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1.  Trastuzumab treatment for breast cancer during pregnancy 
Canadian Family Physician  2008;54(1):31-32.
QUESTION One of my patients has been diagnosed with breast cancer and started treatment with trastuzumab. She has recently discovered that she is pregnant and wishes to continue the pregnancy. What are the consequences of trastuzumab treatment during pregnancy and can she continue her pregnancy?
ANSWER Human data regarding the safety of trastuzumab during pregnancy are scarce. Only 3 case reports could be located in the published literature. Anhydramnios was observed in a case where the exposure to trastuzumab occurred during the second trimester, which reversed after discontinuation of the drug without any apparent consequences to the baby. Evidence is insufficient to provide any recommendations, but in light of the case reports, pregnancies exposed to trastuzumab during the second trimester should be closely followed with particular attention to amniotic fluid volume.
PMCID: PMC2329906  PMID: 18208949
2.  Complementary role of magnetic resonance imaging after ultrasound examination in assessing fetal renal agenesis: a case report 
Ultrasonography is used routinely during pregnancy to screen and detect fetal abnormalities. However, there are some conditions like anhydramnios (a prevalent state in renal agenesis) or maternal obesity that may limit the diagnostic accuracy of ultrasonography. Magnetic resonance imaging has proven to be useful when ultrasound alone is insufficient to make a correct diagnosis.
Case presentation
We present the case of a 22-year-old Caucasian woman who was admitted to our unit at the 26th week of gestation for a detailed anatomy scan. Anhydramnios and failure to visualize the kidneys, bladder and renal vessels were confirmed with the use of sonography in our department. Since the lack of amniotic fluid limited the acoustic window for fetal ultrasonography, a magnetic resonance imaging scan was requested to confirm suspected renal agenesis. A fetal magnetic resonance imaging scan was performed and confirmed the suspected diagnosis. A baby boy was born by breech vaginal delivery after spontaneous onset of labor at the 34th week of gestation. The boy weighed 1690g, with Apgar scores of 6 and 4 at two and five minutes respectively, and died one hour after delivery. The diagnosis of bilateral renal agenesis was confirmed on autopsy.
The aim of this study was to evaluate the potential contribution of magnetic resonance imaging in diagnostic procedure after inconclusive ultrasound examination during the assessment of fetal urinary tract abnormalities in the third trimester.
PMCID: PMC3976151  PMID: 24618008
Magnetic resonance imaging; Fetus; Renal agenesis
3.  Reference Ranges of Amniotic Fluid Index in Late Third Trimester of Pregnancy: What Should the Optimal Interval between Two Ultrasound Examinations Be? 
Journal of Pregnancy  2015;2015:319204.
Background. Amniotic fluid index (AFI) is one of the major and deciding components of fetal biophysical profile and by itself it can predict pregnancy outcome. Very low values are associated with intrauterine growth restriction and renal anomalies of fetus, whereas high values may indicate fetal GI anomalies, maternal diabetes mellitus, and so forth. However, before deciding the cut-off standards for abnormal values for a local population, what constitutes a normal range for specific gestational age and the ideal interval of testing should be defined. Objectives. To establish reference standards for AFI for local population after 34 weeks of pregnancy and to decide an optimal scan interval for AFI estimation in third trimester in low risk antenatal women. Materials and Methods. A prospective estimation of AFI was done in 50 healthy pregnant women from 34 to 40 weeks at weekly intervals. The trend of amniotic fluid volume was studied with advancing gestational age. Only low risk singleton pregnancies with accurately established gestational age who were available for all weekly scan from 34 to 40 weeks were included in the study. Women with gestational or overt diabetes mellitus, hypertensive disorders of the pregnancy, prelabour rupture of membranes, and congenital anomalies in the foetus and those who delivered before 40 completed weeks were excluded from the study. For the purpose of AFI measurement, the uterine cavity was arbitrarily divided into four quadrants by a vertical and horizontal line running through umbilicus. Linear array transabdominal probe was used to measure the largest vertical pocket (in cm) in perpendicular plane to the abdominal skin in each quadrant. Amniotic fluid index was obtained by adding these four measurements. Statistical analysis was done using SPSS software (Version 16, Chicago, IL). Percentile curves (5th, 50th, and 95th centiles) were constructed for comparison with other studies. Cohen's d coefficient was used to examine the magnitude of change at different time intervals. Results. Starting from 34 weeks till 40 weeks, 50 ultrasound measurements were available at each gestational age. The mean (standard deviation) of AFI values (in cms) were 34 W: 14.59 (1.79), 35 W: 14.25 (1.57), 36 W: 13.17 (1.56), 37 W: 12.48 (1.52), 38 W: 12.2 (1.7), and 39 W: 11.37 (1.71). The 5th percentile cut-off was 8.7 cm at 40 weeks. There was a gradual decline of AFI values as the gestational age approached term. Significant drop in AFI was noted at two-week intervals. AFI curve generated from the study varied significantly when compared with already published data, both from India and abroad. Conclusion. Normative range for AFI values for late third trimester was established. Appreciable changes occurred in AFI values as gestation advanced by two weeks. Hence, it is recommended to follow up low risk antenatal women every two weeks after 34 weeks of pregnancy. The percentile curves of AFI obtained from the present study may be used to detect abnormalities of amniotic fluid for our population.
PMCID: PMC4312643
4.  Midtrimester amniotic fluid concentrations of interleukin-6 and interferon-gamma-inducible protein-10: evidence for heterogeneity of intra-amniotic inflammation and associations with spontaneous early (< 32 weeks) and late (> 32 weeks) preterm delivery 
Journal of perinatal medicine  2012;40(4):329-343.
Intra-amniotic inflammation is traditionally defined as an elevation of amniotic fluid interleukin (IL)-6. Previous case control studies have suggested an association between an elevated midtrimester amniotic fluid IL-6 and preterm delivery, although such an association has been recently challenged. Intra-amniotic inflammation can also be defined by an elevation of the T-cell chemokine, Interferongamma-inducible protein (IP)-10. An elevation in amniotic fluid IP-10 has been associated with chronic chorioamnionitis, a lesion frequently found in late spontaneous preterm birth and fetal death. In contrast, an elevation in amniotic fluid IL-6 is typically associated with acute chorioamnionitis and funisitis. This study was conducted to examine the relationship between an elevation in amniotic fluid IL-6 in the midtrimester and preterm delivery at or before 32 weeks of gestation, and the amniotic fluid concentration of IP-10 and preterm delivery after 32 weeks of gestation.
Materials and methods
This cohort study included 847 consecutive women undergoing genetic midtrimester amniocentesis; in 796 cases, amniotic fluid and pregnancy outcome was available for study after exclusion of abnormal karyotype and/or fetal congenital anomalies. Spontaneous preterm delivery was defined as early (≤ 32 weeks) or late (after 32 completed weeks of pregnancy). The amniotic fluid and maternal blood concentrations of IL-6 and IP-10 were measured by specific immunoassays.
