Upfront resection versus no resection of the primary tumor in patients with synchronous metastatic colorectal cancer: the randomized phase III CAIRO4 study conducted by the Dutch Colorectal Cancer Group and the Danish Colorectal Cancer Group.

BACKGROUND: Upfront primary tumor resection (PTR) has been associated with longer overall survival (OS) in patients with synchronous unresectable metastatic colorectal cancer (mCRC) in retrospective analyses. The aim of the CAIRO4 study was to investigate whether the addition of upfront PTR to systemic therapy resulted in a survival benefit in patients with synchronous mCRC without severe symptoms of their primary tumor. PATIENTS AND METHODS: This randomized phase III trial was conducted in 45 hospitals in The Netherlands and Denmark. Eligibility criteria included previously untreated mCRC, unresectable metastases, and no severe symptoms of the primary tumor. Patients were randomized (1 : 1) to upfront PTR followed by systemic therapy or systemic therapy without upfront PTR. Systemic therapy consisted of first-line fluoropyrimidine-based chemotherapy with bevacizumab in both arms. Primary endpoint was OS in the intention-to-treat population. The study was registered at ClinicalTrials.gov, NCT01606098. RESULTS: Between August 2012 and February 2021, 206 patients were randomized. In the intention-to-treat analysis, 204 patients were included (n = 103 without upfront PTR, n = 101 with upfront PTR) of whom 116 were men (57%) with median age of 65 years (interquartile range 59-71 years). Median follow-up was 69.4 months. Median OS in the arm without upfront PTR was 18.3 months (95% confidence interval 16.0-22.2 months) compared with 20.1 months (95% confidence interval 17.0-25.1 months) in the upfront PTR arm (P = 0.32). The number of grade 3-4 events was 71 (72%) in the arm without upfront PTR and 61 (65%) in the upfront PTR arm (P = 0.33). Three deaths (3%) possibly related to treatment were reported in the arm without upfront PTR and four (4%) in the upfront PTR arm. CONCLUSIONS: Addition of upfront PTR to palliative systemic therapy in patients with synchronous mCRC without severe symptoms of the primary tumor does not result in a survival benefit. This practice should no longer be considered standard of care.

Cannabidiol (Epidyolex®) for severe behavioral manifestations in patients with tuberous sclerosis complex, mucopolysaccharidosis type III and fragile X syndrome: protocol for a series of randomized, placebo-controlled N-of-1 trials.

BACKGROUND: Many rare genetic neurodevelopmental disorders (RGNDs) are characterized by intellectual disability (ID), severe cognitive and behavioral impairments, potentially diagnosed as a comorbid autism spectrum disorder or attention-deficit hyperactivity disorder. Quality of life is often impaired due to irritability, aggression and self-injurious behavior, generally refractory to standard therapies. There are indications from previous (case) studies and patient reporting that cannabidiol (CBD) may be an effective treatment for severe behavioral manifestations in RGNDs. However, clear evidence is lacking and interventional research is challenging due to the rarity as well as the heterogeneity within and between disease groups and interindividual differences in treatment response. Our objective is to examine the effectiveness of CBD on severe behavioral manifestations in three RGNDs, including Tuberous Sclerosis Complex (TSC), mucopolysaccharidosis type III (MPS III), and Fragile X syndrome (FXS), using an innovative trial design. METHODS: We aim to conduct placebo-controlled, double-blind, block-randomized, multiple crossover N-of-1 studies with oral CBD (twice daily) in 30 patients (aged ≥ 6 years) with confirmed TSC, MPS III or FXS and severe behavioral manifestations. The treatment is oral CBD up to a maximum of 25 mg/kg/day, twice daily. The primary outcome measure is the subscale irritability of the Aberrant Behavior Checklist. Secondary outcome measures include (personalized) patient-reported outcome measures with regard to behavioral and psychiatric outcomes, disease-specific outcome measures, parental stress, seizure frequency, and adverse effects of CBD. Questionnaires will be completed and study medication will be taken at the participants' natural setting. Individual treatment effects will be determined based on summary statistics. A mixed model analysis will be applied for analyzing the effectiveness of the intervention per disorder and across disorders combining data from the individual N-of-1 trials. DISCUSSION: These N-of-1 trials address an unmet medical need and will provide information on the effectiveness of CBD for severe behavioral manifestations in RGNDs, potentially generating generalizable knowledge at an individual-, disorder- and RGND population level. TRIAL REGISTRATION: EudraCT: 2021-003250-23, registered 25 August 2022, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-003250-23/NL .

Magnesium hydroxide versus macrogol/electrolytes in the prevention of opioid-induced constipation in incurable cancer patients: study protocol for an open-label, randomized controlled trial (the OMAMA study).

