Perioperative or adjuvant mFOLFIRINOX for resectable pancreatic cancer (PREOPANC-3): study protocol for a multicenter randomized controlled trial.

BACKGROUND: Surgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach. METHODS: This multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and ≤ 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2 at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m2). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized. DISCUSSION: The multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer. TRIAL REGISTRATION: Clinical Trials: NCT04927780. Registered June 16, 2021.

Clinical outcome of endoscopic treatment of symptomatic Hepaticojejunal anastomotic strictures after pancreatoduodenectomy.

BACKGROUND: Hepaticojejunostomy anastomotic stricture (HJAS) is an adverse event after pancreatoduodenectomy (PD) which can result in jaundice and/or cholangitis. With endoscopy, HJAS can be managed. However, few studies report the specific success and adverse event rates of endoscopic therapy after PD. METHODS: Patients with symptomatic HJAS, who underwent an endoscopic retrograde cholangiopancreatography at the Erasmus MC between 2004-2020, were retrospectively included. Primary outcomes were short-term clinical success defined as no need for re-intervention <3 months and long-term <12 months. Secondary outcome measures were cannulation success and adverse events. Recurrence was defined as symptoms with radiological/endoscopic confirmation. RESULTS: A total of 62 patients were included. The hepaticojejunostomy was reached in 49/62 (79%) of the patients, subsequently cannulated in 42/49 (86%) and in 35/42 patients (83%) an intervention was performed. Recurrence of symptomatic HJAS after technically successful intervention occurred in 20 (57%) patients after median time to recurrence of 7.5 months [95%CI, 7.2-NA]. Adverse events were reported in 4% of the procedures (8% of patients), mostly concerning cholangitis. DISCUSSION: Endoscopic treatment for symptomatic HJAS after PD has a moderate technical success rate and a high recurrence rate. Future studies should optimize endoscopic treatment protocols and compare percutaneous versus endoscopic treatment.

The effect of attendance in the Dutch breast cancer screening program on breast tumor characteristics among migrant women.

BACKGROUND: In general, migrant women have a lower breast cancer (BC) incidence rate and higher BC mortality than autochthonous women. Further, migrant women show lower participation in the national BC screening program. To further investigate those aspects, we aimed to determine differences in incidence and tumor characteristics between autochthonous and migrant BC patients in Rotterdam, the Netherlands. METHODS: We selected women diagnosed with BC in Rotterdam during 2012-2015 from the Netherlands Cancer Registry. Incidence rates were calculated by migrant status (i.e., women with or without migration background). Multivariable analyses revealed adjusted odds ratios (OR) and 95% confidence intervals (CI) on the association between migration status and patient and tumor characteristics, additionally stratified by screening attendance (yes/no). RESULTS: In total 1372 autochthonous and 450 migrant BC patients were included for analysis. BC incidence was lower among migrants than among autochthonous women. Overall, migrant women were younger at BC diagnosis (53 vs. 64 years, p < 0.001), and had higher risks of positive lymph nodes (OR 1.76, 95% CI 1.33-2.33) and high grade tumors (OR 1.35, 95% CI 1.04-1.75). Especially non-screened migrant women had higher risk of positive nodes (OR 2.73, 95% CI 1.43-5.21). Among the subgroup of screened women, we observed no significant differences between migrant and autochthonous patients. CONCLUSION: Migrant women have lower BC incidence than autochthonous women, but diagnosis was more often at younger age and with unfavorable tumor characteristics. Attending the screening program strongly reduces the latter. Therefore, promotion of participation in the screening program is recommended.

Improvement of physical activity levels in children and adolescents after surgery for congenital heart disease: preferences and use of physical therapy.

