Risk factors for cancer of unknown primary: a literature review.

Cancer of Unknown Primary (CUP) is metastatic cancer with an unidentifiable primary tumour origin during life. It remains difficult to study the occurrence and aetiology of CUP. Hitherto, it is unclear whether risk factors are associated with CUP, yet identifying these factors could reveal whether CUP is a specific entity or a cluster of metastasised cancers from various primary tumour origins. Epidemiological studies on possible CUP risk factors were systematically searched in PubMed and Web of Science on February 1st, 2022. Studies, published before 2022, were included if they were observational human-based, provided relative risk estimates, and investigated possible CUP risk factors. A total of 5 case-control and 14 cohort studies were included. There appears to be an increased risk for smoking in relation to CUP. However, limited suggestive evidence was found to link alcohol consumption, diabetes mellitus, and family history of cancer as increased risks for CUP. No conclusive associations could be made for anthropometry, food intake (animal or plant-based), immunity disorders, lifestyle (overall), physical activity, or socioeconomic status and CUP risk. No other CUP risk factors have been studied. This review highlights smoking, alcohol consumption, diabetes mellitus and family history of cancer as CUP risk factors. Yet, there remains insufficient epidemiological evidence to conclude that CUP has its own specific risk factor profile.

Vegetable and fruit consumption and cancer of unknown primary risk: results from the Netherlands cohort study on diet and cancer.

BACKGROUND: Cancer of Unknown Primary (CUP) is a metastatic cancer for which the primary lesion remains unidentifiable during life and little is also known about the modifiable risk factors that contribute to its development. This study investigates whether vegetables and fruits are associated with CUP risk. METHODS: We used data from the prospective Netherlands Cohort Study on Diet and Cancer which includes 120,852 participants aged between 55 and 69 years in 1986. All participants completed a self-administered questionnaire on cancer risk factors at baseline. Cancer follow-up was established through record linkage to the Netherlands Cancer Registry and the Dutch Pathology Registry. As a result, 867 incident CUP cases and 4005 subcohort members were available for case-cohort analyses after 20.3 years of follow-up. Multivariable adjusted hazard ratios were calculated using proportional hazards models. RESULTS: We observed no associations between total vegetable and fruit consumption (combined or as separate groups) and CUP risk. However, there appeared to be an inverse association between the consumption of raw leafy vegetables and CUP. With respect to individual vegetable and fruit items, we found neither vegetable nor fruit items to be associated with CUP risk. CONCLUSIONS: Overall, vegetable and fruit intake were not associated with CUP incidence within this cohort.

Type 2 diabetes mellitus and cancer of unknown primary risk: results from the Netherlands Cohort Study.

OBJECTIVE: Cancer of unknown primary (CUP) is a metastatic malignancy with an unidentifiable primary tumour origin. Previous studies suggest that type 2 diabetes mellitus (T2DM) and CUP risk are associated. This study examines the association in greater depth by investigating T2DM status, T2DM duration, T2DM age at diagnosis, and medication that was being used in relation to CUP. METHODS: Data were utilized from the Netherlands Cohort Study, a prospective cohort that includes 120 852 participants aged 55-69 years at baseline in 1986. All participants completed a self-administered questionnaire on cancer risk factors. CUP cases were identified through record linkage with the Netherlands Cancer Registry and Dutch Pathology Registry. After 20.3 years of follow-up, 963 incident CUP cases and 4288 subcohort members were available for case-cohort analyses. Proportional hazards models were employed to estimate multivariable-adjusted hazard ratios (HRs). RESULTS: Overall, we observed a nonsignificant positive association between T2DM status and CUP risk [HR, 1.35; 95% confidence interval (CI), 0.92-1.99], which increased in women after stratification for sex (HR, 1.55; 95% CI, 0.90-2.64). For participants who were aged less than 50 years at diagnosis of T2DM, a statistically significant positive association was found in relation to CUP (HR, 2.42; 95% CI, 1.26-4.65), compared with participants without T2DM. CONCLUSION: Our findings indicate that there is a nonsignificant positive association between T2DM and CUP risk and that the association became stronger in women in stratified analyses.