BACKGROUND: Opioid-induced constipation (OIC) is a common symptom in cancer patients treated with opioids with a prevalence of up to 59%. International guidelines recommend standard laxatives such as macrogol/electrolytes and magnesium hydroxide to prevent OIC, although evidence from randomized controlled trials is largely lacking. The aim of our study is to compare magnesium hydroxide with macrogol /electrolytes in the prevention of OIC in patients with incurable cancer and to compare side-effects, tolerability and cost-effectiveness. METHODS: Our study is an open-label, randomized, multicenter study to examine if magnesium hydroxide is non-inferior to macrogol/electrolytes in the prevention of OIC. In total, 330 patients with incurable cancer, starting with opioids for pain management, will be randomized to treatment with either macrogol/electrolytes or magnesium hydroxide. The primary outcome measure is the proportion of patients with a score of < 30 on the Bowel Function Index (BFI), measured on day 14. The Rome IV criteria for constipation, side effects of and satisfaction with laxatives, pain scores, quality of life (using the EQ-5D-5L), daily use of laxatives and escape medication, and cost-effectiveness will also be assessed. DISCUSSION: In this study we aim to examine if magnesium hydroxide is non-inferior to macrogol/electrolytes in the prevention of OIC. The outcome of our study will contribute to prevention of OIC and scientific evidence of guidelines on (opioid-induced) constipation. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov: NCT05216328 and in the Dutch trial register: NTR80508. EudraCT number 2022-000408-36.

Effect of single- versus double-layer uterine closure during caesarean section on postmenstrual spotting (2Close): multicentre, double-blind, randomised controlled superiority trial.

OBJECTIVE: To evaluate whether double-layer uterine closure after a first caesarean section (CS) is superior compared with single-layer uterine closure in terms of postmenstrual spotting and niche development in the uterine caesarean scar. DESIGN: Multicentre, double-blind, randomised controlled superiority trial. SETTING: Thirty-two hospitals in the Netherlands. POPULATION: A total of 2292 women aged ≥18 years undergoing a first CS were randomly assigned to each procedure (1:1): 1144 women were assigned to single-layer uterine closure and 1148 women were assigned to double-layer uterine closure. METHODS: Single-layer unlocked closure and double-layer unlocked closure, with the second layer imbricating the first. MAIN OUTCOME MEASURES: Number of days with postmenstrual spotting during one menstrual cycle 9 months after CS. SECONDARY OUTCOMES: perioperative and menstrual characteristics; transvaginal ultrasound measurements. RESULTS: A total of 774 (67.7%) women from the single-layer group and 770 (67.1%) women from the double-layer group were evaluable for the primary outcome, as a result of drop-out and amenorrhoea. The mean number of postmenstrual spotting days was 1.33 (bootstrapped 95% CI 1.12-1.54) after single-layer closure and 1.26 (bootstrapped 95% CI 1.07-1.45) after double-layer closure (adjusted mean difference -0.07, 95% CI -0.37 to 0.22, P = 0.810). The operative time was 3.9 minutes longer (95% CI 3.0-4.9 minutes, P < 0.001) and niche prevalence was 4.7% higher (95% CI 0.7-8.7%, P = 0.022) after double-layer closure. CONCLUSIONS: The superiority of double-layer closure compared with single-layer closure in terms of postmenstrual spotting after a first CS was not shown. Long-term obstetric follow-up of our trial is needed to assess whether uterine caesarean closure guidelines should be adapted. TWEETABLE ABSTRACT: Double-layer uterine closure is not superior for postmenstrual spotting after a first caesarean; single-layer closure performs slightly better on other outcomes.

Predicting poor outcome in patients with suspected COVID-19 presenting to the Emergency Department (COVERED) - Development, internal and external validation of a prediction model.

BACKGROUND: A recent systematic review recommends against the use of any of the current COVID-19 prediction models in clinical practice. To enable clinicians to appropriately profile and treat suspected COVID-19 patients at the emergency department (ED), externally validated models that predict poor outcome are desperately needed. OBJECTIVE: Our aims were to identify predictors of poor outcome, defined as mortality or ICU admission within 30 days, in patients presenting to the ED with a clinical suspicion of COVID-19, and to develop and externally validate a prediction model for poor outcome. METHODS: In this prospective, multi-center study, we enrolled suspected COVID-19 patients presenting at the EDs of two hospitals in the Netherlands. We used backward logistic regression to develop a prediction model. We used the area under the curve (AUC), Brier score and pseudo-R2 to assess model performance. The model was externally validated in an Italian cohort. RESULTS: We included 1193 patients between March 12 and May 27 2020, of whom 196 (16.4%) had a poor outcome. We identified 10 predictors of poor outcome: current malignancy (OR 2.774; 95%CI 1.682-4.576), systolic blood pressure (OR 0.981; 95%CI 0.964-0.998), heart rate (OR 1.001; 95%CI 0.97-1.028), respiratory rate (OR 1.078; 95%CI 1.046-1.111), oxygen saturation (OR 0.899; 95%CI 0.850-0.952), body temperature (OR 0.505; 95%CI 0.359-0.710), serum urea (OR 1.404; 95%CI 1.198-1.645), C-reactive protein (OR 1.013; 95%CI 1.001-1.024), lactate dehydrogenase (OR 1.007; 95%CI 1.002-1.013) and SARS-CoV-2 PCR result (OR 2.456; 95%CI 1.526-3.953). The AUC was 0.86 (95%CI 0.83-0.89), with a Brier score of 0.32 and, and R2 of 0.41. The AUC in the external validation in 500 patients was 0.70 (95%CI 0.65-0.75). CONCLUSION: The COVERED risk score showed excellent discriminatory ability, also in an external validation. It may aid clinical decision making, and improve triage at the ED in health care environments with high patient throughputs.

