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1.  Development and Evaluation of a Prediction Model for Underestimated Invasive Breast Cancer in Women with Ductal Carcinoma In Situ at Stereotactic Large Core Needle Biopsy 
PLoS ONE  2013;8(10):e77826.
We aimed to develop a multivariable model for prediction of underestimated invasiveness in women with ductal carcinoma in situ at stereotactic large core needle biopsy, that can be used to select patients for sentinel node biopsy at primary surgery.
From the literature, we selected potential preoperative predictors of underestimated invasive breast cancer. Data of patients with nonpalpable breast lesions who were diagnosed with ductal carcinoma in situ at stereotactic large core needle biopsy, drawn from the prospective COBRA (Core Biopsy after RAdiological localization) and COBRA2000 cohort studies, were used to fit the multivariable model and assess its overall performance, discrimination, and calibration.
348 women with large core needle biopsy-proven ductal carcinoma in situ were available for analysis. In 100 (28.7%) patients invasive carcinoma was found at subsequent surgery. Nine predictors were included in the model. In the multivariable analysis, the predictors with the strongest association were lesion size (OR 1.12 per cm, 95% CI 0.98-1.28), number of cores retrieved at biopsy (OR per core 0.87, 95% CI 0.75-1.01), presence of lobular cancerization (OR 5.29, 95% CI 1.25-26.77), and microinvasion (OR 3.75, 95% CI 1.42-9.87). The overall performance of the multivariable model was poor with an explained variation of 9% (Nagelkerke’s R2), mediocre discrimination with area under the receiver operating characteristic curve of 0.66 (95% confidence interval 0.58-0.73), and fairly good calibration.
The evaluation of our multivariable prediction model in a large, clinically representative study population proves that routine clinical and pathological variables are not suitable to select patients with large core needle biopsy-proven ductal carcinoma in situ for sentinel node biopsy during primary surgery.
PMCID: PMC3795649  PMID: 24147085
2.  Famine in the Young and Risk of Later Hospitalization for COPD and Asthma 
PLoS ONE  2013;8(12):e82636.
Undernutrition during critical periods of growth and development may permanently affect lung physiology and function.
To investigate whether acute undernutrition in childhood or young adulthood increases the risk of later hospitalization for obstructive airways disease, chronic obstructive pulmonary disease (COPD), or asthma.
We studied 7,841 women from Prospect-EPIC who experienced the 1944–45 Dutch famine between ages 0 and 21. Pulmonary outcomes were measured by registered hospital admissions and exposure-blinded computed tomography (CT) in a subgroup of 295 women. With Cox proportional hazard regression we explored effects of famine exposure on risk of hospitalization for obstructive airways disease, COPD, and asthma. With logistic regression we explored effects of famine on risk of CT evidence of pulmonary disease.
Risks of hospitalization for obstructive airways disease, COPD, and asthma were increased after moderate famine exposure, and significantly increased after severe famine exposure: hazard ratios for obstructive airways disease were 1.31 (95% CI: 0.97 to 1.77) and 1.57 (95% CI: 1.10 to 2.23) respectively. Associations between famine exposure and hospitalization for COPD were stronger in ever-smokers than in never-smokers.
Acute undernutrition in childhood or young adulthood is associated with an increased risk of later COPD and asthma hospitalization, possibly through increased sensitivity for tobacco smoke.
PMCID: PMC3871614  PMID: 24376558
3.  Famine in childhood and postmenopausal coronary artery calcification: a cohort study 
BMJ Open  2013;3(11):e003818.
To assess the effects of famine exposure during childhood on coronary calcium deposition and, secondarily, on cardiac valve and aortic calcifications.
Retrospective cohort.
286 postmenopausal women with individual measurements of famine exposure during childhood in the Netherlands during World War II.
Famine exposure during childhood.
Main outcome measures
Coronary artery calcifications measured by CT scan and scored using the Agatston method; calcifications of the aorta and cardiac valves (mitral and/or aortic) measured semiquantitatively. Logistic regression was used for coronary Agatston score of >100 or ≤100, valve or aortic calcifications as the dependent variable and an indicator for famine exposure as the independent variable. These models were also used for confounder adjustment and stratification based on age groups of 0–9 and 10–17 years.
