A Systematic Review of Diagnostic Modalities and Strategies for the Assessment of Complications in Adult Patients with Neurofibromatosis Type 1.

BACKGROUND: Neurofibromatosis Type 1 is an autosomal dominant tumour-predisposition condition commonly diagnosed in childhood and fully penetrant by adulthood. Long-term monitoring through imaging is inconsistent and varies between high- and low-income countries. Implementation of a clinical practice guideline through a multidisciplinary clinic is instrumental to the care of adult Neurofibromatosis Type 1 patients. We aim to systematically review international diagnostic modalities and strategies to evaluate any association between a country's socioeconomic status and diagnostic modalities or strategies used for Neurofibromatosis Type 1 patients. METHODS: We searched PubMed, Embase, Web of Science, and Cochrane. Relevant clinical information on the surveillance of adult Neurofibromatosis Type 1 patients worldwide was reviewed, extracted, and synthesised. RESULTS: We identified 51 papers reporting on 7724 individuals. Multiple imaging modalities are actively employed in high-income and upper-middle-income countries for surveying adult Neurofibromatosis Type 1 patients. We did not find any relevant papers from low- and middle-income countries. CONCLUSIONS: This systematic review suggests that there is robust data on diagnostic modalities for adult Neurofibromatosis Type 1 patients in high-income countries, but not for low- and middle-income countries. There is a lack of data on consolidated diagnostic strategies from both high- and low-income countries. Efforts should be made to publish data on usual clinical practice in low- and middle-income countries to develop clinical practice guidelines describing best medical practice to fit a local context.

Experience and Perceptions of a Family Health History Risk Assessment Tool among Multi-Ethnic Asian Breast Cancer Patients.

A family health history-based risk assessment is particularly valuable for guiding cancer screening and treatment strategies, yet an optimal implementation depends upon end-users' values and needs. This is not only true prior to disease development, but also for those already affected. The aim of this study is to explore perceptions of the value of knowing one's family health history (FHH)-based risk, experience using a patient-facing FHH tool and the potential of the tool for wider implementation. Twenty multi-ethnic Asian patients undergoing breast cancer treatment in Singapore completed an FHH-based risk assessment. Semi-structured one-on-one interviews were conducted and data were thematically analyzed. All participants were female and slightly more than half were Chinese. The acceptance and usage of an FHH risk assessment tool for cancers and its broader implementation was affected by a perceived importance of personal control over early detection, patient concerns of anxiety for themselves and their families due to risk results, concerns for genetic discrimination, adequacy of follow-up care plans and Asian cultural beliefs toward disease and dying. This study uniquely sheds light on the factors affecting Asian breast cancer patients' perceptions about undergoing an FHH-based risk assessment, which should inform steps for a broader implementation in Asian healthcare systems.

Clinical implementation of an oncology-specific family health history risk assessment tool.

BACKGROUND: The presence of hereditary cancer syndromes in cancer patients can have an impact on current clinical care and post-treatment prevention and surveillance measures. Several barriers inhibit identification of hereditary cancer syndromes in routine practice. This paper describes the impact of using a patient-facing family health history risk assessment platform on the identification and referral of breast cancer patients to genetic counselling services. METHODS: This was a hybrid implementation-effectiveness study completed in breast cancer clinics. English-literate patients not previously referred for genetic counselling and/or gone through genetic testing were offered enrollment. Consented participants were provided educational materials on family health history collection, entered their family health history into the platform and completed a satisfaction survey. Upon completion, participants and their clinicians were given personalized risk reports. Chart abstraction was done to identify actions taken by patients, providers and genetic counsellors. RESULTS: Of 195 patients approached, 102 consented and completed the study (mean age 55.7, 100 % women). Sixty-six (65 %) met guideline criteria for genetic counseling of which 24 (36 %) were referred for genetic counseling. Of those referred, 13 (54 %) participants attended and eight (33 %) completed genetic testing. On multivariate logistic regression, referral was not associated with age, cancer stage, or race but was associated with clinical provider (p = 0.041). Most providers (71 %) had higher referral rates during the study compared to prior. The majority of participants found the experience useful (84 %), were more aware of their health risks (83 %), and were likely to recommend using a patient-facing platform to others (69 %). CONCLUSIONS: 65 % of patients attending breast cancer clinics in this study are at-risk for hereditary conditions based on current guidelines. Using a patient-facing risk assessment platform enhances the ability to identify these patients systematically and with widespread acceptability and recognized value by patients. As only a third of at-risk participants received referrals for genetic counseling, further understanding barriers to referral is needed to optimize hereditary risk assessment in oncology practices. TRIAL REGISTRATION: NIH Clinical Trials registry, NCT04639934 . Registered Nov 23, 2020 -- Retrospectively registered.