1) The prevalence of preterm delivery was 8.3% (66/796), while those of early and late spontaneous preterm delivery were 1.5% (n = 12), and 4.5% (n = 36), respectively; 2) patients who had a spontaneous preterm delivery after 32 weeks of gestation had a higher median amniotic fluid IP-10 concentration than those who delivered at term [median 713 pg/mL, inter-quartile range (IQR) 509 – 1427 pg/mL vs. median 589 pg/mL, IQR 402 – 953 pg/mL; P = 0.006] and an elevation of amniotic fluid IP-10 concentration above 502 pg/mL (derived from an ROC curve) was associated with late spontaneous preterm delivery [odds ratio 3.9 (95% CI 1.6 – 9.9)]; 3) patients who had a spontaneous preterm delivery ≤ 32 weeks of gestation had a higher median amniotic fluid IL-6 concentration than those who delivered at term [median 2052 pg/mL, IQR 435 – 3015 pg/mL vs. median 414 pg/mL, IQR 209 – 930 pg/mL; P = 0.006], and an elevated amniotic fluid IL-6 concentration above 1740 pg/mL (derived from an ROC curve) was associated with early spontaneous preterm delivery [odds ratio 9.5 (95% CI 2.9 – 31.1)]; 4) subclinical intra-amniotic inflammation, defined as an elevation of IL-6 (≥ 2.9 ng/mL) or IP-10 (≥ 2.2 ng/mL) concentration above the 95th percentile of patients who had uncomplicated term delivery (n = 652 for IL-6 and n = 633 for IP-10), was observed in 6.3% (50/796) and 5.8% (45/770) of cases, respectively. Although each type of inflammation is a risk factor for spontaneous preterm delivery, many patients had a term delivery without complication; 5) the amniotic fluid in the midtrimester did not contain microorganisms detectable with cultivation techniques.
Intra-amniotic inflammation is heterogeneous. Some patients have elevated amniotic fluid concentrations of IL-6, and are at risk for spontaneous preterm delivery before 32 weeks of gestation, while others have an elevated IP-10 (a chemotactic T-cell chemokine) and such patients are at risk for spontaneous preterm delivery after 32 weeks of gestation. A fraction of patients have subclinical intra-amniotic inflammation and deliver at term. The clinical significance of this condition remains to be determined.
PMCID: PMC3498502  PMID: 22752762
Chemokines; chorioamnionitis; chronic chorioamnionitis; cytokines; early preterm labor; late preterm labor; maternal anti-fetal rejection; midtrimester amniocentesis; pregnancy
5.  Fetal Growth and Risk of Stillbirth: A Population-Based Case–Control Study 
PLoS Medicine  2014;11(4):e1001633.
Radek Bukowski and colleagues conducted a case control study in 59 US hospitals to determine the relationship between fetal growth and stillbirth, and find that both restrictive and excessive growth could play a role.
Please see later in the article for the Editors' Summary
Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth.
Methods and Findings
We conducted a population-based case–control study of all stillbirths and a representative sample of live births in 59 hospitals in five geographic areas in the US. Fetal growth abnormalities were categorized as small for gestational age (SGA) (<10th percentile) or large for gestational age (LGA) (>90th percentile) at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms. Gestational age at death was determined using an algorithm that considered the time-of-death interval, postmortem examination, and reliability of the gestational age estimate. Data were weighted to account for the sampling design and differential participation rates in various subgroups. Among 527 singleton stillbirths and 1,821 singleton live births studied, stillbirth was associated with SGA based on population, ultrasound, and individualized norms (odds ratio [OR] [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA was also associated with increased risk of stillbirth using ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). The associations were stronger with more severe SGA and LGA (<5th and >95th percentile). Analyses adjusted for stillbirth risk factors, subset analyses excluding potential confounders, and analyses in preterm and term pregnancies showed similar patterns of association. In this study 70% of cases and 63% of controls agreed to participate. Analysis weights accounted for differences between consenting and non-consenting women. Some of the characteristics used for individualized fetal growth estimates were missing and were replaced with reference values. However, a sensitivity analysis using individualized norms based on the subset of stillbirths and live births with non-missing variables showed similar findings.
Stillbirth is associated with both growth restriction and excessive fetal growth. These findings suggest that, contrary to current practices and recommendations, stillbirth prevention strategies should focus on both severe SGA and severe LGA pregnancies.
Please see later in the article for the Editors' Summary
Editors' Summary
Pregnancy is usually a happy time, when the parents-to-be anticipate the arrival of a new baby. But, sadly, about 20% of pregnancies end in miscarriage—the early loss of a fetus (developing baby) that is unable to survive independently. Other pregnancies end in stillbirth—fetal death after 20 weeks of pregnancy (in the US; after 24 weeks in the UK). Stillbirths, like miscarriages, are common. In the US, for example, one in every 160 pregnancies ends in stillbirth. How women discover that their unborn baby has died varies. Some women simply know something is wrong and go to hospital to have their fears confirmed. Others find out when a routine check-up detects no fetal heartbeat. Most women give birth naturally after their baby has died, but if the mother's health is at risk, labor may be induced. Common causes of stillbirth include birth defects and infections. Risk factors for stillbirth include being overweight and smoking during pregnancy.
Why Was This Study Done?
Stillbirths are often associated with having a “small for gestational age” (SGA) fetus. Gestation is the period during which a baby develops in its mother's womb. Gestational age is estimated from the date of the woman's last menstrual period and/or from ultrasound scans. An SGA fetus is lighter than expected for its age based on observed distributions (norms) of fetal weights for gestational age. Although stillbirth is clearly associated with impaired fetal growth, the exact relationship between fetal growth and stillbirth remains unclear for two reasons. First, studies investigating this relationship have used gestational age at delivery rather than gestational age at death as an estimate of fetal age, which overestimates the gestational age of stillbirths and leads to errors in estimates of the proportions of SGA and “large for gestational age” (LGA) stillbirths. Second, many characteristics that affect normal fetal growth are also associated with the risk of stillbirth, and this has not been allowed for in previous studies. In this population-based case–control study, the researchers investigate the fetal growth abnormalities associated with stillbirth using a new approach to estimate gestational age and accounting for the effect of characteristics that affect both fetal growth and stillbirth. A population-based case–control study compares the characteristics of patients with a condition in a population with those of unaffected people in the same population.
What Did the Researchers Do and Find?
The researchers investigated all the stillbirths and a sample of live births that occurred over 2.5 years at 59 hospitals in five US regions. They used a formula developed by the Stillbirth Collaborative Research Network to calculate the gestational age at death of the stillbirths. They categorized fetuses as SGA if they had a weight for gestational age within the bottom 10% (below the 10th percentile) of the population and as LGA if they had a weight for gestational age above the 90th percentile at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms of fetal weight for gestational age. Population norms incorporate weights for gestational age from normal pregnancies and from pregnancies complicated by growth abnormalities, whereas the other two norms include weights for gestational age from normal pregnancies only. Having an SGA fetus was associated with a 3- to 4-fold increased risk of stillbirth compared to having a fetus with “appropriate” weight for gestational age based on all three norms. LGA was associated with an increased risk of stillbirth based on the ultrasound and individualized norms but not the population norms. Being more severely SGA or LGA (below the 5th percentile or above the 95th percentile) was associated with an increased risk of stillbirth.