In the overall analysis, no statistically significant association was found between severe famine exposure in childhood and a high coronary calcium score (OR 1.80, 95% CI 0.87 to 3.78). However, when looking at specific risk periods, severe famine exposure during adolescence was related to a higher risk for a high coronary calcium score than non-exposure to famine, both in crude (OR 3.47, 95% CI 1.00 to 12.07) and adjusted analyses (OR 4.62, 95% CI 1.16 to 18.43). No statistically significant association was found between childhood famine exposure and valve or aortic calcification (OR 1.66, 95% CI 0.69 to 4.10).
Famine exposure in childhood, especially during adolescence, seems to be associated with a higher risk of coronary artery calcification in late adulthood. However, the association between childhood famine exposure and cardiac valve/aortic calcification is less clear.
PMCID: PMC3845053  PMID: 24293207
4.  The potential of hypoxia markers as target for breast molecular imaging – a systematic review and meta-analysis of human marker expression 
BMC Cancer  2013;13:538.
Molecular imaging of breast cancer is a promising emerging technology, potentially able to improve clinical care. Valid imaging targets for molecular imaging tracer development are membrane-bound hypoxia-related proteins, expressed when tumor growth outpaces neo-angiogenesis. We performed a systematic literature review and meta-analysis of such hypoxia marker expression rates in human breast cancer to evaluate their potential as clinically relevant molecular imaging targets.
We searched MEDLINE and EMBASE for articles describing membrane-bound proteins that are related to hypoxia inducible factor 1α (HIF-1α), the key regulator of the hypoxia response. We extracted expression rates of carbonic anhydrase-IX (CAIX), glucose transporter-1 (GLUT1), C-X-C chemokine receptor type-4 (CXCR4), or insulin-like growth factor-1 receptor (IGF1R) in human breast disease, evaluated by immunohistochemistry. We pooled study results using random-effects models and applied meta-regression to identify associations with clinicopathological variables.
Of 1,705 identified articles, 117 matched our selection criteria, totaling 30,216 immunohistochemistry results. We found substantial between-study variability in expression rates. Invasive cancer showed pooled expression rates of 35% for CAIX (95% confidence interval (CI): 26-46%), 51% for GLUT1 (CI: 40-61%), 46% for CXCR4 (CI: 33-59%), and 46% for IGF1R (CI: 35-70%). Expression rates increased with tumor grade for GLUT1, CAIX, and CXCR4 (all p < 0.001), but decreased for IGF1R (p < 0.001). GLUT1 showed the highest expression rate in grade III cancers with 58% (45-69%). CXCR4 showed the highest expression rate in small T1 tumors with 48% (CI: 28-69%), but associations with size were only significant for CAIX (p < 0.001; positive association) and IGF1R (p = 0.047; negative association). Although based on few studies, CAIX, GLUT1, and CXCR4 showed profound lower expression rates in normal breast tissue and benign breast disease (p < 0.001), and high rates in carcinoma in situ. Invasive lobular carcinoma consistently showed lower expression rates (p < 0.001).
Our results support the potential of hypoxia-related markers as breast cancer molecular imaging targets. Although specificity is promising, combining targets would be necessary for optimal sensitivity. These data could help guide the choice of imaging targets for tracer development depending on the envisioned clinical application.
PMCID: PMC3903452  PMID: 24206539
Breast cancer; Carbonic anhydrase-IX; CAIX; Glucose transporter-1; GLUT1; C-X-C chemokine receptor type-4; CXCR4; Insulin-like growth factor-1 receptor; IGF1R; Expression prevalence; Systematic review; Meta-analysis; Molecular imaging; Immunohistochemistry; Carcinoma in situ; Benign breast disease; Normal breast tissue
5.  Famine Exposure in the Young and the Risk of Type 2 Diabetes in Adulthood 
Diabetes  2012;61(9):2255-2260.
The developmental origins hypothesis proposes that undernutrition during early development is associated with an increased type 2 diabetes risk in adulthood. We investigated the association between undernutrition during childhood and young adulthood and type 2 diabetes in adulthood. We studied 7,837 women from Prospect-EPIC (European Prospective Investigation Into Cancer and Nutrition) who were exposed to the 1944–1945 Dutch famine when they were between age 0 and 21 years. We used Cox proportional hazards regression models to explore the effect of famine on the risk of subsequent type 2 diabetes in adulthood. We adjusted for potential confounders, including age at famine exposure, smoking, and level of education. Self-reported famine exposure during childhood and young adulthood was associated with an increased type 2 diabetes risk in a dose-dependent manner. In those who reported moderate famine exposure, the age-adjusted type 2 diabetes hazard ratio (HR) was 1.36 (95% CI [1.09–1.70]); in those who reported severe famine exposure, the age-adjusted HR was 1.64 (1.26–2.14) relative to unexposed women. These effects did not change after adjustment for confounders. This study provides the first direct evidence, using individual famine exposure data, that a short period of moderate or severe undernutrition during postnatal development increases type 2 diabetes risk in adulthood.