Treatment effect of oil-based contrast is related to experienced pain at HSG: a post-hoc analysis of the randomised H2Oil study.

STUDY QUESTION: Does pain or volume of used contrast medium impact the effectiveness of oil-based contrast during hysterosalpingography (HSG)? SUMMARY ANSWER: In women who report moderate to severe pain during HSG, the use of oil-based contrast resulted in more ongoing pregnancies compared to the use of water-based contrast, whereas in women who reported mild or no pain, no difference in ongoing pregnancies was found. WHAT IS KNOWN ALREADY: We recently showed that in infertile women undergoing HSG, the use of oil-based contrast results in more ongoing pregnancies within 6 months as compared to the use of water-based contrast. However, the underlying mechanism of this fertility-enhancing effect remains unclear. STUDY DESIGN, SIZE, DURATION: We performed a post-hoc analysis of the H2Oil study, a multicentre randomised controlled trial (RCT) evaluating the therapeutic effect of oil- and water-based contrast at HSG. Here, we evaluated the impact of pain experienced at HSG and volume of used contrast media during HSG on ongoing pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: In a subset of 400 participating women, pain during HSG by means of the Visual Analogue Scale (VAS) (range: 0.0-10.0 cm) was reported, while in 512 women, we registered the volume of used contrast (in millilitres). We used logistic regression analyses to assess whether pain and volume of used contrast media modified the effect of oil-based contrast on ongoing pregnancy rates. Data were analysed according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: In 400 women in whom pain scores were reported, the overall median pain score was 5.0 (Interquartile range (IQR) 3.0-6.8) (oil group (n = 199) 4.8 (IQR 3.0-6.4); water group (n = 201) 5.0 (IQR 3.0-6.7); P-value 0.28). There was a significant interaction between pain (VAS ≤5 versus VAS ≥6) and the primary outcome ongoing pregnancy (P-value 0.047). In women experiencing pain (VAS ≥6), HSG with oil-based contrast resulted in better 6-month ongoing pregnancy rates compared to HSG with water-based contrast (49.4% versus 29.6%; RR 1.7; 95% CI, 1.1-2.5), while in women with a pain score ≤5, 6-month ongoing pregnancy rates were not significantly different between the use of oil- (28.8%) versus water-based contrast (29.2%) (RR 0.99; 95% CI, 0.66-1.5). In the 512 women in whom we recorded contrast, median volume was 9.0 ml (IQR 5.7-15.0) in the oil group versus 8.0 ml (IQR 5.9-13.0) in the water group, respectively (P-value 0.72). Volume of used contrast was not found to modify the effect of oil-based contrast on ongoing pregnancy (P-value for interaction 0.23). LIMITATIONS, REASONS FOR CAUTION: This was a post-hoc analysis that should be considered as hypothesis generating. The RCT was restricted to infertile ovulatory women, younger than 39 years of age and with a low risk for tubal pathology. Therefore, our results should not be generalised to infertile women who do not share these features. WIDER IMPLICATIONS OF THE FINDINGS: The underlying mechanism of the fertility-enhancing effect induced by HSG with the use of oil-based contrast remains unclear. However, these findings suggest a possible mechanistic pathway, that is increasing intrauterine pressure occurring prior to dislodging pregnancy hindering debris or mucus plugs from the proximal part of otherwise normal fallopian tubes. This information might help in the search of the underlying fertility-enhancing mechanism found by using oil-based contrast during HSG. STUDY FUNDING/COMPETING INTEREST(S): The original H2Oil RCT was an investigator-initiated study that was funded by the two academic institutions (AMC and VUmc) of the Amsterdam UMC. The funders had no role in study design, collection, analysis and interpretation of the data. K.D. reports consultancy for Guerbet. H.V. reports consultancy fees from Ferring. C.B.L. reports speakers' fees from Ferring and research grants from Ferring, Merck and Guerbet. V.M. reports receiving travel and speakers fees as well as research grants from Guerbet. B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research grants from Merck KGaA and Guerbet. The other authors do not report conflict of interests. TRIAL REGISTRATION NUMBER: The H2Oil study was registered at the Netherlands Trial Registry (NTR 3270). TRIAL REGISTRATION DATE: 1 February 2012. DATE OF FIRST PATIENT'S ENROLMENT: 3 February 2012.