Adherence to the World Cancer Research Fund and the American Institute for Cancer Research lifestyle recommendations for cancer prevention and Cancer of Unknown Primary risk.

BACKGROUND & AIMS: The World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) updated their cancer prevention recommendations in 2018. Adherence to these recommendations has been associated with lower cancer risk and mortality. However, adherence in relation to Cancer of Unknown Primary (CUP) risk has not been studied. This study investigates whether adherence to the WCRF/AICR recommendations is associated with CUP risk. METHODS: Data from the prospective Netherlands Cohort Study on diet and cancer was used to measure adherence to the recommendations in relation to CUP risk. The cohort includes 120 852 participants (aged 55-69 years), who completed a self-administered questionnaire on cancer risk factors at baseline. Adherence was investigated with respect to body fatness, physical activity, plant foods, meat consumption and alcohol. Incident CUP cases were identified through record linkage to the Netherlands Cancer Registry and Dutch Pathology Registry. A follow-up of 20.3 years, resulted in 856 incident CUP cases and 3911 subcohort members with complete information available for case-cohort analyses. Multivariable adjusted hazard ratios were estimated using proportional hazards models and were adjusted for age at baseline, sex, cigarette smoking (status, frequency, and duration) and total energy intake. RESULTS: Highest adherence appeared to be associated with decreased CUP risk in the age-sex adjusted model (HR: 0.76, 95% CI: 0.62-0.92). After additional adjustment for cigarette smoking (status, frequency, and duration), the association attenuated and was no longer statistically significant. No multiplicative interactions were observed between sex nor smoking status and overall adherence in relation to CUP. CONCLUSION: Within this cohort, highest adherence to the WCRF/AICR recommendations is not statistically significantly associated with decreased CUP risk after multivariable adjustment.

Family history of cancer in first degree relatives and risk of cancer of unknown primary.

OBJECTIVE: Cancer of Unknown Primary (CUP) refers to the presence of metastatic lesions, with no identifiable primary site during the patient's lifetime. Poor survival and lack of available treatment highlight the need to identify potential CUP risk factors. We investigated whether a family history of cancer is associated with increased CUP risk. METHODS: We performed a case cohort analysis using data from the Netherlands Cohort Study, which included a total of 963 CUP cases and 4,288 subcohort members. A Cox Proportional Hazards Regression was used to compare CUP risk in participants who reported to have a family member with cancer to those who did not, whilst adjusting for confounders. RESULTS: In general, we observed no increased CUP risk in those who reported a family history of cancer. CUP risk appeared slightly increased in those who reported cancer in a sibling (HR: 1.16, 95% CI: 0.97-1.38), especially in those with a sister with cancer compared with those without (HR: 1.23, 95% CI: 0.99-1.53), although these findings are not statistically significant. CONCLUSION: Having a family history of cancer is not an independent risk factor of CUP.

Meat consumption and cancer of unknown primary (CUP) risk: results from The Netherlands cohort study on diet and cancer.

PURPOSE: Cancer of unknown primary (CUP) is a metastasised cancer for which no primary lesion could be identified during life. Research into CUP aetiology with respect to dietary factors is particularly scarce. This study investigates whether meat consumption is associated with CUP risk. METHODS: Data was utilised from the prospective Netherlands cohort study that includes 1,20,852 participants aged 55-69 years. All participants completed a self-administered questionnaire on diet and other cancer risk factors at baseline. Cancer follow-up was established through record linkage to the Netherlands Cancer Registry and the Dutch Pathology Registry. A total of 899 CUP cases and 4111 subcohort members with complete and consistent dietary data were available for case-cohort analyses after 20.3 years of follow-up. Multivariable adjusted hazard ratios (HRs) were calculated using proportional hazards models. RESULTS: We found a statistically significant positive association with beef and processed meat consumption and CUP risk in women (multivariable adjusted HR Q4 vs. Q1 1.47, 95% CI 1.04-2.07, Ptrend = 0.004 and Q4 vs. Q1 1.53, 95% CI 1.08-2.16, Ptrend = 0.001, respectively), and a non-significant positive association with processed meat consumption and CUP risk in men (multivariable adjusted HR Q4 vs. Q1 1.33, 95% CI 0.99-1.79, Ptrend = 0.15). No associations were observed between red meat (overall), poultry or fish consumption and CUP risk. CONCLUSION: In this cohort, beef and processed meat consumption were positively associated with increased CUP risk in women, whereas a non-significant positive association was observed between processed meat consumption and CUP risk in men.