Cost-effectiveness of olaparib maintenance therapy when used with and without restriction by BRCA1/2 mutation status for platinum-sensitive relapsed ovarian cancer.

Objectives: To determine whether olaparib maintenance therapy, used with and without restriction by BRCA1/2 mutation status, is cost-effective at the population level for platinum-sensitive relapsed ovarian cancer in Singapore.Methods: A partitioned survival model compared three management strategies: 1) treat all patients with olaparib; 2) test for germline BRCA1/2 mutation, followed by targeted olaparib use in mutation carriers only; 3) observe all patients. Mature overall survival (OS) data from Study 19 and a 15-year time horizon were used and direct medical costs were applied. Sensitivity analyses were conducted to explore uncertainties.Results: Treating all patients with olaparib was the most costly and effective strategy, followed by targeted olaparib use, and observation of all patients. Base-case incremental cost-effectiveness ratios (ICERs) for all-olaparib and targeted use strategies were SGD133,394 (USD100,926) and SGD115,736 (USD87,566) per quality-adjusted life year (QALY) gained, respectively, compared to observation. ICERs were most sensitive to the cost of olaparib, time horizon and discount rate for outcomes. When these parameters were varied, ICERs remained above SGD92,000 (USD69,607)/QALY.Conclusions: At the current price, olaparib is not cost-effective when used with or without restriction by BRCA1/2 mutation status in Singapore, despite taking into account potential OS improvement over a long time horizon.

Understanding the Psychological Impact of COVID-19 Pandemic on Patients With Cancer, Their Caregivers, and Health Care Workers in Singapore.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has had a global impact, and Singapore has seen 33,000 confirmed cases. Patients with cancer, their caregivers, and health care workers (HCWs) need to balance the challenges associated with COVID-19 while ensuring that cancer care is not compromised. This study aimed to evaluate the psychological effect of COVID-19 on these groups and the prevalence of burnout among HCWs. METHODS: A cross-sectional survey of patients, caregivers, and HCWs at the National Cancer Centre Singapore was performed over 17 days during the lockdown. The Generalized Anxiety Disorder-7 and Maslach Burnout Inventory were used to assess for anxiety and burnout, respectively. Self-reported fears related to COVID-19 were collected. RESULTS: A total of 624 patients, 408 caregivers, and 421 HCWs participated in the study, with a response rate of 84%, 88%, and 92% respectively. Sixty-six percent of patients, 72.8% of caregivers, and 41.6% of HCWs reported a high level of fear from COVID-19. The top concern of patients was the wide community spread of COVID-19. Caregivers were primarily worried about patients dying alone. HCWs were most worried about the relatively mild symptoms of COVID-19. The prevalence of anxiety was 19.1%, 22.5%, and 14.0% for patients, caregivers, and HCWs, respectively. Patients who were nongraduates and married, and caregivers who were married were more anxious. The prevalence of burnout in HCWs was 43.5%, with more anxious and fearful HCWs reporting higher burnout rates. CONCLUSION: Fears and anxiety related to COVID-19 are high. Burnout among HCWs is similar to rates reported prepandemic. An individualized approach to target the specific fears of each group will be crucial to maintain the well-being of these vulnerable groups and prevent burnout of HCWs.