PURPOSE: After surgery for congenital heart disease in children and adolescents, an active lifestyle is important to achieve and maintain good physical fitness. This study aimed to describe physical activity, as well as the use of patients' and parents' preferences for rehabilitative care after surgery for congenital heart disease. METHODS: This cross-sectional study included patients aged 4-16 years old, who had undergone surgery for congenital heart disease 2 years prior to the study onset. Patients and/or parents were invited to complete questionnaires on physical activity, and on their preferences for, and -use of, rehabilitative care after surgery. RESULTS: Forty-five of the 92 eligible patients and/or parents completed the questionnaires. The median age of the children was 12.2 years (IQR 7.8-16.1). Two children (4%) met the recommendations for taking part in moderate physical activity and 13 (29%) having done so for vigorous physical activity. Postoperatively 15 children (33%) had had physical therapy in primary care. More than 50% of the patients/parents would have preferred to have had more information on physical activity and to have taken part in an individual exercise program delivered during their primary care. CONCLUSION: The majority of eligible patients do not meet public health recommendations for engaging in physical activity and do not use physical therapy after surgery for congenital heart disease. The majority of patients and parents preferred more information as well as individual physical therapy treatments.Implications for rehabilitationsTwo years after surgery for congenital heart disease children and adolescents are less active compared to typically developing peers.Patients with a congenital heart disease and their parents need more information and support regarding stimulation of physical activity and physical fitness after heart surgery.In the postoperative process, a well-structured and supportive (individual) rehabilitation program should be introduced to improve physical activity and physical fitness.

Toward an Optimized Staging System for Pancreatic Ductal Adenocarcinoma: A Clinically Interpretable, Artificial Intelligence-Based Model.

PURPOSE: The American Joint Committee on Cancer (AJCC) eighth edition schema for pancreatic ductal adenocarcinoma treats T and N stage as independent factors and uses positive lymph nodes (PLNs) to define N stage, despite data favoring lymph node ratio (LNR). We used artificial intelligence-based techniques to compare PLN with LNR and investigate interactions between tumor size and nodal status. METHODS: Patients who underwent pancreatic ductal adenocarcinoma resection between 2000 and 2017 at six institutions were identified. LNR and PLN were compared through shapley additive explanations (SHAP) analysis, with the best predictor used to define nodal status. We trained optimal classification trees (OCTs) to predict 1-year and 3-year risk of death, incorporating only tumor size and nodal status as variables. The OCTs were compared with the AJCC schema and similarly trained XGBoost models. Variable interactions were explored via SHAP. RESULTS: Two thousand eight hundred seventy-four patients comprised the derivation and 1,231 the validation cohort. SHAP identified LNR as a superior predictor. The OCTs outperformed the AJCC schema in the derivation and validation cohorts (1-year area under the curve: 0.681 v 0.603; 0.638 v 0.586, 3-year area under the curve: 0.682 v 0.639; 0.675 v 0.647, respectively) and performed comparably with the XGBoost models. We identified interactions between LNR and tumor size, suggesting that a negative prognostic factor partially overrides the effect of a concurrent favorable factor. CONCLUSION: Our findings highlight the superiority of LNR and the importance of interactions between tumor size and nodal status. These results and the potential of the OCT methodology to combine them into a powerful, visually interpretable model can help inform future staging systems.

A comparative multicentre study evaluating gluteal turnover flap for wound closure after abdominoperineal resection for rectal cancer.

BACKGROUND: The aim of this study was to compare perineal wound healing between gluteal turnover flap and primary closure in patients undergoing abdominoperineal resection (APR) for rectal cancer. METHODS: Patients who underwent APR for primary or recurrent rectal cancer with gluteal turnover flap in two university hospitals (2016-2021) were compared to a multicentre cohort of primary closure (2000-2017). The primary endpoint was uncomplicated perineal wound healing within 30 days. Secondary endpoints were long-term wound healing, related re-interventions, and perineal herniation. The perineal hernia rate was assessed using Kaplan Meier analysis. RESULTS: Twenty-five patients had a gluteal turnover flap and 194 had primary closure. The uncomplicated perineal wound-healing rate within 30 days was 68% (17/25) after gluteal turnover flap versus 64% (124/194) after primary closure, OR 2.246; 95% CI 0.734-6.876; p = 0.156 in multivariable analysis. No major wound complications requiring surgical re-intervention occurred after flap closure. Eighteen patients with gluteal turnover flap completed 12-month follow-up, and none of them had chronic perineal sinus, compared to 6% (11/173) after primary closure (p = 0.604). The symptomatic 18-month perineal hernia rate after flap closure was 0%, compared to 9% after primary closure (p = 0.184). CONCLUSIONS: The uncomplicated perineal wound-healing rate after the gluteal turnover flap and primary closure after APR is similar, and no chronic perineal sinus or perineal hernia occurred after flap closure. Future studies have to confirm potential benefits of the gluteal turnover flap.