Alcohol consumption, cigarette smoking and cancer of unknown primary risk: Results from the Netherlands Cohort Study.

Cancer of unknown primary (CUP) is a metastasised malignancy with no identifiable primary tumour origin. Despite the frequent occurrence and bleak prognosis of CUP, research into its aetiology is scarce. Our study investigates alcohol consumption, tobacco smoking and CUP risk. We used data from the Netherlands Cohort Study, a cohort that includes 120 852 participants aged 55 to 69 years, who completed a self-administered questionnaire on cancer risk factors at baseline. Cancer follow-up was established through record linkage to the Netherlands Cancer Registry and Dutch Pathology Registry. After 20.3 years of follow-up, 963 CUP cases and 4288 subcohort members were available for case-cohort analyses. Multivariable-adjusted hazard ratios (HRs) were calculated using proportional hazard models. In general, CUP risk increased with higher levels of alcohol intake (Ptrend = .02). The association was more pronounced in participants who drank ≥30 g of ethanol per day (HR: 1.57, 95% confidence interval [CI]: 1.20-2.05) compared to abstainers. Current smokers were at an increased CUP risk (HR: 1.59, 95% CI: 1.29-1.97) compared to never smokers. We observed that the more the cigarettes or the longer a participant smoked, the higher the CUP risk was (Ptrend = .003 and Ptrend = .02, respectively). Interaction on additive scale was found for participants with the highest exposure categories of alcohol consumption and cigarette smoking frequency and CUP risk. Our findings demonstrate that alcohol consumption and cigarette smoking are associated with increased CUP risk. Lifestyle recommendations for cancer prevention regarding not drinking alcohol and avoiding exposure to smoking are therefore also valid for CUP.

Anthropometry, physical activity and cancer of unknown primary (CUP) risk: Results from the Netherlands cohort study.

BACKGROUND: Cancer of Unknown Primary (CUP) is a metastatic disease for which the primary tumour origin could not be identified during life. Few studies have investigated the risk factors associated with this disease. This study investigates anthropometry, physical activity and CUP risk. METHODS: Data is used from the Netherlands Cohort Study, which includes 120,852 participants aged 55-69 years. All cohort members completed a self-administered questionnaire on cancer risk factors at baseline in 1986. Cancer follow-up was established through record linkage to the Netherlands Cancer Registry and the Dutch Pathology Registry. After a follow-up of 20.3 years, 926 incident CUP cases and 4099 subcohort members were available for case-cohort analyses. Proportional hazards models were used to compute multivariable adjusted hazard ratios (HRs). RESULTS: We found no associations between height, body mass index (BMI) at baseline, BMI at age 20 years, change in BMI since age 20 years, clothing size (trouser/skirt size), or non-occupational physical activity and CUP risk. CONCLUSION: Our findings indicate that neither anthropometry nor physical activity are associated with the development of CUP.

Commutability of proficiency testing material containing amitriptyline and nortriptyline: A study within the framework of the Dutch Calibration 2.000 project.

