Accurate staging of non-metastatic colon cancer with CT: the importance of training and practice for experienced radiologists and analysis of incorrectly staged cases.

PURPOSE: To investigate whether locoregional staging of colon cancer by experienced radiologists can be improved by training and feedback to minimize the risk of over-staging into the context of patient selection for neoadjuvant therapy and to identify potential pitfalls of CT staging by characterizing pathologic traits of tumors that remain challenging for radiologists. METHODS: Forty-five cases of stage I-III colon cancer were included in this retrospective study. Five experienced radiologists evaluated the CTs; 5 baseline scans followed by 4 sequential batches of 10 scans. All radiologists were trained after baseline scoring and 2 radiologists received feedback. The learning curve, diagnostic performance, reader confidence, and reading time were evaluated with pathologic staging as reference. Pathology reports and H&E slides of challenging cases were reviewed to identify potential pitfalls. RESULTS: Diagnostic performance in distinguishing T1-2 vs. T3-4 improved significantly after training and with increasing number of reviewed cases. Inaccurate staging was more frequently related to under-staging rather than over-staging. Risk of over-staging was minimized to 7% in batch 3-4. N-staging remained unreliable with an overall accuracy of 61%. Pathologic review identified two tumor characteristics causing under-staging for T-stage in 5/7 cases: (1) very limited invasive part beyond the muscularis propria and (2) mucinous composition of the invading part. CONCLUSION: The high accuracy and specificity of T-staging reached in our study indicate that sufficient training and practice of experienced radiologists can ensure high validity for CT staging in colon cancer to safely use neoadjuvant therapy without significant risk of over-treatment, while N-staging remained unreliable.

Daily practice in guideline adherence to adjuvant chemotherapy in stage III colon cancer and predictors of outcome.

INTRODUCTION: Although guidelines recommend adjuvant chemotherapy for stage III colon cancer patients, many patients do not receive adjuvant chemotherapy. The aim of this study was to identify reasons for guideline non-adherence and assess the effect on patient outcomes in a multicenter cohort of stage III colon cancer patients who received surgery plus adjuvant chemotherapy or surgery alone. METHODS: Patients who underwent surgery between 2007 and 2017 were included. Reasons for non-adherence were determined. Propensity score analyses with inverse probability weighting were performed to adjust for confounding factors. Cox proportional hazards regression and risk stratified analyses were performed to assess the association of guideline adherence and other potential predictors with recurrence free survival (RFS). RESULTS: Data of 575 patients were included of whom 61% received adjuvant chemotherapy. In 87 of 222 patients (39%) who did not receive adjuvant chemotherapy, no reason was documented. Only age was predictive for receiving chemotherapy. Patients who received adjuvant chemotherapy had longer RFS (HR 0.42, 95%CI 0.29-0.62, p < 0.001). High T- and N-stage were associated with poorer RFS HR 2.0 (95%CI 1.58-2.71, p < 0.001) and HR 2.19 (95%CI 1.60-2.99, p < 0.001) respectively. Risk groups were identified with distinct prognosis and treatment effect and a nomogram is presented to visualize individualized RFS differences. CONCLUSION: This study shows considerable variation in guideline adherence to adjuvant chemotherapy and poor documentation on reasons for non-adherence. Optimizing adherence and gaining insight in reasons for non-adherence is advocated as this can lead to significant RFS benefit, especially in patients with high T-and N-stage tumors.

Improving clinical management of colon cancer through CONNECTION, a nation-wide colon cancer registry and stratification effort (CONNECTION II trial): rationale and protocol of a single arm intervention study.

BACKGROUND: It is estimated that around 15-30% of patients with early stage colon cancer benefit from adjuvant chemotherapy. We are currently not capable of upfront selection of patients who benefit from chemotherapy, which indicates the need for additional predictive markers for response to chemotherapy. It has been shown that the consensus molecular subtypes (CMSs), defined by RNA-profiling, have prognostic and/or predictive value. Due to postoperative timing of chemotherapy in current guidelines, tumor response to chemotherapy per CMS is not known, which makes the differentiation between the prognostic and predictive value impossible. Therefore, we propose to assess the tumor response per CMS in the neoadjuvant chemotherapy setting. This will provide us with clear data on the predictive value for chemotherapy response of the CMSs. METHODS: In this prospective, single arm, multicenter intervention study, 262 patients with resectable microsatellite stable cT3-4NxM0 colon cancer will be treated with two courses of neoadjuvant and two courses of adjuvant capecitabine and oxaliplatin. The primary endpoint is the pathological tumor response to neoadjuvant chemotherapy per CMS. Secondary endpoints are radiological tumor response, the prognostic value of these responses for recurrence free survival and overall survival and the differences in CMS classification of the same tumor before and after neoadjuvant chemotherapy. The study is scheduled to be performed in 8-10 Dutch hospitals. The first patient was included in February 2020. DISCUSSION: Patient selection for adjuvant chemotherapy in early stage colon cancer is far from optimal. The CMS classification is a promising new biomarker, but a solid chemotherapy response assessment per subtype is lacking. In this study we will investigate whether CMS classification can be of added value in clinical decision making by analyzing the predictive value for chemotherapy response. This study can provide the results necessary to proceed to future studies in which (neo) adjuvant chemotherapy may be withhold in patients with a specific CMS subtype, who show no benefit from chemotherapy and for whom possible new treatments can be investigated. TRIAL REGISTRATION: This study has been registered in the Netherlands Trial Register (NL8177) at 11-26-2019, https://www.trialregister.nl/trial/8177 . The study has been approved by the medical ethics committee Utrecht (MEC18/712).