What Do These Findings Mean?
These findings indicate that, when the time of death is accounted for and norms for weight for gestational age only from uncomplicated pregnancies are used, stillbirth is associated with both restricted and excessive fetal growth. Overall, abnormal fetal growth was identified in 25% of stillbirths using population norms and in about 50% of stillbirths using ultrasound or individualized norms. Although the accuracy of these findings is likely to be affected by aspects of the study design, these findings suggest that, contrary to current practices, strategies designed to prevent stillbirth should focus on identifying both severely SGA and severely LGA fetuses and should use norms for the calculation of weight for gestational age based on normal pregnancies only. Such an approach has the potential to identify almost half of the pregnancies likely to result in stillbirth.
Additional Information
Please access these websites via the online version of this summary at
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on stillbirth
Tommy's, a UK nonprofit organization that funds research into stillbirth, premature birth, and miscarriage and provides information for parents-to-be, also provides information on stillbirth (including personal stories)
The UK National Health Service Choices website provides information about stillbirth (including a video about dealing with grief after a stillbirth)
MedlinePlus provides links to other resources about stillbirth (in English and Spanish)
Information about the Stillbirth Collaborative Research Network is available
PMCID: PMC3995658  PMID: 24755550
6.  Health-Related Quality of Life With Adjuvant Docetaxel- and Trastuzumab-Based Regimens in Patients with Node-Positive and High-Risk Node-Negative, HER2-Positive Early Breast Cancer: Results from the BCIRG 006 Study 
The Oncologist  2013;18(7):812-818.
In the BCIRG 006 trial, eligible patients were randomly assigned to either four cycles of adjuvant doxorubicin and cyclophosphamide followed by four cycles of docetaxel or one of two trastuzumab-containing regimens: adjuvant doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab administered for 1 year or six cycles of docetaxel plus carboplatin combined with trastuzumab administered for 1 year. Health-related quality-of-life outcomes for adjuvant docetaxel and trastuzumab-based regimens were favorable and support docetaxel plus carboplatin combined with trastuzumab as a more tolerable treatment option.
This study aims to describe and compare health-related quality of life (HRQL) in patients with node-positive and high-risk node-negative HER2-positive early breast cancer receiving adjuvant docetaxel and trastuzumab-based or docetaxel-based regimens alone.
Eligible patients (n = 3,222) were randomly assigned to either four cycles of adjuvant doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC→T) or one of two trastuzumab-containing regimens: adjuvant doxorubicin and cyclophosphamide followed by docetaxel plus trastuzumab administered for 1 year (AC→TH) or six cycles of docetaxel plus carboplatin combined with trastuzumab administered for 1 year (TCH). The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and BR-23 were administered at baseline, the start of cycle 4 (mid), and the end of chemotherapy (EOC), as well as at 6, 12, and 24 months after chemotherapy.
Compliance rates for the EORTC questionnaires were acceptable at 72%–93% of eligible patients out to the 12-month assessment. Systemic side effect (SE) change scores were significantly improved for TCH-treated patients compared with AC→TH and AC→T at EOC, suggesting improved tolerability. Physical functioning (PF) was only slightly worse at midpoint for those receiving TCH, compared with patients who were just starting on taxane in an AC→TH regimen, but was otherwise similar between arms. All treatment arms recovered from the deterioration in SE, PF, and Global Health Scale scores by 1 year and median future perspective change scores continued to improve throughout treatment and follow-up.
HRQL outcomes for adjuvant docetaxel and trastuzumab-based regimens are favorable and support TCH as a more tolerable treatment option.
PMCID: PMC3720634  PMID: 23814044
Breast cancer; BCIRG 006; Docetaxel; Trastuzumab; Chemotherapy; Quality of life; Anthracycline-induced cardiotoxicity; Adjuvant therapy
7.  Cardiac Safety Analysis of Doxorubicin and Cyclophosphamide Followed by Paclitaxel With or Without Trastuzumab in the North Central Cancer Treatment Group N9831 Adjuvant Breast Cancer Trial 
To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial.
Patients and Methods
Patients with HER2-positive operable early breast cancer were randomized to 1 of 3 treatment arms: doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (Arm A); paclitaxel then trastuzumab (Arm B); or paclitaxel plus trastuzumab then trastuzumab alone (Arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18–21 months post-registration.
A total of 1944 patients completed AC with a satisfactory LVEF and proceeded to post-AC therapy. Post-AC cardiac events (congestive heart failure [CHF] or cardiac death [CD]) were: Arm A, n=3 (2 CHF, 1 CD); Arm B, n=19 (18 CHF, 1 CD); Arm C, n=19 (all CHF); 3-year cumulative incidence was 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event after AC in Arms B and C were older age (P<.003), prior/current antihypertensive agents (P=.005), and lower registration LVEF (P=.033). Incidence of asymptomatic LVEF decreases requiring trastuzumab to be held was 8–10%; LVEF recovered and trastuzumab was restarted in approximately 50% of these patients.
The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus control arm but by <4%. Older age, lower registration LVEF, and antihypertensive medications increase the risk of cardiac dysfunction in patients receiving trastuzumab following AC.
PMCID: PMC4048960  PMID: 18250349
HER2; trastuzumab; adjuvant; breast cancer; doxorubicin; cyclophosphamide; paclitaxel; cardiac safety
8.  Amniotic fluid insulin and C-peptide as predictive markers for fetal macrosomia, birth injuries, and delivery complications? 
Gestational diabetes mellitus (GDM) occurs in 3–5% of all pregnancies. GDM increases both maternal and fetal risks, causes fetal macrosomia, and hence increases the rates of caesarean sections and delivery complications such as shoulder dystocia. An early predictive marker and consequent early treatment could be beneficial, so amniotic fluid insulin and C-peptide have been examined in several studies. Increased amniotic fluid insulin in early amniocentesis between the 14th and 20th gestational week predicted a later GDM. A potential direct association with fetal macrosomia remains to be determined.
This retrospective study investigated amniotic fluid insulin/C-peptide from amniocenteses between 14 and 20 weeks of gestation in correlation with fetal birth weight, type of delivery, and complications. To focus on effects of fetal hyperinsulinism apart from therapeutic confounders, we included patients who did not participate in GDM screening. Insulin and C-peptide were measured in 144 samples of frozen amniotic fluid. Birth weight, type of delivery, complications, and birth injuries were noted.
Birth weights ranged from 760 g to 4410 g with a mean weight of 3424 g at an average of 40 weeks gestation. The mean amniotic fluid insulin was 4.36 μU/ml and the mean C-peptide concentration was 0.076 ng/ml. There was no correlation between amniotic fluid insulin or C peptide and birth weight, type of delivery, complications, and birth injuries.
Amniotic fluid insulin and C-peptide are unsuitable as predictive marker for fetal macrosomia, type of delivery, complications, or birth injuries.
PMCID: PMC3907493  PMID: 24423633
amniocentesis; gestational diabetes; macrosomia; amniotic fluid; insulin; C-peptide
9.  Measurement, Characterization, and Source of Somatostatin-like Immunoreactivity in Human Amniotic Fluid 
Journal of Clinical Investigation  1979;64(3):737-742.