BACKGROUND: External quality assessment schemes (EQAS) can provide important information regarding accuracy and comparability of different measurement methods if the sample matrices are composed of commutable material. The aim of this study was to assess the commutability of different matrices for the material used in an EQAS for amitriptyline and nortriptyline. METHODS: Proficiency testing material (PTM) and patient samples containing amitriptyline and nortriptyline were prepared, collected, pooled, and distributed to participating laboratories for analysis. Low, medium and high concentrations of both drugs in liquid pooled human, lyophilized human and lyophilized bovine serum were tested in this study. The measurement deviation of the PTM results to the patient serum regression line were normalized by dividing trough the average within-laboratory SD (SDwl) derived from the results reported in the official EQAS, resulting in a relative residual. The commutability decision limit was set at 3 SDwl. RESULTS: With 10 laboratories participating in this study, 45 laboratory couples were formed. All matrix types delivered several relative residuals outside the commutability decision limit. The number and the magnitude of relative residuals for both drugs were lower for liquid human sera as compared to lyophilized human and bovine sera. CONCLUSIONS: The PTM used for amitriptyline and nortriptyline is preferably prepared with human serum, although not all relative residuals are within the commutability decision limit.

[Favourable course of cancer of unknown primary]. / Gunstig beloop bij een onbekende primaire tumor.

Favourable course of cancer of unknown primary Background Most patients with cancer of unknown primary have a very poor prognosis. Case description A 61-year-old woman was diagnosed with a cancer of unknown primary that had metastasised to the lymph nodes in the right axilla and the peritoneum. Because she could not be allocated to a treatable sub-group, she was eligible for treatment as part of a clinical trial. Prior to commencing treatment, molecular testing was conducted, the result of which suggested the primary tumour was a melanoma. We subsequently treated the patient with ipilimumab. Four years after diagnosis, there is no evidence of active disease and the patient remains in an excellent state of health. Conclusion Molecular and genetic testing can improve diagnosis and treatment options in patients with CUP. In the near future, PET-CT diagnostics and whole genome sequencing will probably suffice to identify the primary tumour.

Biomarker results from a phase II study of MEK1/2 inhibitor binimetinib (MEK162) in patients with advanced NRAS- or BRAF-mutated melanoma.

BRAF and RAS are the most frequently mutated mitogen-activated protein kinase (MAPK) genes in melanoma. Binimetinib is a highly selective MAPK kinase (MEK) 1/2 inhibitor with clinical antitumor activity in NRAS- and BRAF V600-mutant melanoma. We performed a nonrandomized, open-label phase II study, where 183 metastatic melanoma patients received binimetinib 45 mg / 60 mg twice-daily (BRAF arms), or binimetinib 45 mg twice-daily (NRAS arm). Biomarker analyses were prespecified as secondary and exploratory objectives. Here we report the extent of MAPK pathway inhibition by binimetinib, genetic pathway alterations of interest, and potential predictive markers for binimetinib efficacy. Twenty-five fresh pre- and post-dose tumor sample pairs were collected for biomarker analyses, which included assessment of binimetinib on MEK/MAPK signaling by pharmacodynamic analysis of pERK and DUSP6 expression in pre- vs post-dose tumor biopsies; identification of pERK and DUSP6 expression/efficacy correlations; assessment of baseline tumor molecular status; and exploration of potential predictive biomarkers of efficacy of binimetinib. The postbaseline pERK and DUSP6 expression decreased across all arms; no association between reduced pERK or DUSP6 levels with clinical efficacy was observed. Genetic aberrations were similar to previously reported data on clinical melanoma samples. Genetic pathway alterations occurred predominantly within CDKN2A/B, PTEN, and TRRAP (BRAF-mutation) and CDKN2A/B, TP53, and NOTCH2 (NRAS-mutation). Several patients with BRAF mutations had amplification of genes on chromosome 7q; these patients tended to have shorter progression-free survival than other patients with BRAF-mutant melanoma. Further analysis of genetic alterations, including amplifications of growth factor genes, will determine utility as biomarkers for efficacy.

A cost analysis of upfront DPYD genotype-guided dose individualisation in fluoropyrimidine-based anticancer therapy.