Total neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine for resectable and borderline resectable pancreatic cancer (PREOPANC-2 trial): study protocol for a nationwide multicenter randomized controlled trial.

BACKGROUND: Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including single-agent chemotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer patients. METHODS: This nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and ≤ 90 degrees venous involvement; borderline resectable pancreatic cancer is defined as ≤90 degrees arterial and ≤ 270 degrees venous involvement without occlusion. Patients receive 8 cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle, followed by surgery and 4 cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients assuming an accrual period of 3 years and 1.5 years follow-up. DISCUSSION: The PREOPANC-2 trial directly compares two neoadjuvant regimens for patients with resectable and borderline resectable pancreatic cancer. Our study will provide evidence on the neoadjuvant treatment of choice for patients with resectable and borderline resectable pancreatic cancer. TRIAL REGISTRATION: Primary registry and trial identifying number: EudraCT: 2017-002036-17 . Date of registration: March 6, 2018. Secondary identifying numbers: The Netherlands National Trial Register - NL7094 , NL61961.078.17, MEC-2018-004.

Mental stress may cause high gas consumption and accelerated heart rate in fast-descending divers.

The descent is a critical part of a dive, both physically and mentally. Pulmonary ventilation, expressed as respiratory minute volume (RMV) and heart rate (HR) were recorded during fast and slow descents to 35 meters (m) in open water while breathing compressed air, and during swimming horizontally at moderate velocity at an 11-m depth. Values of both types of descents were compared with reference values recorded at 11 m, the "plateau" phase, halfway through the 35-m dives. It is hypothesized that the "slow-descent" and "plateau-phase" values will be less than 'fast-descent values. Depth, cylinder pressure, water temperature and HR were recorded with a dive computer yielding time-averaged means (mRMV and mHR) for the descent and for plateau. Of the 18 divers included, 16 performed the fast descents and 11 made the slow descents. The fast descents (23 m·min-1 vertically), performed with 0-8 fin kicks, yielded mRMVDescent=28 ambient L (aL)·min-1, which is 82% higher (P⟨0.001) than mRMVPlateau of 15 aL·min-1. Further, mHRDescent was121 beats·min-1 23% higher (P⟨0.001), than mHRPlateau of 100 bpm. Slow descents (2.4 m·min-1 vertically) yielded 17 aL·min-1 with mHR=101 beats·min-1, values only slightly higher than at Plateau. The 11-m dive (swimming horizontally) yielded 24 m·min-1 with 32 fin kicks·min-1, mRMV=35 aL·min-1 and mHR=115 beats·min-1. Fast descents cause a higher RMV and HR that cannot be explained by physiology alone. Presumably mental stress is a main contributor. For dives deeper than 20 m, a descent velocity of 10 m·min-1 is recommended to reduce cardiac stress, in particular for older divers.

Implementation of Value Based Breast Cancer Care.

PURPOSE: Adding value of care to patients is crucial for all stakeholders. The use of both provider and patient reported outcome data was implemented in a single academic breast cancer center. We describe the development of the outcomes set, data integration within electronical health records (EHR) and clinical use. METHODS: An Integrated Practice Unit (IPU) was constructed providing the full care cycle for breast cancer patients. Provider reported outcomes and patient reported outcomes (PROs) were defined, reflecting the entire cycle of care and long-term sustainability of quality of life. Multidisciplinary provider and patient perspectives were obtained via focus groups and surveys. Patient pathways were redesigned in order to identify suitable opportunities for data collection during the entire care cycle. RESULTS: A Standard Set for Breast Cancer Outcomes together with case-mix variables and timelines was agreed upon within the IPU. A secure electronic platform, directly linked to the EHR, was designed to measure PROs during the outpatient phase. First year evaluation showed a decrease of response rates over time, from 83.3% at baseline to 45.2% at 12 months after surgery. Patients reacted positively to the use of PROMs in daily clinical cancer care. CONCLUSION: Assessment of patient reported as well as provider reported outcomes was implemented within our standard of breast cancer care. For this, dedicated resources, change of culture and practice, and improved knowledge and awareness about Value-based healthcare (VBHC) were essential. Our proposed framework aims to serve as a blueprint for implementation of VBHC in daily care.

Quality of life after bone sarcoma surgery around the knee: A long-term follow-up study.