Somatostatin-like immunoreactivity (SLI) is widely distributed in tissues and biological fluids. To determine whether SLI is also present in amniotic fluid, samples obtained by amniocentesis from 30 normal and 27 abnormal pregnancies were studied by radioimmunoassay. Direct incubation of [125I-Tyr1]tetradecapeptide somatostatin (SRIF) with amniotic fluid resulted in 89% tracer degradation. Damage was reduced to <5% when samples were acidified and boiled before the assay. With this technique, SLI was detectable in all normal amniotic fluid samples; the mean level at 15-20 wk of gestation (320±55 pg/ml, n = 15) being 4.5 times higher than the mean at 32-43 wk (70±12 pg/ml, n = 15) (P < 0.001). In cases of preeclampsia (n = 6), gestational diabetes (n = 5), anencephaly (n = 1), and meningomyelocele (n = 1), SLI values were in the normal range, but in one juvenile diabetic and one patient with chronic renal failure, SLI was undetectable (<10 pg/ml). In a pair of monochorionic diamniotic twins, SLI levels were very different (33 and 197 pg/ml), which suggests that fetal factors are more important than materno-placental ones in determining amniotic fluid SLI. Serial dilutions of amniotic fluid showed parallelism with standard SRIF. When concentrates of pooled amniotic fluid were chromatographed on Sephadex G-25 columns, all SLI eluted in the void volume ahead of SRIF even after treatment with 8 M urea and dithiothreitol. This “big” SLI incubated in amniotic fluid showed 100% stability over 24 h at 37°C, whereas SRIF was rapidly inactivated (t½ ≅ 7 min). Extracts of placenta and fetal membranes contained no SLI, but small amounts (6-20% of total amniotic fluid SLI) were found in cells from fresh fluid. Radioimmunoassay of SLI in extracts of seven paired cord arterial and venous plasma samples showed no arteriovenous gradient consistent with fetal origin of cord blood SLI. It is concluded that (a) amniotic fluid contains SLI which is of fetal origin and (b) normal levels vary with gestational age. The SLI has a higher molecular weight (≥5,000) and is more stable in amniotic fluid than SRIF.
PMCID: PMC372175  PMID: 468988
10.  Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring 
British Journal of Cancer  2009;100(5):684-692.
More women are living with and surviving breast cancer, because of improvements in breast cancer care. Trastuzumab (Herceptin®▾) has significantly improved outcomes for women with HER2-positive tumours. Concerns about the cardiac effects of trastuzumab (which fundamentally differ from the permanent myocyte loss associated with anthracyclines) led to the development of cardiac guidelines for adjuvant trials, which are used to monitor patient safety in clinical practice. Clinical experience has shown that the trial protocols are not truly applicable to the breast cancer population as a whole, and exclude some women from receiving trastuzumab, even though they might benefit from treatment without long-term adverse cardiac sequelae. Consequently, five oncologists who recruited patients to trastuzumab trials, some cardiologists with whom they work, and a cardiovascular lead general practitioner reviewed the current cardiac guidelines in the light of recent safety data and their experience with adjuvant trastuzumab. The group devised recommendations that promote proactive pharmacological management of cardiac function in trastuzumab-treated patients, and that apply to all patients who are likely to receive standard cytotoxic chemotherapy. Key recommendations include: a monitoring schedule that assesses baseline and on-treatment cardiac function and potentially reduces the overall number of assessments required; intervention strategies with cardiovascular medication to improve cardiac status before, during, and after treatment; simplified rules for starting, interrupting and discontinuing trastuzumab; and a multidisciplinary approach to breast cancer care.
PMCID: PMC2653760  PMID: 19259090
trastuzumab; cardiac; monitoring; UK; recommendations
11.  Phase II Trial of Weekly Nanoparticle Albumin-Bound Paclitaxel With Carboplatin and Trastuzumab as First-line Therapy for Women With HER2-Overexpressing Metastatic Breast Cancer 
Clinical breast cancer  2010;10(4):10.3816/CBC.2010.n.036.
This multicenter phase II trial evaluated the efficacy and safety of weekly nanoparticle albumin-bound paclitaxel with carboplatin and weekly trastuzumab as first-line therapy for women with HER2-overexpressing metastatic breast cancer (MBC).
Patients and Methods
We treated 32 patients who had measurable MBC that was HER2-positive defined by an immunohistochemical staining score of 3+ or gene amplification by fluorescence in situ hybridization, required for those with an IHC of 2+. Patients were treated with albumin-bound paclitaxel 100 mg/m2 and carboplatin at area under the curve (AUC) = 2 on days 1, 8, and 15 of a 28-day cycle. Trastuzumab was administered at 2 mg/kg weekly after a loading dose of 4 mg/kg. Because of hypersensitivity reactions occurring during carboplatin infusion numbers 6-8 in 4 of the first 13 patients with this premedication-free regimen, the protocol was amended for carboplatin and dosed at AUC = 6 day 1 each 28-day cycle, in lieu of introducing steroid prophylaxis. Patients were treated with 6 cycles and allowed to continue with all 3 drugs or trastuzumab alone if free of progression and unacceptable toxicity after 6 cycles.
The overall response rate (ORR) was 62.5% (95% CI, 45.7%-79.3%) with 3 confirmed complete responders (CRs; 9%) and 17 confirmed partial responses (PRs; 53%). An additional 6 patients (19%) had stable disease (SD) for greater than 16 weeks for a clinical benefit rate (ORR + SD > 16 weeks) of 81%. As of April 16, 2009, 20 patients (63%) had progressed with a median progression-free survival (PFS) of 16.6 months (95% CI, 7.5-26.5 months). Antitumor activity was similar for patients treated with weekly carboplatin and every-4-week carboplatin (ORR, 65% vs. 67%, respectively). Hematologic toxicities were the only grade 4 toxicities noted and were infrequent with grade 4 neutropenia in 3 patients (9%) and 1 febrile neutropenia. Grade 2/3 peripheral neuropathy was uncommon (13%/3%).
Weekly albumin-bound paclitaxel with carboplatin and trastuzumab is highly active in HER2-overexpressing MBC. In the absence of corticosteroid premedication, which we avoided with albumin-bound paclitaxel, carboplatin seems best dosed every 4 weeks rather than weekly because of carboplatin-associated hypersensitivity reactions. The regimen was very well tolerated with few grade 3 and 4 nonhematologic toxicities experienced, and severe hematologic toxicity and peripheral neuropathy were infrequent.
PMCID: PMC3883128  PMID: 20705560
Nab-paclitaxel; Neutropenia; Platinum agents; Progression-free survival
12.  The Effects of Intravenous Hydration on Amniotic Fluid Volume and Pregnancy Outcomes in Women with Term Pregnancy and Oligohydramnios: A Randomized Clinical Trial 
Journal of Caring Sciences  2012;1(3):123-128.