Single- versus double-layer closure of the caesarean (uterine) scar in the prevention of gynaecological symptoms in relation to niche development - the 2Close study: a multicentre randomised controlled trial.

BACKGROUND: Double-layer compared to single-layer closure of the uterus after a caesarean section (CS) leads to a thicker myometrial layer at the site of the CS scar, also called residual myometrium thickness (RMT). It possibly decreases the development of a niche, which is an interruption of the myometrium at the site of the uterine scar. Thin RMT and a niche are associated with gynaecological symptoms, obstetric complications in a subsequent pregnancy and delivery and possibly with subfertility. METHODS: Women undergoing a first CS regardless of the gestational age will be asked to participate in this multicentre, double blinded randomised controlled trial (RCT). They will be randomised to single-layer closure or double-layer closure of the uterine incision. Single-layer closure (control group) is performed with a continuous running, unlocked suture, with or without endometrial saving technique. Double-layer closure (intervention group) is performed with the first layer in a continuous unlocked suture including the endometrial layer and the second layer is also continuous unlocked and imbricates the first. The primary outcome is the reported number of days with postmenstrual spotting during one menstrual cycle nine months after CS. Secondary outcomes include surgical data, ultrasound evaluation at three months, menstrual pattern, dysmenorrhea, quality of life, and sexual function at nine months. Structured transvaginal ultrasound (TVUS) evaluation is performed to assess the uterine scar and if necessary saline infusion sonohysterography (SIS) or gel instillation sonohysterography (GIS) will be added to the examination. Women and ultrasound examiners will be blinded for allocation. Reproductive outcomes at three years follow-up including fertility, mode of delivery and complications in subsequent deliveries will be studied as well. Analyses will be performed by intention to treat. 2290 women have to be randomised to show a reduction of 15% in the mean number of spotting days. Additionally, a cost-effectiveness analysis will be performed from a societal perspective. DISCUSSION: This RCT will provide insight in the outcomes of single- compared to double-layer closure technique after CS, including postmenstrual spotting and subfertility in relation to niche development measured by ultrasound. TRIAL REGISTRATION: Dutch Trial Register ( NTR5480 ). Registered 29 October 2015.

Uterine caesarean closure techniques affect ultrasound findings and maternal outcomes: a systematic review and meta-analysis.

BACKGROUND: Caesarean section (CS) rates are rising globally. Long-term adverse outcomes after CS might be reduced when the optimal uterine closure technique becomes evident. OBJECTIVE: To determine the effect of uterine closure techniques after CS on maternal and ultrasound outcomes. SEARCH STRATEGY: Literature search in electronic databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) or prospective cohort studies that evaluated uterine closure techniques and reported on ultrasound findings, perioperative or long-term outcomes. DATA COLLECTION AND ANALYSIS: Twenty studies (15 053 women) were included in our meta-analyses for various outcomes. We calculated pooled risk ratios (RR) and weighted mean differences (WMD) with 95% CI through random-effect analysis. MAIN RESULTS: Residual myometrium thickness (RMT), reported in eight studies (508 women), decreased by 1.26 mm after single- compared with double-layer closure (95% CI -1.93 to -0.58), particularly when locked sutures were used. Healing ratio [RMT/adjacent myometrium thickness (AMT)] decreased after single-layer closure (WMD -7.74%, 95% CI -13.31 to -2.17), particularly in the case of locked sutures. Niche prevalence increased (RR 1.71, 95% CI 1.11-2.62) when the decidua was excluded. Dysmenorrhea occurred more often in the single-layer group (RR 1.23, 95% CI 1.01-1.48), whereas incidence of uterine rupture was similar (RR 1.91, 95% CI 0.63-5.74). CONCLUSION: Double-layer unlocked sutures are preferable to single-layer locked sutures regarding RMT, healing ratio and dysmenorrhoea. Excluding the decidua seems to result in higher niche prevalence. As thin residual myometrium or niches may serve as intermediates for gynaecological and reproductive outcomes, future studies should focus on these outcomes. TWEETABLE ABSTRACT: #Uterineclosuretechniques after #caesarean affect #longtermoutcomes.

Transanal total mesorectal excision for rectal cancer: evaluation of the learning curve.

