

The incidence of melanoma is increasing and prolonged exposure to ultraviolet (UV) radiation remains the main risk factor. Public health measures have been vital in tackling the increased incidence and prevalence of melanoma. The management of melanoma has been revolutionised with the approval of new immunotherapy treatments (anti PD-1, CTLA-4 and LAG-3 antibodies) and targeted therapies (BRAF and MEK inhibitors). With some of these therapies becoming the standard of care in the management of advanced disease, it is likely we will see their use increase in the adjuvant and neoadjuvant setting. Recently, literature has demonstrated the benefits patients could derive from the combination of immune checkpoint inhibitors (ICIs) due to the promising results on its efficacy when compared to monotherapy. However, greater clarity on its use is needed in more unique presentations such as BRAF-wild type melanoma, where the lack of driver mutations makes disease management more challenging. Surgical resection remains an integral part of the management of earlier stages of the disease with a consequent decrease in reliance on other forms of therapy such as chemotherapy and radiotherapy. Finally, we evaluated the novel emerging experimental approaches to treatment such as adoptive T cell therapy, novel oncolytic treatments and cancer vaccines. We discussed how their use could improve patients' prognosis, enhance treatment efficacy, and potentially achieve cure.

Immunotherapy for advanced urothelial carcinoma (UC): rational and current evidence.

Combination platinum-based chemotherapy has been the standard of care for several decades in first-line treatment of advanced urothelial carcinoma (UC) patients. UC is often chemosensitive, though durable responses are quite rare and the development of chemoresistance still leads to poor clinical outcomes. Up until a few years ago, UC patients could not benefit from any valuable alternatives to cytotoxic chemotherapy, but the scenario has been recently transformed by the advent of immunotherapy. Molecular biology of UC is characterised by a relatively high prevalence of alterations in DNA damage response pathway, genomic instability, high tumour burden, and elevated programmed cell death ligand 1 (PD-L1) protein expression, which are established factors predicting favourable response to immune checkpoint inhibitors (ICIs) in several tumour types. To date, various ICIs have been approved as systemic anti-cancer therapy for advanced UC in multiple settings, including first-line, maintenance, and second-line therapy. ICIs are also in development either as monotherapy or in combination with chemotherapy or other targeted agents. Moreover, a number of alternative ICIs, interleukins, and novel immune molecules have been identified as promising agents in advanced UC. Herein, we review rational and current literature evidence supporting the clinical development and current indications of immunotherapy, particularly focusing on ICIs.

External validation of a risk model predicting failure of salvage focal ablation for prostate cancer.

OBJECTIVES: To externally validate a published model predicting failure within 2 years after salvage focal ablation in men with localised radiorecurrent prostate cancer using a prospective, UK multicentre dataset. PATIENTS AND METHODS: Patients with biopsy-confirmed ≤T3bN0M0 cancer after previous external beam radiotherapy or brachytherapy were included from the FOcal RECurrent Assessment and Salvage Treatment (FORECAST) trial (NCT01883128; 2014-2018; six centres), and from the high-intensity focussed ultrasound (HIFU) Evaluation and Assessment of Treatment (HEAT) and International Cryotherapy Evaluation (ICE) UK-based registries (2006-2022; nine centres). Eligible patients underwent either salvage focal HIFU or cryotherapy, with the choice based predominantly on anatomical factors. Per the original multivariable Cox regression model, the predicted outcome was a composite failure outcome. Model performance was assessed at 2 years post-salvage with discrimination (concordance index [C-index]), calibration (calibration curve and slope), and decision curve analysis. For the latter, two clinically-reasonable risk threshold ranges of 0.14-0.52 and 0.26-0.36 were considered, corresponding to previously published pooled 2-year recurrence-free survival rates for salvage local treatments. RESULTS: A total of 168 patients were included, of whom 84/168 (50%) experienced the primary outcome in all follow-ups, and 72/168 (43%) within 2 years. The C-index was 0.65 (95% confidence interval 0.58-0.71). On graphical inspection, there was close agreement between predicted and observed failure. The calibration slope was 1.01. In decision curve analysis, there was incremental net benefit vs a 'treat all' strategy at risk thresholds of ≥0.23. The net benefit was therefore higher across the majority of the 0.14-0.52 risk threshold range, and all of the 0.26-0.36 range. CONCLUSION: In external validation using prospective, multicentre data, this model demonstrated modest discrimination but good calibration and clinical utility for predicting failure of salvage focal ablation within 2 years. This model could be reasonably used to improve selection of appropriate treatment candidates for salvage focal ablation, and its use should be considered when discussing salvage options with patients. Further validation in larger, international cohorts with longer follow-up is recommended.