PMCID: PMC3425424  PMID: 22648386
6.  Reducing false-positive biopsies: a pilot study to reduce benign biopsy rates for BI-RADS 4A/B assessments through testing risk stratification and new thresholds for intervention 
The aim of this study is to evaluate Breast Imaging Reporting and Data Systems (BI-RADS) 4A/B subcategory risk estimates for ductal carcinoma in situ (DCIS) and invasive cancer (IC), determining whether changing the proposed cutoffs to a higher biopsy threshold could safely increase cancer-to-biopsy yields while minimizing false-positive biopsies. A prospective clinical trial was performed to evaluate BI-RADS 4 lesions from women seen in clinic between January 2006 and March 2007. An experienced radiologist prospectively estimated a percent risk-estimate for DCIS and IC. Truth was determined by histopathology or 4-year follow-up negative for malignancy. Risk estimates were used to generate receiver-operating characteristic (ROC) curves. Biopsy rates, cancer-to-biopsy yields, and type of malignancies missed were then calculated across postulated risk thresholds. A total of 124 breast lesions were evaluated from 213 women. An experienced radiologist gave highly accurate risk estimates for IC, DCIS alone, or the combination with an area under ROC curve of 0.91 (95 % CI 0.84–0.99) (p < 0.001), 0.81 (95 % CI 0.69–0.93) (p = 0.011), and 0.89 (95 % CI 0.83–0.95) (p < 0.001), respectively. The cancer-to-biopsy yield was 30 %. Three hypothetical thresholds for intervention were analyzed: (1) DCIS or IC ≥ 10 %; (2) DCIS ≥ 50 % or IC ≥ 10 %; and (3) IC ≥ 10 %, which translated to 22, 48, and 56 % of biopsies avoided; cancer-to-biopsy yields of 36, 47, and 46 %; and associated chance of missing an IC of 0, 1, and 2 %, respectively. Expert radiologists estimate risk of IC and DCIS with a high degree of accuracy. Increasing the cut off point for recommending biopsy, substituting with a short-term follow-up protocol with biopsy if any change, may safely reduce the number of false-positive biopsies.
PMCID: PMC3695318  PMID: 23764994
False-positive biopsy; Mammography screening; BI-RADS; Biopsy thresholds
7.  Optical Imaging with HER2-targeted Affibody Molecules can monitor Hsp90 treatment response in a breast cancer xenograft mouse model 
Clinical Cancer Research  2012;18(4):1073-1081.
To determine if optical imaging can be used for in vivo therapy response monitoring as an alternative to radionuclide techniques. For this we evaluated the known Her2 response to 17-DMAG treatment, a Hsp90 inhibitor.
Experimental design
After in vitro 17-DMAG treatment response evaluation of MCF7 parental cells and two HER2 transfected clones (Clone A medium, B high Her2 expression), we established human breast cancer xenografts in nude mice (only parental and clone B) for in vivo evaluation. Mice received 120 mg/kg of 17-DMAG in 4 doses at 12 hour intervals i.p. (n=14), or PBS as carrier control (n=9). Optical images were obtained both pre-treatment (day 0) and post-treatment (day 3, 6, and 9), always 5 hours post-injection of 500 pmol of anti-Her2 Affibody-AlexaFluor680 via tail vein (with pre-injection background subtraction). Day 3 and 9 in vivo optical imaging signal was further correlated with ex vivo Her2 levels by western blot after sacrifice.
Her2 expression decreased with 17-DMAG dose in vitro. In vivo optical imaging signal was reduced by 22.5% in Clone B (p=0.003) and by 9% in MCF7 parental tumors (p=0.23) at 3 days after 17-DMAG treatment; optical imaging signal recovered in both tumor types at day 6–9. In the carrier group no signal reduction was observed. Pearson correlation of in vivo optical imaging signal with ex vivo Her2 levels ranged from 0.73 to 0.89.
Optical imaging with an affibody can be used to non-invasively monitor changes in Her2 expression in vivo as a response to treatment with an Hsp90 inhibitor, with results similar to response measurements in PET imaging studies.
PMCID: PMC3288571  PMID: 22235098
Optical imaging; molecular imaging; HER2; treatment monitoring; Affibody
8.  A novel method to quantify IRDye800CW fluorescent antibody probes ex vivo in tissue distribution studies 
EJNMMI Research  2012;2:50.