BACKGROUND: Transanal total mesorectal excision (TaTME) provides an excellent view of the resection margins for rectal cancer from below, but is challenging due to few anatomical landmarks. During implementation of this technique, patient safety and optimal outcomes need to be ensured. The aim of this study was to evaluate the learning curve of TaTME in patients with rectal cancer in order to optimize future training programs. METHODS: All consecutive patients after TaTME for rectal cancer between February 2012 and January 2017 were included in a single-center database. Influence of surgical experience on major postoperative complications, leakage rate and operating time was evaluated using cumulative sum charts and the splitting model. Correction for potential case-mix differences was performed. RESULTS: Over a period of 60 months, a total of 138 patients were included in this study. Adjusted for case-mix, improvement in postoperative outcomes was clearly seen after the first 40 patients, showing a decrease in major postoperative complications from 47.5 to 17.5% and leakage rate from 27.5 to 5%. Mean operating time (42 min) and conversion rate (from 10% to zero) was lower after transition to a two-team approach, but neither endpoint decreased with experience. Readmission and reoperation rates were not influenced by surgical experience. CONCLUSIONS: The learning curve of TaTME affected major (surgical) postoperative complications for the first 40 patients. A two-team approach decreased operative time and conversion rate. When implementing this new technique, a thorough teaching and supervisory program is recommended to shorten the learning curve and improve the clinical outcomes of the first patients.

Immobilization or mobilization after IUI: an RCT.

STUDY QUESTION: Does 15 min of immobilization after IUI improve pregnancy rates? SUMMARY ANSWER: Immobilization for 15 min after IUI does not improve pregnancy rates. WHAT IS KNOWN ALREADY: Prior RCTs report a beneficial effect of supine immobilization for 15 min following IUI compared to immediate mobilization, however, these studies can be criticized. Given the importance for the logistics in daily practice and the lack of biological plausibility we planned a replication study prior to potential implementation of this procedure. STUDY DESIGN, SIZE, DURATION: A single centre RCT, based in an academic setting in the Netherlands, was performed. Participants were randomly assigned for 15 min of supine immobilization following IUI for a maximum of six cycles compared to the standard procedure of immediate mobilization following IUI. Participants and caregivers were not blinded to group assignment. An independent researcher used computer-generated tables to allocate treatments. Stratification occurred to the indication of IUI (unexplained or mild male subfertility). Revelation of allocation took place just before the insemination by the caregiver. The primary outcome was ongoing pregnancy rate per couple. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 498 couples diagnosed with unexplained or mild male subfertility and an indication for treatment with IUI were approached and randomized in the study, of which 244 participants were assigned to 15 min of supine immobilization and 254 participants to immediate mobilization. MAIN RESULTS AND THE ROLE OF CHANCE: Participant characteristics were comparable between the groups, and 236 participants were analysed in the immobilization group, versus 245 in the mobilization group. The ongoing pregnancy rate per couple was not found to be superior in the immobilization group (one-sided P-value = 0.97) with 76/236 ongoing pregnancies (32.2%) being accomplished in the immobilization and 98/245 ongoing pregnancies (40.0%) in the immediate mobilization group (relative risk 0.81; 95% CI [0.63, 1.02], risk difference: -7.8%, 95% CI [-16.4%, 0.8%]). No difference was found in miscarriage rate, multiple gestation rate, live birth rate and time to pregnancy between the groups. LIMITATIONS, REASONS FOR CAUTION: Owing to discontinuation of the planned treatment not all participants reached six IUI cycles or an ongoing pregnancy. However, this is as expected in IUI treatment and mirrors clinical practice. These participants were equally distributed across the two groups. Women with tubal pathology and endocrine disorders were excluded for this trial, and this might narrow generalizability. WIDER IMPLICATIONS OF THE FINDINGS: This study shows no positive effect of 15 min of immobilization following IUI on pregnancy rates. Based on available evidence today, including our study, a possible beneficial effect of supine immobilization after IUI is at least doubtful and straightforward implementation does not seem to be justified. STUDY FUNDING/COMPETING INTEREST(S): No funding was received. All authors have nothing to disclose. TRIAL REGISTRATION NUMBER: Dutch Trial Register NTR 2418. TRIAL REGISTRATION DATE: 20 July 2010. DATE OF FIRST PATIENT's ENROLMENT: 11 August 2010.

Delays in diagnosis and treatment of childhood cancer in Indonesia.

BACKGROUND: Emphasizing timely diagnosis and treatment of cancer are important themes in pediatric cancer management, as delays adversely impact survival. This study explores various delay types among children with cancer and determines factors that influence delays. METHODS: This cross-sectional study was conducted at an Indonesian academic hospital. Parents of newly diagnosed patients were interviewed between October 2013 and September 2014 using semistructured questionnaires. Patient, physician, diagnosis, treatment, healthcare system (HCS), and total delay were analyzed. RESULTS: Parents of 145 children (response rate 89%) with cancer were interviewed. Median total delay was 70 days (range 5-4,055). Patient delay (median 5 days, range 0-189) was significantly shorter than HCS delay (median 49 days, range 4-4,025, P < 0.001). Diagnosis delay (median 58 days, range 3-4,015) was significantly longer than treatment delay (median 3 days, range 1-89, P < 0.001). Older age at diagnosis significantly lengthened patient delay (P = 0.044). Using alternative treatment was associated with significantly longer patient and total delay (P = 0.025, 0.024, respectively). Cancer type significantly influenced physician, diagnosis, treatment, HCS, and total delay (P = 0.001, P = 0.004, P < 0.001, P < 0.001, P < 0.001, respectively). Neurological tumors had the longest delays, whereas hematological tumors had the shortest. Sex, parents' education or income level, disease stage at diagnosis, health insurance status, distance from hospital, and first attended health-facility type did not significantly impact the length of any delay type. CONCLUSIONS: Healthcare providers need training to improve recognition of cancer symptoms and speed up subsequent diagnostic processes. Using alternative treatment increased patient and total delays. Community campaigns to encourage families to seek conventional cancer treatments are recommended.