Impact of subsidies on cancer genetic testing uptake in Singapore.

PURPOSE: Previous reports cite high costs of clinical cancer genetic testing as main barriers to patient's willingness to test. We report findings of a pilot study that evaluates how different subsidy schemes impact genetic testing uptake and total cost of cancer management. METHODS: We included all patients who attended the Cancer Genetics Service at the National Cancer Centre Singapore (January 2014-May 2016). Two subsidy schemes, the blanket scheme (100% subsidy to all eligible patients), and the varied scheme (patients received 50%-100% subsidy dependent on financial status) were compared. We estimated total spending on cancer management from government's perspective using a decision model. RESULTS: 445 patients were included. Contrasting against the blanket scheme, the varied scheme observed a higher attendance of patients (34 vs 8 patients per month), of which a higher proportion underwent genetic testing (5% vs 38%), while lowering subsidy spending per person (S$1098 vs S$1161). The varied scheme may potentially save cost by reducing unnecessary cancer surveillance when first-degree relatives uptake rate is above 36%. FINDINGS: Provision of subsidy leads to a considerable increase in genetic testing uptake rate. From the government's perspective, subsidising genetic testing may potentially reduce total costs on cancer management.

Using Quality Improvement Methods and Time-Driven Activity-Based Costing to Improve Value-Based Cancer Care Delivery at a Cancer Genetics Clinic.

PURPOSE: To meet increasing demand for cancer genetic testing and improve value-based cancer care delivery, National Cancer Centre Singapore restructured the Cancer Genetics Service in 2014. Care delivery processes were redesigned. We sought to improve access by increasing the clinic capacity of the Cancer Genetics Service by 100% within 1 year without increasing direct personnel costs. METHODS: Process mapping and plan-do-study-act (PDSA) cycles were used in a quality improvement project for the Cancer Genetics Service clinic. The impact of interventions was evaluated by tracking the weekly number of patient consultations and access times for appointments between April 2014 and May 2015. The cost impact of implemented process changes was calculated using the time-driven activity-based costing method. RESULTS: Our study completed two PDSA cycles. An important outcome was achieved after the first cycle: The inclusion of a genetic counselor increased clinic capacity by 350%. The number of patients seen per week increased from two in April 2014 (range, zero to four patients) to seven in November 2014 (range, four to 10 patients). Our second PDSA cycle showed that manual preappointment reminder calls reduced the variation in the nonattendance rate and contributed to a further increase in patients seen per week to 10 in May 2015 (range, seven to 13 patients). There was a concomitant decrease in costs of the patient care cycle by 18% after both PDSA cycles. CONCLUSION: This study shows how quality improvement methods can be combined with time-driven activity-based costing to increase value. In this paper, we demonstrate how we improved access while reducing costs of care delivery.

Cost Effectiveness of Universal Hepatitis B Virus Screening in Patients Beginning Chemotherapy for Sarcomas or GI Stromal Tumors.

PURPOSE: The value of screening for hepatitis B virus (HBV) infection before chemotherapy for nonhematopoietic solid tumors remains unsettled. We evaluated the cost effectiveness of universal screening before systemic therapy for sarcomas, including GI stromal tumors (GISTs). PATIENTS AND METHODS: Drawing from the National Cancer Centre Singapore database of 1,039 patients with sarcomas, we analyzed the clinical records of 485 patients who received systemic therapy. Using a Markov model, we compared the cost effectiveness of a screen-all versus screen-none strategy in this population. RESULTS: A total of 237 patients were screened for HBV infection. No patients developed HBV reactivation during chemotherapy. The incremental cost-effectiveness ratio per quality-adjusted life-year (QALY) of offering HBV screening to all patients with sarcomas and patients with GISTs exceeded the cost-effectiveness threshold of SG$100,000 per QALY. This result was robust in one-way sensitivity analysis. Our results show that only changes in mortality rate secondary to HBV reactivation could make the incremental cost-effectiveness ratio cross the cost-effectiveness threshold. CONCLUSION: Universal HBV screening in patients with sarcomas or GISTs undergoing chemotherapy is not cost effective at a willingness to pay of SG$100,000 per QALY and may not be required.