We describe a new method for biodistribution studies with IRDye800CW fluorescent antibody probes. This method allows the quantification of the IRDye800CW fluorescent tracer in percentage of injected dose per gram of tissue (% ID/g), and it is herein compared to the generally used reference method that makes use of radioactivity.
Cetuximab was conjugated to both the near-infrared fluorophore IRDye800CW and/or the positron emitter 89-zirconium, which was injected in nude mice bearing A431 human tumor xenografts. Positron emission tomography (PET) and optical imaging were performed 24 h post-injection (p.i.). For the biodistribution study, organs and tumors were collected 24 h p.i., and each of these was halved. One half was used for the determination of probe uptake by radioactivity measurement. The other half was homogenized, and the content of the fluorescent probe was determined by extrapolation from a calibration curve made with the injected probe.
Tumors were clearly visualized with both modalities, and the calculated tumor-to-normal tissue ratios were very similar for optical and PET imaging: 3.31 ± 1.09 and 3.15 ± 0.99, respectively. Although some variations were observed in ex vivo analyses, tumor uptake was within the same range for IRDye800CW and gamma ray quantification: 15.07 ± 3.66% ID/g and 13.92 ± 2.59% ID/g, respectively.
The novel method for quantification of the optical tracer IRDye800CW gives similar results as the reference method of gamma ray quantification. This new method is considered very useful in the context of the preclinical development of IRDye800CW fluorescent probes for optical molecular imaging, likely contributing to the selection of lead compounds that are the most promising for clinical translation.
PMCID: PMC3519726  PMID: 23009555
Optical molecular imaging; Tracer quantification; Biodistribution studies; Antibodies; EGFR
9.  The effect of ultrapro or prolene mesh on postoperative pain and well-being following endoscopic Totally Extraperitoneal (TEP) hernia repair (TULP): study protocol for a randomized controlled trial 
Trials  2012;13:76.
The purpose of this study was to describe the rationale and design of a randomized controlled trial analyzing the effects of mesh type (Ultrapro versus Prolene mesh) on postoperative pain and well-being following an endoscopic Totally Extraperitoneal (TEP) repair for inguinal hernias (short: TULP trial).
Methods and design
The TULP trial is a prospective, two arm, double blind, randomized controlled trial to assess chronic postoperative pain and quality of life following implantation of a lightweight (Ultrapro) and heavyweight (Prolene) mesh in endoscopic TEP hernia repair. The setting is a high-volume single center hospital, specializing in TEP hernia repair. All patients are operated on by one of four surgeons. Adult male patients (≥18 years of age) with primary, reducible, unilateral inguinal hernias and no contraindications for TEP repair are eligible for inclusion in the study. The primary outcome is substantial chronic postoperative pain, defined as moderate to severe pain persisting ≥ 3 months postoperatively (Numerical Rating Scale, NRS 4–10). Secondary endpoints are the individual development of pain until three years after the TEP procedure, the quality of life (QoL), recurrence rate, patient satisfaction and complications.
Large prospective randomized controlled studies with a long follow-up evaluating the incidence of chronic postoperative pain following implantation of lightweight and heavyweight mesh in endoscopic (TEP) hernia repair are limited. By studying the presence of pain and quality of life, but also complications and recurrences in a large patient population, a complete efficiency and feasibility assessment of both mesh types in TEP hernia repair will be performed.
Trial registration
The TULP study is registered in the Dutch Trial Register (NTR2131)
PMCID: PMC3404916  PMID: 22676248
Endoscopic hernia repair; TEP; Mesh; Chronic postoperative pain; Quality of life
10.  Male infertility after endoscopic Totally Extraperitoneal (Tep) hernia repair (Main): rationale and design of a prospective observational cohort study 
BMC Surgery  2012;12:7.
To describe the rationale and design of an observational cohort study analyzing the effects of endoscopic Totally Extraperitoneal (TEP) hernia repair on male fertility (MAIN study).