Introduction: Amniotic fluid is an important factor in the prediction of fetal survival. The aim of this research was to evaluate the effects of intravenous hydration of mothers on amniotic fluid volume and in turn on pregnancy outcomes. Methods: The current single blind controlled clinical trial was conducted on 20 pregnant mothers with amniotic fluid index of lower or equal to 5 cm and gestational age of 37-41 weeks. The subjects were divided into two groups of case and control through simple random sampling. Amniotic fluid index was measured in all participants. The case group received one liter of isotonic saline during 30 minutes by the bolus method. Reevaluations of amniotic fluid index in both groups were made 90 minutes after baseline measurement. Independent t-test and paired t-test were used to compare the two groups and mean amniotic fluid index before and after treatment, respectively. Results: Hydration of mothers significantly increased the amniotic fluid index in the case group (mean change: 1.5 cm; 95%CI: 0.46 - 2.64; P = 0.01). The mean change of amniotic fluid index in the control group did not significantly increase (P = 0.06). The elevation of amniotic fluid index in the hydration group (32%) was significantly higher than the control group (1%) (P = 0.03). Conclusion: In this study intravenous hydration increased amniotic fluid index of mothers with term pregnancy and oligohydramnios. Since it caused no complications for the mother and the fetus, it can be used as an effective method in management of oligohydramnios.
PMCID: PMC4161079  PMID: 25276686
Hydration of mothers; Oligohydramnios; Amniotic fluid index; Clinical trial
13.  Cardiotoxicity with adjuvant trastuzumab use in breast cancer: A single institution’s experience 
Trastuzumab use in Her-2-neu positive breast cancer patients is the current standard of care. Trastuzumab is known to result in cardiotoxicity. The toxicity seems to be dose-dependent, and serial cardiology assessment with echocardiography is advised. In spite of this, patients do develop cardiotoxicity and identification of patients at high risk and, if possible, any preventive means is of paramount importance.
We performed a retrospective analysis of medical records of all breast cancer patients presenting at King Khalid University Hospital from 02/2006 to 06/2009 and receiving adjuvant trastuzumab on the basis of either immunohistochemistry showing Her-2-neu (3+) or FISH positive Her-2-neu receptor status. Patients received adjuvant trastuzumab at an 8 mg/kg loading dose over 90 min, followed by 6 mg/kg every 3 weeks. A repeat multigated acquisition scan/echocardiogram was done after every 4 courses. Patient characteristics, such as age, menopausal status, tumor size, lymph nodal status, distant metastasis at presentation, grade of tumor, estrogen and progesterone receptor status, comorbid conditions (diabetes, hypertension, ischemic heart diseases), chemotherapy received, total dose of trastuzumab, timing of cardiotoxicity, and number of patients having cardiotoxicity, were recorded. A patient was said to have cardiotoxicity if the ejection fraction dropped by 10% of the original value or if there was a drop in the ejection fraction below the normal value.
A total number of 98 breast cancer patient records were analyzed in this study. A total of 11 patients developed cardiotoxicity, evident by a drop in the ejection fraction on an echocardiogram. Seven patients out of 11 had a drop in ejection fraction below 10% of the baseline value, and 4 patients out of 11 had a drop in ejection fraction below normal values. A total of 5 patients became symptomatic with dyspnea on exertion, with 2 being of NYC Class I, 2 being of NYC Class II, 1 being of NYC Class III, and none being of NYC Class IV. Seven patients out of 11 with cardiotoxicity had diabetes and hypertension as comorbid conditions. Patients receiving doxorubicin in neoadjuvant and adjuvant settings were associated with cardiotoxicity. The total dose of trastuzumab had a strong association, with the patient getting more than 60 mg/kg in a 3-weekly fashion being associated with cardiotoxicity.
Trastuzumab is associated with significant cardiotoxicity. Asymptomatic and symptomatic cardiotoxicity and toxicity seem to be dose-dependent in an adjuvant setting. At the end of therapy, more frequent than usual monitoring of cardiac function is suggested to prevent this toxicity.
PMCID: PMC3727509  PMID: 23960606
Cardiotoxicity; Trastuzumab
Pulmonary surfactant is a complex molecule of lipids and proteins synthesized and secreted by type II alveolar cells into the alveolar epithelial lining. Both lipids and protein components are essential for lung function in postnatal life. Infection is a well-established cause of preterm delivery and several inflammatory cytokines play a role in the mechanisms of preterm parturition. An increased concentration of inflammatory cytokines in amniotic fluid or fetal plasma has been linked to the onset of preterm parturition and fetal/neonatal injury including cerebral palsy and chronic lung disease. Experimental evidence indicated that inflammatory mediators also regulated surfactant protein synthesis and histologic chorioamnionitis was associated with a decreased incidence of hyaline membrane disease in neonates. This study was conducted to determine if amniotic fluid concentration of surfactant protein (SP)-A, SP-B and SP-D changes in patients with and without intra-amniotic infection (IAI).
A case-control study was conducted to determine amniotic fluid concentrations of SP-A, SP-B, SP-D, and total protein in patients who had an amniocentesis performed between 18 and 34 weeks of gestation for the detection of IAI in patients with spontaneous preterm labor with intact membranes (n=42) and cervical insufficiency prior to the application for cerclage (n=6). Amniotic fluid samples were selected from a bank of biological specimens and included patients with (n=16) and without (n=32) IAI matched for gestational age at amniocentesis. Intra-amniotic infection was defined a positive amniotic fluid culture for microorganisms. Each group was further subdivided according to a history of corticosteroid administration within 7 days prior to amniocentesis into the following subgroups: 1) patients without IAI who had received antenatal corticosteroid (n=21); 2) patients with IAI who had received antenatal corticosteroid (n=9); 3) patients without IAI who had not received antenatal corticosteroid (n=11); and 4) patients with IAI who had not received antenatal corticosteroid (n=7). Amniotic fluid was obtained by trans-abdominal amniocentesis. SP-A, SP-B, and SP-D concentrations in amniotic fluid were determined by enzyme-linked immunosorbent assay (ELISA). Non-parametric statistics were used for analysis.
Women with IAI had a higher median amniotic fluid concentration of SP-B and of SP-B/total protein, but not other SPs, than those without IAI (both p=0.03). Among patients who had received antenatal corticosteroids, the median amniotic fluid concentration of SP-B and of SP-B/total protein was significantly higher in patients with IAI than in those without IAI (SP-B; IAI: median 148 ng/ml, range 37.3-809 ng/ml vs. without IAI: median 7.2 ng/ml, range 0 -1,035 ng/ml; p=0.005 and SP-B/total protein; IAI: median 14.1 ng/mg, range 4.3-237.5 ng/mg vs. without IAI: median 1.45 ng/mg, range 0 79.5 ng/mg; p=0.003). Among women who had not received antenatal corticosteroid, the median amniotic fluid concentration of SP-B and of SP-B/total protein was not significantly different between patients with and without IAI (SP-B; IAI: median 4 ng/ml, range 0-31.4 ng/ml vs. without IAI: median 3.4 ng/ml, range 0-37 ng/ml; p=0.8 and SP-B/total protein; IAI: median 0.55 ng/mg, range 0-6.96 ng/mg vs. without IAI: median 0.59 ng/mg, range 0-3.28 ng/mg; p=0.9). The median amniotic fluid concentrations of SP-A, SP-A/total protein, SP-D and SP-D/total protein were not significantly different between patients with and without IAI whether they received antenatal corticosteroid or not (all p>0.05).