Detecting Germline PTEN Mutations Among At-Risk Patients With Cancer: An Age- and Sex-Specific Cost-Effectiveness Analysis.

PURPOSE: Cowden syndrome (CS) is an autosomal dominant disorder characterized by benign and malignant tumors. One-quarter of patients who are diagnosed with CS have pathogenic germline PTEN mutations, which increase the risk of the development of breast, thyroid, uterine, renal, and other cancers. PTEN testing and regular, intensive cancer surveillance allow for early detection and treatment of these cancers for mutation-positive patients and their relatives. Individual CS-related features, however, occur commonly in the general population, making it challenging for clinicians to identify CS-like patients to offer PTEN testing. PATIENTS AND METHODS: We calculated the cost per mutation detected and analyzed the cost-effectiveness of performing selected PTEN testing among CS-like patients using a semi-quantitative score (the PTEN Cleveland Clinic [CC] score) compared with existing diagnostic criteria. In our model, first-degree relatives of the patients with detected PTEN mutations are offered PTEN testing. All individuals with detected PTEN mutations are offered cancer surveillance. RESULTS: CC score at a threshold of 15 (CC15) costs from $3,720 to $4,573 to detect one PTEN mutation, which is the most inexpensive among the different strategies. At base-case, CC10 is the most cost-effective strategy for female patients who are younger than 40 years, and CC15 is the most cost-effective strategy for female patients who are between 40 and 60 years of age and male patients of all ages. In sensitivity analyses, CC15 is robustly the most cost-effective strategy for probands who are younger than 60 years. CONCLUSION: Use of the CC score as a clinical risk calculator is a cost-effective prescreening method to identify CS-like patients for PTEN germline testing.

Hereditary Syndromes Manifesting as Endometrial Carcinoma: How Can Pathological Features Aid Risk Assessment?

Endometrial carcinoma is the most common gynecological tumor worldwide. It can be the presenting malignancy, acting as the harbinger, of an undiagnosed hereditary syndrome. Up to 50% of females with Lynch syndrome present in this manner. Differentiation between Lynch, Muir-Torre, and Cowden syndromes can at times be challenging due to the overlapping features. Our review emphasizes on the strengths, pitfalls, and limitations of microscopic features as well as immunohistochemical and polymerase chain reaction- (PCR-) based tests used by laboratories to screen for DNA mismatch repair (MMR) and PTEN gene mutations in patients to enable a more targeted and cost effective approach in the use of confirmatory gene mutational analysis tests. This is crucial towards initiating timely and appropriate surveillance measures for the patient and affected family members. We also review the evidence postulating on the possible inclusion of uterine serous carcinoma as part of the spectrum of malignancies seen in hereditary breast and ovarian carcinoma syndrome, driven by mutations in BRCA1/2.

PTEN hamartoma tumor syndrome: clinical risk assessment and management protocol.

The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is an important phosphatase that counteracts one of the most critical cancer pathways: the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathways. Clinically, deregulation of PTEN function resulting in reduced PTEN expression and activity is implicated in human diseases. Cowden syndrome (CS) is an autosomal dominant disorder characterized by benign and malignant tumors. CS-related individual features occur commonly in the general population. Approximately 25% of patients diagnosed with CS have pathogenic germline PTEN mutations, which increase lifetime risks of breast, thyroid, uterine, renal and other cancers. PTEN testing and intensive cancer surveillance allow for early detection and treatment of these cancers for mutation positive patients and their relatives. In this review, we highlight our current knowledge of germline PTEN mutations in relation to human disease. We review current clinical diagnosis and management recommendations for PHTS including recent discoveries in understanding PTEN function regulation and how this can be exploited therapeutically.