It remains unclear if quality of life (QoL) improvements could be expected in young patients after malignant bone tumour surgery after 2 years. To assess the course of QoL over time during a long-term follow-up, malignant bone tumour survivors of a previous short-term study were included. Assessments were done at least 5 years after surgery. QoL was measured with Short-form (SF)-36, TNO-AZL Questionnaire for Adult's Quality of Life (TAAQOL) and Bone tumour (Bt)-DUX. QoL throughout the follow-up was analysed by linear mixed model analysis. From the original cohort of 44 patients; 20 patients were included for this study, 10 males; mean age at surgery 15.1 years and mean follow-up 7.2 years. Twenty-one patients of the initial cohort (47%) deceased. Fifteen patients (75%) underwent limb-salvage and five (25%) ablative surgery. QoL improved significantly during follow-up at Physical Component Summary Scale scale of the SF-36 and TAAQOL and all subscales of the Bt-DUX (p < .01). No significant differences were found between current evaluations and previous evaluations at 2 years after surgery (p = .41-.98). Significant advantages after limb-salvage were seen at the PCS scale of the SF-36 (MD 13.7, p = .05) and the cosmetic scale of the Bt-DUX (MD 17.7, p = .04).

TUmor-volume to breast-volume RAtio for improving COSmetic results in breast cancer patients (TURACOS); a randomized controlled trial.

BACKGROUND: Cosmetic result following breast conserving surgery (BCS) for cancer influences quality of life and psychosocial functioning in breast cancer patients. A preoperative prediction of expected cosmetic result following BCS is not (yet) standard clinical practice and therefore the choice for either mastectomy or BCS is still subjective. Recently, we showed that tumour volume to breast volume ratio as well as tumour location in the breast are independent predictors of superior cosmetic result following BCS. Implementation of a prediction model including both factors, has not been studied in a prospective manner. This study aims to improve cosmetic outcome by implementation of a prediction model in the treatment decision making for breast cancer patients opting for BCS. METHODS/DESIGN: Multicentre, single-blinded, randomized controlled trial comparing standard preoperative work-up to a preoperative work-up with addition of the prediction model. Tumour volume to breast volume ratio and tumour location in the breast will be used to predict cosmetic outcome in invasive breast cancer patients opting for BCS. Three dimensional (3D)-ultrasonography will be used to measure the tumour volume to breast volume ratio needed for the prediction model. Sample size was estimated based on a 14% improvement in incidence of superior cosmetic result one year after BCS (71% in the control group versus 85% in the intervention group). Primarily cosmetic outcome will be evaluated by a 6-member independent panel. Secondary endpoints include; (1) patient reported outcome measured by BREAST-Q, EORTC-QLQ-C30/BR23 and EQ-5D-5 L (2) cosmetic outcome as assessed through the BCCT.core software, (3) radiation-induced reaction (4) surgical treatment performed, (5) pathological result and (6) cost-effectiveness. Follow-up data will be collected for 3 years after surgery or finishing radiotherapy. DISCUSSION: This randomized controlled trial examines the value of a preoperative prediction model for the treatment-decision making. It aims for a superior cosmetic result in breast cancer patients opting for BCS. We expect improvement of patients' quality of life and psychosocial functioning in a cost-effective way. TRIAL REGISTRATION: Prospectively registered, February 17th 2015, at 'Nederlands Trialregister - NTR4997 '.

Combined thermal and herbicide stress in functionally diverse coral symbionts.

Most reef building corals rely on symbiotic microalgae (genus Symbiodinium) to supply a substantial proportion of their energy requirements. Functional diversity of different Symbiodinium genotypes, endorsing the host with physiological advantages, has been widely reported. Yet, the influence of genotypic specificity on the symbiont's susceptibility to contaminants or cumulative stressors is unknown. Cultured Symbiodinium of presumed thermal-tolerant clade D tested especially vulnerable to the widespread herbicide diuron, suggesting important free-living populations may be at risk in areas subjected to terrestrial runoff. Co-exposure experiments where cultured Symbiodinium were exposed to diuron over a thermal stress gradient demonstrated how fast-growing clade C1 better maintained photosynthetic capability than clade D. The mixture toxicity model of Independent Action, considering combined thermal stress and herbicide contamination, revealed response additivity for inhibition of photosynthetic yield in both tested cultures, emphasizing the need to account for cumulative stressor impacts in ecological risk assessment and resource management.

Pathological response after chemoradiation for T3 rectal cancer.