Evaluating the impact of the metastatic spinal cord compression coordinator in a regional cancer network: a prospective, non-randomized pilot study.

BACKGROUND: Extradural metastatic spinal cord compression (MSCC) is a debilitating and potentially irreversible complication of cancer. Delay in treatment could lead to irreversible neurological damage, adverse quality of life and a burden on health care resources. Lack of effective communication between teams has been identified as one of the reasons for delay in treatment. The MSCC coordinator (often a nurse, radiotherapy radiographer or a doctor) is responsible for coordinating the diagnosis and management of patients with MSCC. The role has been shown to streamline service, ensure timely decision-making and improved survival outcomes. However, available data are anecdotal or from limited series presented as abstracts in conferences. In this study, we assessed the impact (time to treatment) of the newly introduced role on the treatment pathway compared to similar period in the preceding year. METHODS: This was a multi-centre, prospective, pilot study carried out in Kent, UK between 1st April to 30th June 2021. Patients were considered eligible if they had magnetic resonance imaging (MRI)-confirmed cauda equina or cord compression. The data prospectively collected include: (I) time from diagnostic imaging to radiotherapy treatment; (II) number of referrals to hospital palliative care (HPC), occupational/physiotherapy (OPH) and community hospice referrals (CHP). A comparative retrospective data for (I) was collected for the same time period in the preceding year. The study outcome assessed was reduction in time from radiological diagnosis of MSCC to receiving radiotherapy. RESULTS: Fifty-eight patients in 2020 and 24 patients in 2021 were included in the dataset. The MSCC coordinator role (introduced in 2021) led to reduction in the time from imaging to treatment (P=0.045). Compared to 2020, there was a shorter mean/median time to treatment, seeing more patients being treated within 24 hours. All hospitals except East Kent Hospitals saw more patients being treated within 24 hours. 7 referrals each made to HPC, OPH and CHP respectively. CONCLUSIONS: Introduction of MSCC coordinator role led to improved time from imaging to radiotherapy treatment. The new service led to engagement with rehabilitative and palliative services. Future work should be done to assess the long-term impact of this role on utilization of support services and patient recovery.

MRI fat fraction imaging of nodal and bone metastases in prostate cancer.

KEY POINTS: • Characterisation and quantification of tissue fat on MRI can be used to provide information on disease processes. • Fat in bone and lymph nodes up until recently have not been exploited for diagnostic purposes or response monitoring in prostate cancer. • Fat imaging on MRI using Dixon/PDFF sequences has the potential to add clinical value in the future but prospective data is needed.

Evaluating Different Quantitative Shear Wave Parameters of Ultrasound Elastography in the Diagnosis of Lymph Node Malignancies: A Systematic Review and Meta-Analysis.

Shear wave elastography (SWE) has shown promise in distinguishing lymph node malignancies. However, the diagnostic accuracies of various SWE parameters that quantify tissue stiffness are yet to be demonstrated. To evaluate the pooled diagnostic accuracy of different SWE parameters for differentiating lymph node malignancies, we conducted a systematic screening of four databases using the PRISMA guidelines. Lymph node biopsy was adopted as the reference standard. Emax (maximum stiffness), Emean (mean stiffness), Emin (minimum stiffness), and Esd (standard deviation) SWE parameters were subjected to separate meta-analyses. A sub-group analysis comparing the use of Emax in cervical (including thyroid) and axillary lymph node malignancies was also conducted. Sixteen studies were included in this meta-analysis. Emax and Esd demonstrated the highest pooled sensitivity (0.78 (95% CI: 0.69-0.87); 0.78 (95% CI: 0.68-0.87)), while Emean demonstrated the highest pooled specificity (0.93 (95% CI: 0.88-0.98)). From the sub-group analysis, the diagnostic performance did not differ significantly in cervical and axillary LN malignancies. In conclusion, SWE is a promising adjunct imaging technique to conventional ultrasonography in the diagnosis of lymph node malignancy. SWE parameters of Emax and Esd have been identified as better choices of parameters for screening clinical purposes.

BRCA Mutations in Ovarian and Prostate Cancer: Bench to Bedside.