Methods and design
The MAIN study is an observational cohort study designed to assess fertility after endoscopic TEP hernia repair. The setting is a high-volume single center hospital, specialized in TEP hernia repair. Male patients of 18-60 years of age, with primary, reducible, bilateral inguinal hernias and no contraindications for endoscopic TEP repair are eligible for inclusion in this study. Patients with an ASA-classification ≥ III and patients with recurrent and/or scrotal hernias and/or a medical history of pelvic surgery and/or radiotherapy, known fertility problems, diabetes and/or other diseases associated with a risk of fertility problems, will be excluded. The primary outcome is the testicular perfusion before and 6 months after TEP hernia repair (assessed by means of a scrotal ultrasonography). Secondary endpoints are the testicular volume (Ultrasound), semen quality and quantity and the endocrinological status, based on serum levels of the sexual hormones follicle-stimulating hormone (FSH), luteinizing hormone (LSH), testosterone and inhibin B before and 6 months after TEP hernia repair.
The use of polypropylene mesh is associated with a strong foreign body reaction which could play a role in chronic groin pain development. Since the mesh in (endoscopic) inguinal hernia repair is placed in close contact to the vas deferens and spermatic vessels, the mesh-induced inflammatory reaction could lead to a dysfunction of these structures. Relevant large and prospective clinical studies on the problem are limited. This study will provide a complete assessment of fertility in male patients who undergo simultaneous bilateral endoscopic TEP hernia repair, by analyzing testicular perfusion and volume, semen quantity and quality and endocrinological status before and 6 months after TEP repair.
Trial registration
The MAIN study is registered in the Dutch Trial Register (NTR2208)
PMCID: PMC3414734  PMID: 22612995
11.  Postnatal Acute Famine and Risk of Overweight: The Dutch Hungerwinter Study 
Objective. To examine the association between undernutrition during postnatal periods of development and the risk of overweight in adulthood. Methods. We studied 8,091 women from Prospect-EPIC, exposed to the Dutch famine at ages between 0 and 21 years, recruited at ages between 49 and 70 years. We used linear and logistic regression models to explore the effect of famine on BMI, waist circumference, and the risk of overweight. Results. Overall, postnatal famine exposure was associated with increased BMI and waist circumference in a dose-dependent manner (P  for trend < 0.01). Furthermore, risk of overweight was increased following famine exposure (P  for trend = 0.01), with those severely exposed at ages 0–9 years having 25% (95% CI 1.05 to 1.50) higher risk compared to unexposed women. Conclusions. This study is the first to directly show a positive association between short and transient undernutrition during postnatal development and BMI, waist circumference, and overweight in adulthood.
PMCID: PMC3352614  PMID: 22611413
12.  Randomized clinical trial of LigaSure versus conventional suture ligation in thyroid surgery 
In thyroid surgery vessel division and haemostasis make up an important and time consuming part of the operation. While the presence of the recurrent laryngeal nerve limits the liberal use of diathermia, the many arterial and venous branches to and from the thyroid gland necessitates the use of numerous conventional suture ligatures.This study evaluates the effect of using a vessel sealing system on operation time during thyroid surgery.
A randomized clinical trial was performed between September 2005 and October 2008 in a teaching hospital. Forty patients undergoing total hemithyroidectomy participated in the trial. Twenty were randomized to the intraoperative use of the LigaSure Precise™ vessel sealing system, and twenty to the use of conventional suture ligatures.
The total median operation time was 10 minutes shorter in the LigaSure group (56 versus 66 minutes, P = 0.001). No significant differences in complications were noticed.
Using an electrothermal vessel sealing system during thyroid surgery is time saving.
Trial registration
This trial was registered in the international standard randomized controlled trials number register (ISRCTNR) under number ISRCTNR82389535.
PMCID: PMC3277470  PMID: 22257756
Operative Surgical Procedures; Thyroid surgery; Blood; Complications; LigaSure; Suture ligation; Operation time
13.  Prognostic Value of Lymph Node Micrometastases in Breast Cancer: A Multicenter Cohort Study 
Annals of Surgical Oncology  2010;18(6):1657-1664.
To evaluate the prognostic meaning of lymph node micrometastases in breast cancer patients.
Between January 2000 and January 2003, 1411 patients with a cT1-2N0 invasive breast carcinoma underwent surgery in 7 hospitals in the Netherlands. Sentinel lymph node biopsy was done in all patients. Based on lymph node status, patients were divided into 4 groups: pN0 (n = 922), pN1micro (n = 103), pN1a (n = 285), and pN≥1b (n = 101). Median follow-up was 6.4 years.