BACKGROUND: Fluoropyrimidine therapy including capecitabine or 5-fluorouracil can result in severe treatment-related toxicity in up to 30% of patients. Toxicity is often related to reduced activity of dihydropyrimidine dehydrogenase, the main metabolic fluoropyrimidine enzyme, primarily caused by genetic DPYD polymorphisms. In a large prospective study, it was concluded that upfront DPYD-guided dose individualisation is able to improve safety of fluoropyrimidine-based therapy. In our current analysis, we evaluated whether this strategy is cost saving. METHODS: A cost-minimisation analysis from a health-care payer perspective was performed as part of the prospective clinical trial (NCT02324452) in which patients prior to start of fluoropyrimidine-based therapy were screened for the DPYD variants DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A and received an initial dose reduction of 25% (c.2846A>T, c.1236G>A) or 50% (DPYD*2A, c.1679T>G). Data on treatment, toxicity, hospitalisation and other toxicity-related interventions were collected. The model compared prospective screening for these DPYD variants with no DPYD screening. One-way and probabilistic sensitivity analyses were also performed. RESULTS: Expected total costs of the screening strategy were €2599 per patient compared with €2650 for non-screening, resulting in a net cost saving of €51 per patient. Results of the probabilistic sensitivity and one-way sensitivity analysis demonstrated that the screening strategy was very likely to be cost saving or worst case cost-neutral. CONCLUSIONS: Upfront DPYD-guided dose individualisation, improving patient safety, is cost saving or cost-neutral but is not expected to yield additional costs. These results endorse implementing DPYD screening before start of fluoropyrimidine treatment as standard of care.

DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis.

BACKGROUND: Fluoropyrimidine treatment can result in severe toxicity in up to 30% of patients and is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly caused by genetic variants in the gene encoding DPD (DPYD). We assessed the effect of prospective screening for the four most relevant DPYD variants (DPYD*2A [rs3918290, c.1905+1G>A, IVS14+1G>A], c.2846A>T [rs67376798, D949V], c.1679T>G [rs55886062, DPYD*13, I560S], and c.1236G>A [rs56038477, E412E, in haplotype B3]) on patient safety and subsequent DPYD genotype-guided dose individualisation in daily clinical care. METHODS: In this prospective, multicentre, safety analysis in 17 hospitals in the Netherlands, the study population consisted of adult patients (≥18 years) with cancer who were intended to start on a fluoropyrimidine-based anticancer therapy (capecitabine or fluorouracil as single agent or in combination with other chemotherapeutic agents or radiotherapy). Patients with all tumour types for which fluoropyrimidine-based therapy was considered in their best interest were eligible. We did prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A. Heterozygous DPYD variant allele carriers received an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G), and DPYD wild-type patients were treated according to the current standard of care. The primary endpoint of the study was the frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 grade ≥3) overall fluoropyrimidine-related toxicity across the entire treatment duration. We compared toxicity incidence between DPYD variant allele carriers and DPYD wild-type patients on an intention-to-treat basis, and relative risks (RRs) for severe toxicity were compared between the current study and a historical cohort of DPYD variant allele carriers treated with full dose fluoropyrimidine-based therapy (derived from a previously published meta-analysis). This trial is registered with ClinicalTrials.gov, number NCT02324452, and is complete. FINDINGS: Between April 30, 2015, and Dec 21, 2017, we enrolled 1181 patients. 78 patients were considered non-evaluable, because they were retrospectively identified as not meeting inclusion criteria, did not start fluoropyrimidine-based treatment, or were homozygous or compound heterozygous DPYD variant allele carriers. Of 1103 evaluable patients, 85 (8%) were heterozygous DPYD variant allele carriers, and 1018 (92%) were DPYD wild-type patients. Overall, fluoropyrimidine-related severe toxicity was higher in DPYD variant carriers (33 [39%] of 85 patients) than in wild-type patients (231 [23%] of 1018 patients; p=0·0013). The RR for severe fluoropyrimidine-related toxicity was 1·31 (95% CI 0·63-2·73) for genotype-guided dosing compared with 2·87 (2·14-3·86) in the historical cohort for DPYD*2A carriers, no toxicity compared with 4·30 (2·10-8·80) in c.1679T>G carriers, 2·00 (1·19-3·34) compared with 3·11 (2·25-4·28) for c.2846A>T carriers, and 1·69 (1·18-2·42) compared with 1·72 (1·22-2·42) for c.1236G>A carriers. INTERPRETATION: Prospective DPYD genotyping was feasible in routine clinical practice, and DPYD genotype-based dose reductions improved patient safety of fluoropyrimidine treatment. For DPYD*2A and c.1679T>G carriers, a 50% initial dose reduction was adequate. For c.1236G>A and c.2846A>T carriers, a larger dose reduction of 50% (instead of 25%) requires investigation. Since fluoropyrimidines are among the most commonly used anticancer agents, these findings suggest that implementation of DPYD genotype-guided individualised dosing should be a new standard of care. FUNDING: Dutch Cancer Society.