Factors influencing time to diagnosis and treatment among pediatric oncology patients in Kenya.

Early diagnosis and start of treatment are fundamental goals in cancer care. This study determines the time lag and the factors that influence the time to diagnosis and start of treatment. Study participants were parents of childhood cancer patients diagnosed between August 2013 and July 2014 in a hospital in Kenya. Patient, physician, diagnosis, treatment, health care system, and total delay were explored using a questionnaire. Demographic and medical data were collected from the patients' medical records. Parents of 99 childhood cancer patients were interviewed (response rate: 80%). Median total delay was 102 (9-1021) days. Median patient delay (4 days) was significantly shorter than health care system delay (median 87 days; P < .001). Diagnosis delay (median 94 days) was significantly longer than treatment delay (median 6 days; P < .001). days. Lack of health insurance at diagnosis and use of alternative medicine before attending conventional health services were associated with a significantly longer patient delay (P = .041 and P = .017, respectively). The type of cancer had a significant effect on treatment delay (P = .020). The type of health facility attended affected only patient delay (P = .03). Gender, age at diagnosis, stage of disease, parents' education level or income, and distance from hospital did not have a significant effect on the length of any type of delay. Training on childhood cancer should be included in the curricula for medical training institutes. In-service workshops should be held for the health workers already working. Families must be obligated to get health insurance. Families should be encourage to attend conventional health facilities and informed on symptoms of cancer through mass media.

Parental experiences of childhood cancer treatment in Kenya.

PURPOSE: Our study explores socioeconomic, treatment-related, and psychological experiences of parents during cancer treatment of their children at an academic hospital in Kenya. METHODS: This cross-sectional study used semi-structured questionnaires. Parents whose children came for cancer treatment consecutively between November 2012 and April 2013 were interviewed. RESULTS: Between 2012 and 2013, 115 oncology patients attended the hospital and 75 families (response rate 65 %) were interviewed. Cancer treatment resulted in financial difficulties (89 %). More information about cancer and treatment was required (88 %). More contact with doctors was needed (83 %). At diagnosis, cancer was perceived as curable (63 %). However, parents were told by health-care providers that most children with cancer die (49 %). Parents had difficulties with understanding doctors' vocabulary (48 %). Common reasons to miss hospital appointments were travel costs (52 %) and hospital costs (28 %). Parents (95 %) used complementary alternative treatment (CAM) for their children. Health-care providers told parents not to use CAM (49 %). Parents had not discussed their CAM use with doctors (71 %). Community members isolated families because their child had cancer (25 %), believed that child was bewitched (57 %), advised to use CAM (61 %), and stopped conventional treatment (45 %). Some families (15 %) never disclosed the child's illness to community members. Parents shared experiences with other parents at the ward (97 %) and would otherwise not understand the disease and its treatment (87 %). CONCLUSIONS: Parents suffer financial hardships and are dissatisfied with doctors' communication regarding their children's condition. CAM is very commonly used. Doctors need to improve their communication skills and discuss CAM more openly. Cancer programs should include more support for parents: financial assistance, a facility where parents and children can stay during the course of therapy, and parent support groups.

Two overlooked contributors to abandonment of childhood cancer treatment in Kenya: parents' social network and experiences with hospital retention policies.