DNA damage repair (DDR) defects are common in different cancer types, and these alterations can be exploited therapeutically. Epithelial ovarian cancer (EOC) is among the tumours with the highest percentage of hereditary cases. BRCA1 and BRCA2 predisposing pathogenic variants (PVs) were the first to be associated with EOC, whereas additional genes comprising the homologous recombination (HR) pathway have been discovered with DNA sequencing technologies. The incidence of DDR alterations among patients with metastatic prostate cancer is much higher compared to those with localized disease. Genetic testing is playing an increasingly important role in the treatment of patients with ovarian and prostate cancer. The development of poly (ADP-ribose) polymerase (PARP) inhibitors offers a therapeutic strategy for patients with EOC. One of the mechanisms of PARP inhibitors exploits the concept of synthetic lethality. Tumours with BRCA1 or BRCA2 mutations are highly sensitive to PARP inhibitors. Moreover, the synthetic lethal interaction may be exploited beyond germline BRCA mutations in the context of HR deficiency, and this is an area of ongoing research. PARP inhibitors are in advanced stages of development as a treatment for metastatic castration-resistant prostate cancer. However, there is a major concern regarding the need to identify reliable biomarkers predictive of treatment response. In this review, we explore the mechanisms of DDR, the potential for genomic analysis of ovarian and prostate cancer, and therapeutics of PARP inhibitors, along with predictive biomarkers.

The future of PSMA PET and WB MRI as next-generation imaging tools in prostate cancer.

Radiolabelled prostate-specific membrane antigen (PSMA)-based PET-CT has been shown in numerous studies to be superior to conventional imaging in the detection of nodal or distant metastatic lesions. 68Ga-PSMA PET-CT is now recommended by many guidelines for the detection of biochemically relapsed disease after radical local therapy. PSMA radioligands can also function as radiotheranostics, and Lu-PSMA has been shown to be a potential new line of treatment for metastatic castration-resistant prostate cancer. Whole-body (WB) MRI has been shown to have a high diagnostic performance in the detection and monitoring of metastatic bone disease. Prospective, randomized, multicentre studies comparing 68Ga-PSMA PET-CT and WB MRI for pelvic nodal and metastatic disease detection are yet to be performed. Challenges for interpretation of PSMA include tracer trapping in non-target tissues and also urinary excretion of tracers, which confounds image interpretation at the vesicoureteral junction. Additionally, studies have shown how long-term androgen deprivation therapy (ADT) affects PSMA expression and could, therefore, reduce tracer uptake and visibility of PSMA+ lesions. Furthermore, ADT of short duration might increase PSMA expression, leading to the PSMA flare phenomenon, which makes the accurate monitoring of treatment response to ADT with PSMA PET challenging. Scan duration, detection of incidentalomas and presence of metallic implants are some of the major challenges with WB MRI. Emerging data support the wider adoption of PSMA PET and WB MRI for diagnosis, staging, disease burden evaluation and response monitoring, although their relative roles in the standard-of-care management of patients are yet to be fully defined.

Microsatellite instability testing in colorectal patients with Lynch syndrome: lessons learned from a case report and how to avoid such pitfalls.

We present the case of a patient with Lynch syndrome and metastatic colorectal carcinoma (mCRC). The initial immunohistochemistry (IHC) test for deficient mismatch repair gave a false negative result. However, the same mutation has accurately been detected with IHC in other cancers with microsatellite instability (MSI). This supports the determining role of somatic missense mutations in MMR IHC. MSI-PCR testing confirmed MSI and the patient benefited from nivolumab with a complete metabolic response. We explain the rationale for immunotherapy in mCRC, current testing strategies and discuss future developments in MSI testing. We advocate for upfront testing using both IHC and MSI-PCR to direct therapy in mCRC, and a greater understanding of IHC and MSI-PCR testing pitfalls.

Bowel cancer that has spread is a serious condition that will often lead to loss of life. There is a new treatment called immunotherapy which helps extend the life of people with cancer that has spread beyond the bowel, but it does not work for everyone. Immunotherapy works best for people whose tumors have lost the ability to repair DNA. People with Lynch syndrome often have these types of tumors because they are born with an inherited predisposition for faulty DNA repair. We treated a patient with Lynch syndrome and bowel cancer, and wanted to use immunotherapy, but the test we used failed to give the right result. We think this is because the test is not very good at picking up unusual types of mutations that can occur and that using another test as well will prevent this mistake from happening to others.

Metastatic Anorectal Melanoma Presenting as Seizures: An Infrequent Culprit.

Anorectal malignant melanoma is a rare culprit of malignancies in the anorectal region. With a presentation that mimics the vastly more common colorectal tumours, clinical misdiagnosis and diagnostic delays often occur, contributing to a dismal prognosis. The authors report a case of metastatic anorectal malignant melanoma presenting as seizures. Though our standard diagnostic pathway for suspected anorectal malignancies was followed, and despite the patient having computerized tomography (CT) of the head earlier, this presentation nonetheless led to a prolongation of time needed to reach histological diagnosis and delay in commencing definitive treatment. It also highlights the paucity of research into the pathophysiology and management of this infrequent but aggressive disease, and the need for raising awareness about this condition to the medical community so that it is considered as a plausible differential diagnosis from the outset and diagnostic pathways adjusted accordingly.