Highly sensitive miniature fluidic flowmeter based on an FBG heated by Co2+-doped fiber.

In this paper, we present a miniature fluidic flow sensor based on a short fiber Bragg grating inscribed in a single mode fiber and heated by Co2+-doped multimode fibers. The proposed flow sensor was employed to measure the flow rates of oil and water, showing good sensitivity of 0.339 nm/(m/s) and 0.578 nm/(m/s) for water and oil, flowing at v = 0.2 m/s. The sensitivity can be increased with higher laser power launched to the Co2+-doped multimode fibers. A small flow rate of 0.005 m/s and 0.002 m/s can be distinguished for a particular phase of water or oil, respectively, at a certain laser power (i.e. ~1.43W). The flow sensor can measure volume speed up to 30 L/min, which is limited by the test rig. The experimental results show that the sensor can discriminate slight variation of flow rates as small as 0.002m/s.

Use of Systemic Therapy Concurrent With Cranial Radiotherapy for Cerebral Metastases of Solid Tumors.

The incidence of brain metastases of solid tumors is increasing. Local treatment of brain metastases is generally straightforward: cranial radiotherapy (e.g., whole-brain radiotherapy or stereotactic radiosurgery) or resection when feasible. However, treatment becomes more complex when brain metastases occur while other metastases, outside of the central nervous system, are being controlled with systemic therapy (chemotherapeutics, molecular targeted agents, or monoclonal antibodies). It is known that some anticancer agents can increase the risk for neurotoxicity when used concurrently with radiotherapy. Increased neurotoxicity decreases quality of life, which is undesirable in this predominantly palliative patient group. Therefore, it is of utmost importance to identify the compounds that should be temporarily discontinued when cranial radiotherapy is needed.This review summarizes the (neuro)toxicity data for combining systemic therapy (chemotherapeutics, molecular targeted agents, or monoclonal antibodies) with concurrent radiotherapy of brain metastases. Because only a limited amount of high-level data has been published, a risk assessment of each agent was done, taking into account the characteristics of each compound (e.g., lipophilicity) and the microenvironment of brain metastasis. The available trials suggest that only gemcitabine, erlotinib, and vemurafenib induce significant neurotoxicity when used concurrently with cranial radiotherapy. We conclude that for most systemic therapies, the currently available literature does not show an increase in neurotoxicity when these therapies are used concurrently with cranial radiotherapy. However, further studies are needed to confirm safety because there is no high-level evidence to permit definitive conclusions. The Oncologist 2017;22:222-235Implications for Practice: The treatment of symptomatic brain metastases diagnosed while patients are receiving systemic therapy continues to pose a dilemma to clinicians. Will concurrent treatment with cranial radiotherapy and systemic therapy (chemotherapeutics, molecular targeted agents, and monoclonal antibodies), used to control intra- and extracranial tumor load, increase the risk for neurotoxicity? This review addresses this clinically relevant question and evaluates the toxicity of combining systemic therapies with cranial radiotherapy, based on currently available literature, in order to determine the need to and interval to interrupt systemic treatment.