Effect of levothyroxine on live birth rate in euthyroid women with recurrent miscarriage and TPO antibodies (T4-LIFE study).

BACKGROUND: Thyroid peroxidase antibodies (TPO-Ab) in euthyroid women are associated with recurrent miscarriage (RM) and other pregnancy complications such as preterm birth. It is unclear if treatment with levothyroxine improves pregnancy outcome. AIM: The aim of this study is to determine the effect of levothyroxine administration on live birth rate in euthyroid TPO-Ab positive women with recurrent miscarriage. METHODS/DESIGN: We will perform a multicenter, placebo controlled randomized trial in euthyroid women with recurrent miscarriage and TPO-Ab. Recurrent miscarriage is defined as two or more miscarriages before the 20th week of gestation. The primary outcome is live birth, defined as the birth of a living fetus beyond 24weeks of gestation. Secondary outcomes are ongoing pregnancy at 12weeks, miscarriage, preterm birth, (serious) adverse events, time to pregnancy and survival at 28days of neonatal life. The analysis will be performed according to the intention to treat principle. We need to randomize 240 women (120 per group) to demonstrate an improvement in live birth rate from 55% in the placebo group to 75% in the levothyroxine treatment group. This trial is a registered trial (NTR 3364, March 2012). Here we discuss the rationale and design of the T4-LIFE study, an international multicenter randomized, double blind placebo controlled, clinical trial aimed to assess the effectiveness of levothyroxine in women with recurrent miscarriage and TPO-Ab.

The role of fibrinogen in massive postpartum haemorrhage, a case report.

•A G2P1 with a complicated obstetric history of massive postpartum haemorrhage (7 L)•Monitoring of fibrinogen levels during pregnancy and labour•Fibrinogen suppletion resulted in only 2 L blood loss during the third stage of labour.•This case report and literature show that fibrinogen levels might play a role in massive postpartum hemorrhage.

Development and qualification of the parallel line model for the estimation of human influenza haemagglutinin content using the single radial immunodiffusion assay.

Infection with human influenza virus leads to serious respiratory disease. Vaccination is the most common and effective prophylactic measure to prevent influenza. Influenza vaccine manufacturing and release is controlled by the correct determination of the potency-defining haemagglutinin (HA) content. This determination is historically done by single radial immunodiffusion (SRID), which utilizes a statistical slope-ratio model to estimate the actual HA content. In this paper we describe the development and qualification of a parallel line model for analysis of HA quantification by SRID in cell culture-derived whole virus final monovalent and trivalent influenza vaccines. We evaluated plate layout, sample randomization, and validity of data and statistical model. The parallel line model was shown to be robust and reproducible. The precision studies for HA content demonstrated 3.8-5.0% repeatability and 3.8%-7.9% intermediate precision. Furthermore, system suitability criteria were developed to guarantee long-term stability of this assay in a regulated production environment. SRID is fraught with methodological and logistical difficulties and the determination of the HA content requires the acceptance of new and modern release assays, but until that moment, the described parallel line model represents a significant and robust update for the current global influenza vaccine release assay.

Validation of an internet questionnaire for risk assessment in preconception care.

AIM: Validation of a self-administered Internet questionnaire for preconception risk assessment. METHODS: Women with an appointment at the outpatient clinics for preconception care or fertility at the Erasmus Medical Center Rotterdam were requested to fill out the online questionnaire prior to attendance. Subsequently, the items of the questionnaire were verified by history taking during the first or next appointment. Agreement between the 2 screening methods (Internet vs. history taking) was calculated using Kappa statistic. RESULTS: Most lifestyle variables, including smoking, alcohol, and dietary items, showed a good to high level of agreement when compared to the interview. Most medical history and obstetric history items also showed a good to high level of agreement. The use of over-the-counter drugs revealed a poor level of agreement (Kappa = 0.21). The items pertaining to women's family history showed a reasonable level of agreement; however, the partner's family history was unreliable and should be checked at the interview. CONCLUSION: The online questionnaire www.zwangerwijzer.nl is a useful tool for the identification of a number of potential risk factors in the preconception care setting and was found to be a an efficient and clear screening instrument by the majority of women. However, additional history taking by trained professionals is necessary to verify several items and to further explore identified risk factors for an adverse pregnancy outcome.