BACKGROUND: The principal reason for childhood cancer treatment failure in low-income countries is treatment abandonment, the most severe form of nonadherence. Two often neglected factors that may contribute to treatment abandonment are as follows: (a) lack of information and guidance by doctors, along with the negative beliefs of family and friends advising parents, which contributes to misconceptions regarding cancer and its treatment, and (b) a widespread policy in public hospitals by which children are retained after doctor's discharge until medical bills are settled. OBJECTIVE: This study explored parents' experiences with hospital retention policies in a Kenyan academic hospital and the impact of attitudes of family and friends on parents' decisions about continuing cancer treatment for their child. METHODS: Home visits were conducted to interview parents of childhood cancer patients who had been diagnosed between 2007 and 2009 and who had abandoned cancer treatment. RESULTS: Retrospective chart review revealed 98 children diagnosed between 2007 and 2009 whose parents had made the decisions to abandon treatment. During 2011-2012, 53 families (54%) could be reached, and 46 (87%) of these agreed to be interviewed. Parents reported the attitudes of community members (grandparents, relatives, friends, villagers, and church members); 61% believed that the child had been bewitched by some individual, and 74% advised parents to seek alternative treatment or advised them to stop medical treatment (54%). Parents also reported that they were influenced by discussions with other parents who had a child being treated, including that their child's life was in God's hands (87%), the trauma to the child and family of forced hospital stays (84%), the importance of completing treatment (81%), the financial burden of treatment (77%), and the incurability of cancer (74%). These discussions influenced their perceptions of cancer treatment and its usefulness (65%). Thirty-six families (78%) had no health insurance, and 19 of these parents (53%) could not pay their medical bills and were not allowed to take their child home when treatment ended. Parents reported feelings of desperation (95%), powerlessness (95%), and sadness (84%) and that their child has been imprisoned (80%), during the period of retention. The majority of parents (87%) felt that hospital retention of children must cease. CONCLUSIONS: The attitudes and beliefs of parents of children with cancer are impacted by those close to them and their community and may influence their perceptions of cancer treatment and decisions to stop treatment. Hospital retention policies are highly distressing for parents and may contribute to both treatment delays and treatment abandonment. These factors jeopardize treatment outcomes for young patients and require attention and modification.

Influence of health-insurance access and hospital retention policies on childhood cancer treatment in Kenya.

BACKGROUND: Kenyan national policies for public hospitals dictate that patients are retained on hospital wards until their hospital bills are paid, but this payment process differs for patients with or without access to National Hospital Insurance Fund (NHIF) at diagnosis. Whether these differences impact treatment outcomes has not been described. Our study explores whether childhood cancer treatment outcomes in Kenya are influenced by health-insurance status and hospital retention policies. PROCEDURE: This study combined retrospective review of medical records with an illustrative case report. We identified children diagnosed with malignancies at a large Kenyan academic hospital between 2007 and 2009, their treatment outcomes, and health-insurance status at diagnosis. RESULTS: Between 2007 and 2009, 222 children were diagnosed with malignancies. Among 180 patients with documented treatment outcome, 54% abandoned treatment, 22% had treatment-related death, 4% progressive/relapsed disease, and 19% event-free survival. Health-insurance status at diagnosis was recorded in 148 children: 23% had NHIF and 77% had no NHIF. For children whose families had NHIF compared with those who did not, the relative risk for treatment abandonment relative to event-free survival was significantly smaller (relative-risk ratio = 0.31, 95% CI = 0.12-0.81, P = 0.016). The case report illustrates difficulties that Kenyan families might face when their child is diagnosed with cancer, has no NHIF, and is retained in hospital. CONCLUSIONS: Children with NHIF at diagnosis had significantly lower chance of abandoning treatment and higher chance of survival. Childhood cancer treatment outcomes could be improved by interventions that prevent treatment abandonment and improve access to NHIF. Hospital retention of patients over unpaid medical bills must stop.

Tailored guidance to apply the Estimand framework to Trials within Cohorts (TwiCs) studies.

Objective: The estimand framework offers a structured approach to define the treatment effect to be estimated in a clinical study. Defining the estimand upfront helps formulating the research question and informs study design, data collection and statistical analysis methods. Since the Trials within Cohorts (TwiCs) design has unique characteristics, the objective of this study is to describe considerations and provide guidance for formulating estimands for TwiCs studies. Methods: The key attributes of an estimand are the target population, treatments that are compared, the endpoint, intercurrent events and their handling, and the population-level summary measure. The estimand framework was applied retrospectively to two TwiCs studies: the SPONGE and UMBRELLA Fit trial. The aim is to demonstrate how the estimand framework can be implemented in TwiCs studies, thereby focusing on considerations relevant for defining the estimand. Three estimands were defined for both studies. For the SPONGE trial, estimators were derived. Results: Intercurrent events considered to occur exclusively or more frequently in TwiCs studies compared to conventional randomized trials included intervention refusal after randomization, misalignment of timing of routine cohort measurements and the intervention period, and participants in the control arm initiating treatments similar to the studied intervention. Considerations for handling refusal after randomization related to decisions on whether the target population should include all eligible participants or the subpopulation that would accept (or undergo) the intervention when offered. Considerations for handling treatment initiation in the control arm and misalignments of timing related to decisions on whether such events should be considered part of treatment policy or whether interest is in a hypothetical scenario where such events do not occur. Conclusion: The TwiCs study design has unique features that pose specific considerations when formulating an estimand. The examples in this study can provide guidance in the definition of estimands in future TwiCs studies.

Health-care providers' perspectives on childhood cancer treatment in Manado, Indonesia.