Expressing analytical performance from multi-sample evaluation in laboratory EQA.

BACKGROUND: To provide its participants with an external quality assessment system (EQAS) that can be used to check trueness, the Dutch EQAS organizer, Organization for Quality Assessment of Laboratory Diagnostics (SKML), has innovated its general chemistry scheme over the last decade by introducing fresh frozen commutable samples whose values were assigned by Joint Committee for Traceability in Laboratory Medicine (JCTLM)-listed reference laboratories using reference methods where possible. Here we present some important innovations in our feedback reports that allow participants to judge whether their trueness and imprecision meet predefined analytical performance specifications. METHODS: Sigma metrics are used to calculate performance indicators named 'sigma values'. Tolerance intervals are based on both Total Error allowable (TEa) according to biological variation data and state of the art (SA) in line with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Milan consensus. RESULTS: The existing SKML feedback reports that express trueness as the agreement between the regression line through the results of the last 12 months and the values obtained from reference laboratories and calculate imprecision from the residuals of the regression line are now enriched with sigma values calculated from the degree to which the combination of trueness and imprecision are within tolerance limits. The information and its conclusion to a simple two-point scoring system are also graphically represented in addition to the existing difference plot. CONCLUSIONS: By adding sigma metrics-based performance evaluation in relation to both TEa and SA tolerance intervals to its EQAS schemes, SKML provides its participants with a powerful and actionable check on accuracy.

Herpes Encephalitis: A Mortal Complication in a Patient Treated with Immunosuppressive Drugs because of Immune-Related Adverse Events after Ipilimumab Treatment.

Until a few years ago, metastatic melanoma had a poor prognosis with limited treatment options. These therapeutics options and thereby median survival have increased obviously over 5 years with the arrival of immunotherapeutic drugs like ipilimumab, nivolumab, and pembrolizumab. Nowadays, ipilimumab is often used in patients with metastatic melanoma. In this paper, we report a case of a 68-year-old man who developed, and eventually died of, herpes encephalitis after introducing ipilimumab as treatment for metastatic melanoma. To our knowledge, this is the first report in which herpes encephalitis as a complication after ipilimumab and infliximab treatment is described and we would like to make physicians aware of this possible serious neurological complication, especially when a patient has a history of herpes simplex infection.

Severe fluoropyrimidine toxicity due to novel and rare DPYD missense mutations, deletion and genomic amplification affecting DPD activity and mRNA splicing.

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). Genetic variations in DPD have emerged as predictive risk factors for severe fluoropyrimidine toxicity. Here, we report novel and rare genetic variants underlying DPD deficiency in 9 cancer patients presenting with severe fluoropyrimidine-associated toxicity. All patients possessed a strongly reduced DPD activity, ranging from 9 to 53% of controls. Analysis of the DPD gene (DPYD) showed the presence of 21 variable sites including 4 novel and 4 very rare aberrations: 3 missense mutations, 2 splice-site mutations, 1 intronic mutation, a deletion of 21 nucleotides and a genomic amplification of exons 9-12. Two novel/rare variants (c.2843T>C, c.321+1G>A) were present in multiple, unrelated patients. Functional analysis of recombinantly-expressed DPD mutants carrying the p.I948T and p.G284V mutation showed residual DPD activities of 30% and 0.5%, respectively. Analysis of a DPD homology model indicated that the p.I948T and p.G284V mutations may affect electron transfer and the binding of FAD, respectively. cDNA analysis showed that the c.321+1G>A mutation in DPYD leads to skipping of exon 4 immediately upstream of the mutated splice-donor site in the process of DPD pre-mRNA splicing. A lethal toxicity in two DPD patients suggests that fluoropyrimidines combined with other therapies such as radiotherapy might be particularly toxic for DPD deficient patients. Our study advocates a more comprehensive genotyping approach combined with phenotyping strategies for upfront screening for DPD deficiency to ensure the safe administration of fluoropyrimidines.