At the end of follow-up, 1121 women were still alive (79.4%), 184 had died (13.0%), and 106 were lost to follow-up (7.5%). Breast cancer recurred in 244 patients: distant metastasis (n = 165), locoregional relapse (n = 83), and contralateral breast cancer (n = 44). Following adjustment for possible confounding characteristics and for adjuvant systemic treatment, overall survival (OS) remained comparable for pN0 and pN1micro and was significantly worse for pN1a and pN≥1b (hazard ratio [HR] 1.18; 95% confidence interval [95% CI] 0.58–2.39, HR 2.47; 95% CI 1.69–3.63, HR 4.36; 95% CI 2.70–7.04, respectively). Disease-free survival (DFS) was similar too in the pN0 and pN1micro group, and worse for pN1a and pN≥1b (HR 0.96; 95% CI 0.56–1.67 vs HR 1.64; 95% CI 1.19–2.27, HR 2.95; CI 1.98–4.42). The distant metastases rate also did not differ significantly between the pN0 and pN1micro group and was worse for pN1a and pN≥1b (HR 1.22; 95% CI 0.60–2.49, HR 2.26; 95% CI 1.49–3.40, HR 3.49; CI 2.12–5.77).
In breast cancer patients survival is not affected by the presence of micrometastatic lymph node involvement.
Electronic supplementary material
The online version of this article (doi:10.1245/s10434-010-1451-z) contains supplementary material, which is available to authorized users.
PMCID: PMC3087878  PMID: 21153885
14.  Long-Term Neurodevelopmental Outcome of Monochorionic and Matched Dichorionic Twins 
PLoS ONE  2009;4(8):e6815.
Monochorionic (MC) twins are at increased risk for perinatal mortality and serious morbidity due to the presence of placental vascular anastomoses. Cerebral injury can be secondary to haemodynamic and hematological disorders during pregnancy (especially twin-to-twin transfusion syndrome (TTTS) or intrauterine co-twin death) or from postnatal injury associated with prematurity and low birth weight, common complications in twin pregnancies. We investigated neurodevelopmental outcome in MC and dichorionic (DC) twins at the age of two years.
This was a prospective cohort study. Cerebral palsy (CP) was studied in 182 MC infants and 189 DC infants matched for weight and age at delivery, gender, ethnicity of the mother and study center. After losses to follow-up, 282 of the 366 infants without CP were available to be tested with the Griffiths Mental Developmental Scales at 22 months corrected age, all born between January 2005 and January 2006 in nine perinatal centers in The Netherlands. Due to phenotypic (un)alikeness in mono-or dizygosity, the principal investigator was not blinded to chorionic status; perinatal outcome, with exception of co-twin death, was not known to the examiner.
Four out of 182 MC infants had CP (2.2%) - two of the four CP-cases were due to complications specific to MC twin pregnancies (TTTS and co-twin death) and the other two cases of CP were the result of cystic PVL after preterm birth - compared to one sibling of a DC twin (0.5%; OR 4.2, 95% CI 0.5–38.2) of unknown origin. Follow-up rate of neurodevelopmental outcome by Griffith's test was 76%. The majority of 2-year-old twins had normal developmental status. There were no significant differences between MC and DC twins. One MC infant (0.7%) had a developmental delay compared to 6 DC infants (4.2%; OR 0.2, 95% 0.0–1.4). Birth weight discordancy did not influence long-term outcome, though the smaller twin had slightly lower developmental scores than its larger co-twin.
There were no significant differences in occurrence of cerebral palsy as well as neurodevelopmental outcome between MC and DC twins. Outcome of MC twins seems favourable in the absence of TTTS or co-twin death.
PMCID: PMC2728837  PMID: 19714240
15.  Transient caloric restriction and cancer risk (The Netherlands) 
Cancer Causes & Control   2007;18(1):1-5.
Over the past century, many animal experiments have shown that caloric restriction can reduce the risk of cancer, a finding that proved to be highly reproducible. Many papers have been published on its potential for human health, but until know little evidence is available on its actual effects in humans. In Utrecht, The Netherlands, we have been investigating the effects of the 1944–1945 Dutch famine on breast cancer risk factors and breast cancer risk, and paradoxically the relatively short-term famine seemed to be related to increased breast cancer risk in later life. One of the differences between the famine situation and the large body of evidence from animal experiments is the duration of caloric restriction. Almost all animal experiments investigated sustained caloric restriction and information on the effects of short-term transient caloric restriction is very scarce. A search in the literature identified some animal experiments on short-term transient caloric restriction and these seemed to be at least supportive to the famine findings. Because caloric restriction in humans for preventive health measures would be mostly short-term, it is important to extend animal research on short-term caloric restriction.
PMCID: PMC1764866  PMID: 17186418
Caloric restriction; Transient; Cancer; Risk; Famine; Human

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