IAI was associated with an increased amniotic fluid concentration of SP-B in patients who received antenatal corticosteroids within 7 days prior to amniocentesis.
PMCID: PMC2585007  PMID: 18828060
Surfactant protein; SP-A; SP-B; SP-D; intra-amniotic infection; amniotic fluid; preterm labor; preterm parturition
15.  Basal/HER2 breast carcinomas 
Cell Cycle  2013;12(2):225-245.
High rates of inherent primary resistance to the humanized monoclonal antibody trastuzumab (Herceptin) are frequent among HER2 gene-amplified breast carcinomas in both metastatic and adjuvant settings. The clinical efficacy of trastuzumab is highly correlated with its ability to specifically and efficiently target HER2-driven populations of breast cancer stem cells (CSCs). Intriguingly, many of the possible mechanisms by which cancer cells escape trastuzumab involve many of the same biomarkers that have been implicated in the biology of CS-like tumor-initiating cells. In the traditional, one-way hierarchy of CSCs in which all cancer cells descend from special self-renewing CSCs, HER2-positive CSCs can occur solely by self-renewal. Therefore, by targeting CSC self-renewal and resistance, trastuzumab is expected to induce tumor shrinkage and further reduce breast cancer recurrence rates when used alongside traditional therapies. In a new, alternate model, more differentiated non-stem cancer cells can revert to trastuzumab-refractory, CS-like cells via the activation of intrinsic or microenvironmental paths-to-stemness, such as the epithelial-to-mesenchymal transition (EMT). Alternatively, stochastic transitions of trastuzumab-responsive CSCs might also give rise to non-CSC cellular states that lack major attributes of CSCs and, therefore, can remain “hidden” from trastuzumab activity. Here, we hypothesize that a better understanding of the CSC/non-CSC social structure within HER2-overexpressing breast carcinomas is critical for trastuzumab-based treatment decisions in the clinic. First, we decipher the biological significance of CSC features and the EMT on the molecular effects and efficacy of trastuzumab in HER2-positive breast cancer cells. Second, we reinterpret the genetic heterogeneity that differentiates trastuzumab-responders from non-responders in terms of CSC cellular states. Finally, we propose that novel predictive approaches aimed at better forecasting early tumor responses to trastuzumab should identify biological determinants that causally underlie the intrinsic flexibility of HER2-positive CSCs to “enter” into or “exit” from trastuzumab-sensitive states. An accurate integration of CSC cellular states and EMT-related biomarkers with the currently available breast cancer molecular taxonomy may significantly improve our ability to make a priori decisions about whether patients belonging to HER2 subtypes differentially enriched with a “mesenchymal transition signature” (e.g., luminal/HER2 vs. basal/HER2) would distinctly benefit from trastuzumab-based therapy ab initio.
PMCID: PMC3575452  PMID: 23255137
basal-like; cancer stem cells; EMT; HER2; trastuzumab; breast cancer; reprogramming
16.  Mechanisms of Adipocytokine-Mediated Trastuzumab Resistance in HER2-Positive Breast Cancer Cell Lines 
Acquired resistance to trastuzumab is a clinical problem in the treatment of HER2-over-expressing metastatic breast cancer. Importantly, an earlier report suggested that high body mass index was associated with reduced overall survival and reduced time to progression in patients with early stage or metastatic HER2-positive breast cancer treated with trastuzumab. Adipocyte-secreted factors may stimulate growth of HER2-positive cancers, blocking the growth inhibitory action of trastuzumab. Leptin and growth differentiation factor 15 (GDF15) are two adipocytokines that have been reported to stimulate HER2-PI3K signaling. We previously showed that cells with acquired trastuzumab resistance express increased levels of GDF15, and that GDF15 knockdown restores sensitivity to trastuzumab. The objective of the current study was to identify potential molecular mechanisms by which adipocytes stimulate resistance to trastuzumab in HER2-over-expressing breast cancer cell lines. Cells were cultured in complete media or conditioned media from differentiated adipocytes (CM). Cell viability of trastuzumab-treated cells was examined under anchorage-dependent and -independent conditions. Phosphorylation of Akt was assessed by Western blotting, and response to trastuzumab was reassessed upon treatment with the PI3K inhibitor LY294002 or after transfection with kinase-dead Akt. We report that CM significantly reduced trastuzumab-mediated growth inhibition of HER2-positive cells, and stimulated rapid phosphorylation of Akt. Pharmacologic or genetic inhibition of PI3K overcame CM-mediated trastuzumab resistance. Leptin and GDF15 were both measured in CM, but only GDF15 conferred resistance to trastuzumab. Leptin, on the other hand, abrogated sensitivity to lapatinib but not trastuzumab. Our observations suggest that adipocyte-secreted factors such as GDF15 stimulate PI3K signaling, resulting in reduced response to trastuzumab. The utility of adipocytokines as predictors of drug resistance and approaches to mitigate the cancer-promoting effects of adipocyte-secreted factors should be further examined. Our work supports additional investigation into GDF15 as a potential biomarker of trastuzumab resistance, and development of approaches to therapeutically target GDF15 in HER2-positive breast cancers that have progressed on trastuzumab.
PMCID: PMC3811155  PMID: 24179558
Cancer therapeutics; GDF15; drug resistance; erbB2; Herceptin; lapatinib; pharmacogenetics; trastuzumab
17.  Hepatotoxicity induced by trastuzumab used for breast cancer adjuvant therapy: a case report 
Trastuzumab is generally considered a highly safe drug, but there have been cases of infusion reaction and cardiotoxicity. This report will present a rare case of hepatotoxicity induced by trastuzumab used for adjuvant therapy of human epidermal growth factor receptor type 2-positive breast cancer.
Case presentation
The patient was a 60-year-old Japanese postmenopausal woman with a non-contributory past medical history. She presented for detailed examination of an abnormality in her left breast. She had left breast cancer (T2N1M0, stage IIB) that was positive for estrogen receptor and progesterone receptor and was human epidermal growth factor receptor type 2 3+. She began receiving epirubicin and cyclophosphamide therapy but developed hepatotoxicity (aspartate aminotransferase 43U/L, alanine aminotransferase 104U/L, alkaline phosphatase 634U/L, and γ-glutamyl transpeptidase 383U/L). Thus, the therapy was discontinued after two cycles, and a weekly paclitaxel therapy was begun. After the absence of an adverse event was confirmed, she also began receiving trastuzumab (4mg/kg) at the second cycle. However, hepatotoxicity (aspartate aminotransferase 267U/L, alanine aminotransferase 246U/L, alkaline phosphatase 553U/L, and γ-glutamyl transpeptidase 240U/L) developed again, and trastuzumab was discontinued. She received paclitaxel monotherapy for a total of four cycles and subsequently underwent partial mastectomy and axillary dissection. After completing adjuvant radiation therapy (breast, 50Gy), she received trastuzumab administration (4mg/kg) but hepatotoxicity (aspartate aminotransferase 47U/L, alanine aminotransferase 102U/L, alkaline phosphatase 377U/L, and γ-glutamyl transpeptidase 91U/L) recurred. Thus, it was discontinued again. There was no hepatitis B or C virus infection, and a drug-induced lymphocyte stimulation test revealed a positive reaction to trastuzumab (stimulation index: 227%). Thereafter she has used only oral letrozole (2.5mg/day) and no recurrent cancer has been observed.