BACKGROUND: Childhood cancer survival in low-income countries is low. OBJECTIVE: Our study investigated health-care providers' perspectives on childhood cancer treatment in Indonesia. Their health beliefs and attitudes toward parental financial difficulties, protocol adherence, parental education, and communication were explored. METHODS: A self-administered questionnaire was filled in by 222 health-care providers (156 doctors, 51 nurses, 6 social workers, 9 administrators) RESULTS: Health of children with cancer is beyond doctor's control and determined by luck, fate or God according to 35% of health-care providers, 30% were uncertain about this statement, and 35% disagreed. Combination of chemotherapy and alternative treatment is best to achieve cure according to 15% of health-care providers, 50% were uncertain, and 35% disagreed. Prosperous parents adhere better with treatment (67%). Doctors adhere better with cancer treatment for prosperous patients (55%). When dealing with poor families, less elaborate explanation is given (62%), more difficult vocabulary is used (49%), and less cooperation is offered (46%). Reasons for non-adherence with treatment protocol were as follows: financial difficulties parents (82%), side-effects (77%), lack of motivation parents (75%), and inadequate drugs supply at pharmacy (70%). Information about cancer and treatment makes parents more afraid or depressed about future, and parents prefer not to know according to 27% of health-care providers, 20% were uncertain, and 53% disagreed. Communication with parents is hindered by differences in status and social hierarchical structures (83%). CONCLUSIONS: Health-care providers' beliefs about childhood cancer treatment are characterized by much uncertainty and contradiction. This likely affects adherence of health-care providers, parents, and childhood cancer treatment outcome.

Outcomes of concurrent chemoradiotherapy in patients with stage III non-small-cell lung cancer and significant comorbidity.

BACKGROUND: published trials of concurrent chemoradiotherapy (CCRT) in stage III non-small-cell lung cancer (NSCLC) generally excluded patients with significant comorbidity. We evaluated outcomes in patients who were selected by using radiation planning parameters and were considered, despite comorbidity, fit enough to receive cisplatin-based chemotherapy. PATIENTS AND METHODS: from 2003 to 2008, 89 patients with stage III NSCLC fit to receive cisplatin-based chemotherapy and a V(20) <42% underwent CCRT at one center outside clinical trials. Most received one cycle of cisplatin-gemcitabine, followed by two to three cycles of cisplatin-etoposide concurrent with involved-field thoracic radiotherapy between 46 and 66 Gy. RESULTS: median age was 64 years; performance status (PS) of zero, one or two in 20/64/5 patients; one or more comorbidities in 41.6%; 14% were treated previously for NSCLC. Median V(20) was 26.6% (range 4%-39.4%). Grade III esophagitis and pneumonitis occurred in 28.1% and 7.9% of patients, respectively, while 4.5% died during treatment. Median overall survival was 18.2 months [95% confidence interval (CI) 13.1-23.3 months]. Independent prognostic factors for overall survival were PS (0 versus ≥ 1, P = 0.041) and planning target volume (P = 0.022). CONCLUSIONS: patients with significant comorbidity who are fit to undergo cisplatin-based CCRT achieve median survivals similar to that reported in phase III trials and with relatively few late toxic effects.

Methylphenidate for attention-deficit/hyperactivity disorder in patients with Smith-Magenis syndrome: protocol for a series of N-of-1 trials.

BACKGROUND: Smith-Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder characterized by intellectual disability and severe behavioural and sleep disturbances. Often, patients with SMS are diagnosed with attention-deficit/hyperactivity disorder (ADHD). However, the effectiveness of methylphenidate (MPH), the first-line pharmacological treatment for ADHD, in patients with SMS is unclear. Our objective is to examine the effectiveness of MPH for ADHD symptoms in individuals with SMS, proposing an alternative trial design as traditional randomized controlled trials are complex in these rare and heterogeneous patient populations. METHODS AND ANALYSIS: We will initiate an N-of-1 series of double-blind randomized and placebo-controlled multiple crossover trials in six patients aged ≥ 6 years with a genetically confirmed SMS diagnosis and a multidisciplinary established ADHD diagnosis, according to a power analysis based on a summary measures analysis of the treatment effect. Each N-of-1 trial consists of a baseline period, dose titration phase, three cycles each including randomized intervention, placebo and washout periods, and follow-up. The intervention includes twice daily MPH (doses based on age and body weight). The primary outcome measure will be the subscale hyperactivity/inattention of the Strengths and Difficulties Questionnaire (SDQ), rated daily. Secondary outcome measures are the shortened version of the Emotion Dysregulation Inventory (EDI) reactivity index, Goal Attainment Scaling (GAS), and the personal questionnaire (PQ). Statistical analysis will include a mixed model analysis. All subjects will receive an assessment of their individual treatment effect and data will be aggregated to investigate the effectiveness of MPH for ADHD in SMS at a population level. CONCLUSIONS: This study will provide information on the effectiveness of MPH for ADHD in SMS, incorporating personalized outcome measures. This protocol presents the first properly powered N-of-1 study in a rare genetic neurodevelopmental disorder, providing a much-needed bridge between science and practice to optimize evidence-based and personalized care. TRIAL REGISTRATION: This study is registered in the Netherlands Trial Register (NTR9125).