OBJECTIVE: The aim of this study was to investigate the effect of preoperative chemoradiotherapy (CRT) on nodal disease in locally advanced rectal adenocarcinoma. METHOD: Thirty-two patients staged uT3N0 and 27 patients staged uT3N1 rectal adenocarcinoma who underwent pre-CRT staging using endoscopic ultrasound or rectal protocol CT were included. The median radiation dose was 50.4 Gy (range: 45-50.4 Gy) at 1.8 Gy per fraction and all patients received concurrent 5-FU or capecitabine-based chemotherapy. Low anterior resection or abdomino-perineal resection occurred at a median of 46 days (range: 27-112 days) after CRT. RESULTS: Eleven of 32 uT3N0 patients (34.4%) and 13 of 26 uT3N1 patients (50.0%) had ypN+ (P = 0.29). For patients with uT3N0, 10 of 20 (50.0%) with ypT2-3 and 1 of 12 (8.3%) with ypT0-1 were ypN+ (P = 0.02). For patients with uT3N1, 12 of 20 (60.0%) with ypT2-3 and 1 of 6 (16.7%) with ypT0-1 were ypN+ (P = 0.16). Overall, the ypN+ rate was 11.1% in the ypT0-yT1 group compared with 55.0% in the ypT2-yT3 group (P = 003). Among patients with uT3N0 disease, the ypN+ rate in patients who had surgery > 46 days vs 46 days vs 46 days vs

In vivo real-time endocytoscopic visualization of blood flow in rectal microvasculature.

Endocytoscopy (ECS) is a new technology that enables endoscopists to visualize gastrointestinal mucosa at the cellular level. This reported case demonstrates the ability to visualize real-time blood flow utilizing ECS. Methylene blue dye was sprayed onto normal rectal mucosa during a routine screening colonoscopy of an asymptomatic patient. High-magnification views of colonic mucosa revealed normal mucosal cellular structure and microvasculature with normal flow of red blood cells. Individual red blood cells were seen circulating through the arterioles. Epithelial colonocytes appeared to be organized in a hexagonal pattern around crypts with borders demarcated by microvasculature. ECS can provide high-magnification views of the gastrointestinal mucosa including microvasculature in real time. This establishes possibilities for future in vivo research in areas such as cancer biology, angiogenesis, and inflammatory bowel disease.

Sexual risk behaviour and HAART: a comparative study of HIV-infected persons on HAART and on preventive therapy in Kenya.

Unprotected sex (UPS) among persons receiving highly active antiretroviral therapy (HAART) remains a concern because of the risk of HIV-transmission. A cross-sectional study comparing the sexual risk behaviour of 179 people living with HIV/AIDS (PLHA) receiving HAART with that of 143 PLHA receiving preventive therapy (PT) with cotrimoxazole/isoniazid was conducted in Mombasa, Kenya. Forty-five percent of all participants were sexually active in the last six months. Participants receiving PT were more likely to report > or =2 partners (13% vs.1%; P = 0.006). Participants receiving PT reported more UPS with regular partners (odds ratio [OR]: 3.9; 95% confidence interval [CI]: 1.8-8.4) and also more sexually transmitted infections (STI) symptoms (OR: 1.7; 95% CI: 1.0-2.8; P = 0.059). More than 40% of all participants did not know the HIV-status of regular partners. Therefore, HAART was not associated with increased sexual risk behaviours though considerable risk of HIV-transmission remains. HIV-care services need to emphasize partner testing and consistent condom use with all partners.

[Structural characterization of tissue-specific galactan from flax fibers by 1H NMR and MALDI TOF mass spectrometry].

A high-molecular-mass polysaccharide galactan (M 2000 kDa) was isolated from flax at the stage of cell wall thickening of the bast fiber development. The polymer structure was studied by 1H NMR spectroscopy and MALDI TOF mass spectrometry. It is built up of Gal (59%), Rha (15%), GalA (23%), and Ara (3%) residues. The galactan backbone consists of successively alternating monomer disaccharide units (--> 4GalA1 --> 2Rha1 -->)n and is similar in its structure to the backbone of rhamnogalacturonan-1 (RG-I). Rhamnose residues bear in position 4 beta-(1 --> 4)-galactose side chains of various lengths with a polymerization degree of up to 28 or higher. A part of the side chains have branchings.