Although trastuzumab is a highly safe drug, one must be mindful of its risk for hepatotoxicity. Periodic monitoring of liver functions is necessary during trastuzumab therapy.
PMCID: PMC4307619  PMID: 25491149
Breast cancer; Hepatotoxicity; Trastuzumab
18.  The Clinical Significance of Eosinophils in the Amniotic Fluid in Preterm Labor 
White blood cells are not traditionally considered to be normally present in amniotic fluid. This study was conducted after the observation that a patient with preterm labor and intact membranes had eosinophils as a predominant cell in the amniotic fluid, and had an episode of asthma during the index pregnancy. The goal of this study was to determine whether women presenting with preterm labor with eosinophils in the amniotic fluid had a different outcome than those without eosinophils as the predominant white blood cell in the amniotic cavity.
This retrospective case-control study included women who presented with preterm labor and intact membranes between 24 and 34 weeks of gestation. Patients underwent an amniocentesis shortly after admission for the assessment of the microbiologic status of the amniotic cavity and/or fetal lung maturity. Amniotic fluid was cultured for aerobic and anaerobic bacteria as well as genital mycoplasmas. Cytologic studies included amniotic fluid white blood cell count and differential, which was performed on cytocentrifuged specimens. Patients with microbial invasion of the amniotic cavity and/or a white blood cell count >20 cells/mm3 were excluded from the study. Cases were defined as women in whom the differential contained >20% of eosinophils. Controls were selected among women with an amniotic fluid eosinophil count ≤20% and matched for gestational age at amniocentesis. The analysis was conducted with non-parametric statistics.
The study population consisted of 10 cases and 50 controls. Gestational age and cervical dilatation at admission were similar in both groups. Cases had a lower gestational age at delivery than controls [34.6 weeks, inter-quartile range (IQR) 32–37.3 weeks vs. 38.0 weeks, IQR 35–40 weeks, respectively; p=0.018]. The prevalence of preterm delivery ≤35 weeks was higher among patients who had >20% eosinophils than in the control group [50% (5/10) vs. 18% (9/50), respectively; p=0.029]. Similar results were observed for delivery at <37 weeks [Cases: 70% (7/10) vs. Controls: 36% (18/50); p=0.046].
Women with preterm labor and intact membranes who have a large proportion of eosinophils in the amniotic fluid are at an increased risk for spontaneous preterm delivery. These patients may have had an episode of preterm labor related to a type I hypersensitivity reaction.
PMCID: PMC3470475  PMID: 19900034
Premature birth; preterm birth; prematurity; premature labor; mast cells; amniotic fluid cells; amniotic fluid white blood cells; allergy; allergy-induced preterm labor; atopy; pregnancy; type I hypersensitivity reaction; parturition; labor; eosinophil granule proteins
19.  Physiology: Maternal Serum C-Reactive Protein Level Does Not Change Significantly After Fetal Reduction: It Could Be Used as an Indicator of Chorioamnionitis 
Purpose: This study was aimed at investigating the diagnostic value of maternal serum C-reactive protein (CRP) in the recognition of chorioamnionitis in patients undergoing fetal reduction.
Methods: Seventy-one gravidas with high-order multifetal pregnancies, including 46 with triplets, 18 with quadruplets, and 7 with quintuplets, who underwent transabdominal fetal reduction to twins during the 10th–14th gestational week were recruited. The subjects were followed up clinically and ultrasonographically 1 week and 1 month after fetal reduction for signs of infection, premature uterine contraction, and premature rupture of the membranes. CRP levels were measured prior to fetal reduction and at follow-up examinations, and were compared.
Results: Among the 71 mothers, 65 (92%) were normal after fetal reduction. The CRP levels were not significantly different prior to the procedure (0.27 ± 0.26 mg/dL), and 1 week (0.23 ± 0.24 mg/dL) and 1 month (0.24 ± 0.20 mg/dL) later. There was no correlation between the number of fetuses reduced and the CRP levels. Six (8%) experienced leakage of amniotic fluid after fetal reduction. Three patients had normal CRP levels at that time and at the following tests. The pregnancies continued smoothly after conservative treatment. The other three patients had elevated CRP levels when leakage of amniotic fluid occurred. Fever and uterine irritability developed subsequently despite parenteral antibiotics and tocolytic therapy. Daily checks showed increasing CRP levels. The pregnancies were aborted, and the histology of the placental membranes revealed chorioamnionitis with infiltration of acute inflammatory cells.
Conclusions: The absorption of inactive gestational tissue after fetal reduction did not affect CRP levels. CRP may be used as a marker of intrauterine infection after fetal reduction.
PMCID: PMC3455844  PMID: 11495410
chorioamnionitis; C-reactive protein; fetal reduction
20.  Prenatal diagnosis of genetic disorders. 
Journal of Medical Genetics  1976;13(3):182-194.
Three hundred and fifty pregnancies were monitored by transabdominal amniocentesis in the fourteenth to sixteenth week of gestation followed by karyotyping or biochemica assays of cultured amniotic fluid cells and analysis of alpha-fetoprotein in the amniotic fluid supernatant. The pregnancy was interrupted in 36 cases (10%) either becasue of a fetal abnormality or the presence of a male fetus in pregnancies at risk for an X-linked disease. Four chromosomal aberrations were found in 87 pregnancies tested because of advanced maternal age. In 101 pregnancies with a recurrence risk of Down's syndrome, 2 fetuses with an abnormal karyotype were detected. In 11 cases, in which 1 parent was a carrier of a balanced translocation, 2 unbalanced fetal karyotypes were found. Fetal chromosome studies in 43 pregancies at risk for an X-linked disease indicated the presence of a male fetus in 21 cases. Prenatal diagnosis of 11 different metabolic diseases was performed in a total of 34 cases. Microchemical techniques were used to allow completion of the diagnosis of seven different enzyme deficiencies within 9 to 22 days after amniocentesis. Alpha-fetoprotein assay in the amniotic fluid supernatant of 47 pregnancies at risk for an open neural tube defect resulted in the detection of 3 anencephalic fetuses during the second half of pregnancy. The safety and reliability of amniocentesis and the possible effects on the outcome of pregnancy are evaluated. Prenatal diagnosis offers a promising alternative for parents who are at risk of having a child with a genetic disease which can be detected in amniotic fluid or in cultured amniotic fluid cells.