Maternal periconceptional biochemical and hematological parameters, vitamin profiles and pregnancy outcome.

OBJECTIVES: To evaluate periconceptional maternal biochemical and hematological parameters and vitamin profiles in relation to the risk of early pregnancy loss and birth weight. DESIGN: Prospective longitudinal study. SETTING: University Medical Centre Nijmegen, Academic Medical Centre, Amsterdam, Maria and Elisabeth Hospitals, Tilburg, and Catharina Hospital, Eindhoven, The Netherlands. SUBJECTS: A cohort of 240 women recruited before pregnancy. INTERVENTIONS: Blood samples were taken preconceptional and at 6 and 10 weeks amenorrhea in which the concentrations of hemoglobin, hematocrit, creatinin, uric acid, total protein, serum iron, total iron-binding capacity, ferritin, and the concentrations of retinol, tocopherol, thiamine, riboflavin, pyridoxal-5'-phosphate, cobalamin and folate were analyzed. MAIN OUTCOME MEASURES: Risk of early pregnancy loss and birth weight. RESULTS: The risk of early pregnancy loss increased with increasing prepregnancy weight, and when the periconceptional decline in hematocrit, creatinin and uric acid was less profound (slope: P<0.01). Maternal smoking was negatively associated with birth weight (mean reduction of 183 g, P<0.05). Maternal age and prepregnancy weight were positively associated with birth weight (P<0.01). No significant associations were found between vitamin concentrations and risk of early pregnancy loss or birth weight. CONCLUSIONS: Several periconceptional biochemical parameters are significantly associated with early pregnancy loss. The effects of maternal periconceptional health on embryonic development and subsequent pregnancy outcome should be further explored. SPONSORSHIP: Dutch Prevention fund, grants no. 28.1358 and 28.1006.

[Preconception counseling: evaluation of an outpatient clinic at a university hospital]. / Preconceptionele advisering: evaluatie van een polikliniek in een academisch ziekenhuis.

OBJECTIVE: To provide an overview of the outcomes from an outpatients' clinic for preconceptional counselling in the Netherlands and to assess its activities in terms of referrals, referral indications, supplementary investigations, treatment policy and a possible future pregnancy. DESIGN: Retrospective, descriptive. METHOD: Data were collected from the medical records of women who were seen at the outpatients' clinic for preconceptional counselling, University Medical Centre St Radboud, Nijmegen, the Netherlands, during the period 1 January 1996-6 July 2000. RESULTS: Of the 484 women studied, medical records were available for 459 (95%); their median age was 31 years (range: 19-44). Most of the women with one or more risk factors were referred by gynaecologists (65%), followed by general practitioners (17%) and other specialists (14%). The main categories of referral were previous complicated obstetric history, previous fetal abnormality, and chronic maternal disease. Half of the women were subjected to supplementary investigations on the basis of an indication; hyperhomocysteinaemia was diagnosed in 24%, other form of thrombophilia (coagulopathy) in 21% and vitamin deficiency in 18%. The most frequent preconceptional interventions were the correction of hyperhomocysteinaemia by means of administering folic acid or other vitamin supplements and a change of therapy or cessation of therapy for potentially teratogenic medications. CONCLUSION: The outpatients' clinic for preconceptional counselling helped to minimise risk factors for adverse pregnancy outcome amongst high-risk women by providing extensive advice as well as by means of the early detection and treatment of diagnosed abnormalities.

Psychological impact of preconception counseling: assessment of anxiety before and during pregnancy.

OBJECTIVE: Assessment of anxiety levels in women and men before and after preconception counseling and during the first trimester of pregnancy. METHODS: Couples were recruited from the fertility clinic of the University Medical Center Nijmegen, the Netherlands. Anxiety was assessed using the 40-item Spielberger State-Trait Anxiety Inventory (STAI). RESULTS: 53 women and 51 men (74%) completed the STAI both before and after counseling. Anxiety levels did not change significantly after counseling or during the first trimester of pregnancy. 83.4% would recommend preconception counseling to others. CONCLUSION: Preconception counseling is valued by the majority of women and men and does not lead to adverse psychological effects.