PMCID: PMC1013391  PMID: 58990
21.  A case report of trastuzumab dose in gastric cancer 
Trastuzumab (Herceptin®, F. Hoffman-La Roche) is now approved for the treatment of metastatic HER2-positive gastric cancer based on the improved survival observed on the phase III Trastuzumab for Gastric Adenocarcinoma (ToGA) study. Standard dosing of trastuzumab is currently extrapolated from breast cancer data: a 3-week schedule (8 mg/kg load, 6 mg/kg q 3 weeks) or a weekly schedule (4 mg/kg load, 2 mg/kg q week).
Case study
Our case study examines an HER2-positive metastatic gastric cancer patient that required a higher than currently recommended standard dose of trastuzumab to achieve treatment response.
Several mechanisms may explain these findings and include higher clearance of trastuzumab, higher tumor burden, and pharmacologic resistance in metastatic gastric cancer versus breast cancer. The question of trastuzumab dosing in gastric cancer is currently being evaluated in a phase III clinical trial.
PMCID: PMC3819770  PMID: 24294514
Trastuzumab; metastatic gastric cancer; pharmacokinetics
22.  Adjuvant Paclitaxel and Trastuzumab for Node-Negative, HER2-Positive Breast Cancer 
The New England journal of medicine  2015;372(2):134-141.
No single standard treatment exists for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)–positive breast cancers, because most of these patients have been ineligible for the pivotal trials of adjuvant trastuzumab.
We performed an uncontrolled, single-group, multicenter, investigator-initiated study of adjuvant paclitaxel and trastuzumab in 406 patients with tumors measuring up to 3 cm in greatest dimension. Patients received weekly treatment with paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy. The primary end point was survival free from invasive disease.
The median follow-up period was 4.0 years. The 3-year rate of survival free from invasive disease was 98.7% (95% confidence interval [CI], 97.6 to 99.8). Among the 12 relapses seen, 2 were due to distant metastatic breast cancer. Excluding contra-lateral HER2-negative breast cancers and nonbreast cancers, 7 disease-specific events were noted. A total of 13 patients (3.2%; 95% CI, 1.7 to 5.4) reported at least one episode of grade 3 neuropathy, and 2 had symptomatic congestive heart failure (0.5%; 95% CI, 0.1 to 1.8), both of whom had normalization of the left ventricular ejection fraction after discontinuation of trastuzumab. A total of 13 patients had significant asymptomatic declines in ejection fraction (3.2%; 95% CI, 1.7 to 5.4), as defined by the study, but 11 of these patients were able to resume trastuzumab therapy after a brief interruption.
Among women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of about 2%; 6% of patients withdrew from the study because of protocol-specified adverse events. (Funded by Genentech; number, NCT00542451.)
PMCID: PMC4313867  PMID: 25564897
23.  Adjuvant Trastuzumab in HER2-Positive Breast Cancer 
The New England Journal of Medicine  2011;365(14):1273-1283.
Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab.
We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety.
At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study.
The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk–benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 number, NCT00021255.)
PMCID: PMC3268553  PMID: 21991949
24.  Revisiting the Role of First Trimester Homocysteine as an Index of Maternal and Fetal Outcome 
Journal of Pregnancy  2014;2014:123024.
Aim. To revisit the role of first trimester homocysteine levels with the maternal and fetal outcome. Methods. This was a cohort study comprising 100 antenatal women between 8 and 12 weeks of gestation. Serum homocysteine levels were checked after overnight fasting. Results. There were significantly elevated homocysteine levels among women with prior history of hypertensive disorders of pregnancy and prior second or third trimester pregnancy losses. There was no significant difference in homocysteine levels among women with previous gestational diabetes mellitus, preterm deliveries, or fetal malformations. Homocysteine levels were significantly elevated in those who developed hypertensive disorder of pregnancy, oligohydramnios, and meconium stained amniotic fluid, had a pregnancy loss, or delivered a low birth weight baby. There was no significant difference in homocysteine levels for those who developed gestational diabetes mellitus. Conclusions. Increased first trimester serum homocysteine is associated with history of pregnancy losses, hypertensive disorders of pregnancy, and preterm birth. This is also associated with hypertensive disorders of pregnancy, pregnancy loss, oligohydramnios, meconium stained amniotic fluid, and low birth weight in the current pregnancy. This trial is registered with CTRI/2013/02/003441.
PMCID: PMC4027023  PMID: 24883207
An anti-angiogenic state has been implicated in the pathophysiology of preeclampsia, fetal growth restriction and fetal death. Vascular endothelial growth factor (VEGF), an indispensible angiogenic factor for embryonic and placental development exerts its angiogenic properties through the VEGF receptor (VEGFR)-2. A soluble form of this protein (sVEGFR-2) has been recently detected in maternal blood. The aim of this study was to determine if fetal death was associated with changes in the concentrations of sVEGFR-2 in maternal plasma and amniotic fluid.
Maternal plasma was obtained from patients with fetal death (n=59) and normal pregnant women (n=134). Amniotic fluid was collected from 36 patients with fetal death and the control group consisting of patients who had an amniocentesis and delivered at term (n=160). Patients with fetal death were classified according to the clinical circumstances into the following groups: 1) unexplained; 2) preeclampsia and/or placental abruption; and 3) chromosomal and/or congenital anomalies. Plasma and amniotic fluid concentrations of sVEGFR-2 were determined by ELISA. Non-parametric statistics and logistic regression analysis were applied.
1) Patients with a fetal death had a significantly lower median plasma concentration of sVEGFR-2 than normal pregnant women (p<0.001). The median plasma concentration of sVEGFR-2 in patients with unexplained fetal death and in those with preeclampsia/abruption, but not that of those with congenital anomalies, was lower than that of normal pregnant women (p=0.006, p<0.001and p=0.2 respectively); 2) the association between plasma sVEGFR-2 concentrations and preterm unexplained fetal death remained significant after adjusting for potential confounders (OR 3.2; 95% CI 1.4–7.3 per each quartile decrease in plasma sVEGFR-2 concentrations); 3) each subgroup of fetal death had a higher median amniotic fluid concentration of sVEGFR-2 than the control group (p<0.001 for each); 4) the association between amniotic fluid sVEGFR-2 concentrations and preterm unexplained fetal death remained significant after adjusting for potential confounders (OR 15.6; 95% CI 1.5–164.2 per each quartile increase in amniotic fluid sVEGFR-2 concentrations); and 5) among women with fetal death, there was no relationship between maternal plasma and amniotic fluid concentrations of sVEGFR-2 (Spearman Rho: 0.02; p=0.9).
Pregnancies with a fetal death, at the time of diagnosis, are characterized by a decrease in the maternal plasma concentration of sVEGFR-2, but an increase in the amniotic fluid concentration of this protein. While a decrease in sVEGFR-2 concentration in maternal circulation depends upon the clinical circumstances of fetal death, an increase in sVEGFR-2 concentration in amniotic fluid seems to be a common feature of fetal death. It remains to be determined if the perturbation in sVEGFR-2 concentrations in maternal and fetal compartments observed herein preceded the death of a fetus.
PMCID: PMC3427783  PMID: 20158395
Amniotic fluid; angiogenesis; angiogenic factor; congenital anomaly; intrauterine demise; sKDR; maternal plasma; preeclampsia; stillbirth; unexplained fetal death; sVEGFR-2

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