Pregnancy, perinatal and childhood outcomes in women with and without polycystic ovary syndrome and metformin during pregnancy: a nationwide population-based study.

BACKGROUND: Polycystic Ovary Syndrome (PCOS) is an endocrine disorder that affects women in reproductive age and represents an unfavourable risk factor for several pregnancy and perinatal outcomes. Despite, no guidelines or pharmaceutical strategies for treating PCOS during pregnancy are available. The aim of this study is to determine the association between polycystic ovary syndrome with or without metformin and the pregnancy, perinatal outcomes as well as the risk of obesity in children born to these mothers. METHODS: In this nationwide population-based cohort study based in Swedish population, all singleton births (n = 1,016,805) from 686,847 women since 2006 up to 2016 were included. Multivariable logistic and Cox regression modelling with odds ratios (OR) and hazard ratios (HR) and 95% confidence intervals were used to study the association between the exposure of maternal PCOS, metformin during pregnancy (or the combination of both) and: 1) Pregnancy outcomes: preeclampsia, gestational diabetes, caesarean section, and acute caesarean section, 2) Perinatal outcomes: preterm birth, stillbirth, low birth weight, macrosomia, Apgar < 7 at 5 min, small for gestational age and large for gestational age, and 3) Childhood Obesity. RESULTS: PCOS in women without metformin use during pregnancy was associated with higher risks of preeclampsia (OR = 1.09, 1.02-1.17), gestational diabetes (OR = 1.71, 1.53-1.91) and caesarean section (OR = 1.08, 1.04-1.12), preterm birth (OR = 1.30, 1.23-1.38), low birth weight (OR = 1.29, 1.20-1.38), low Apgar scores (OR = 1.17, 1.05-1.31) and large for gestational age (OR = 1.11, 1.03-1.20). Metformin use during pregnancy (in women without PCOS) was associated with a 29% lower risks of preeclampsia (OR = 0.71, 0.51-0.97), macrosomia and large for gestational age. Obesity was more common among children born to mothers with PCOS without metformin (HR = 1.61, 1.44-1.81); and those with metformin without PCOS (HR = 1.67, 1.05-2.65). PCOS with metformin was not associated with any adverse outcome. CONCLUSION: PCOS was associated with increased risks of adverse pregnancy and perinatal outcomes and childhood obesity. Metformin appears to reduce these risks in mothers with polycystic ovary syndrome and their children; but may increase the risk of childhood-obesity in children form women without PCOS.

Outcome of Patients Treated Within and Outside a Randomized Clinical Trial on Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: Extrapolation of a Randomized Clinical Trial (CROSS).

BACKGROUND: Randomized clinical trials (RCTs) can provide a high level of evidence for medical decision making, but it is unclear if the results apply to patients treated outside such trials. OBJECTIVE: The aim of this study was to retrospectively compare outcomes of patients with esophageal cancer treated within and outside an RCT. METHODS: All patients receiving neoadjuvant chemoradiotherapy (nCRT) plus surgery for esophageal cancer between 2002 and 2008 (ChemoRadiotherapy for Esophageal cancer followed by Surgery Study [CROSS] cohort) who participated in multicenter, phase II-III trials were compared with patients who underwent the same treatment outside the trial between 2008 and 2013 (post-CROSS cohort). The differences between these cohorts were analyzed using t tests, while logistic regression models were used to evaluate adverse events. Overall and disease-free survival were calculated using the Kaplan-Meier method and Cox regression analyses. RESULTS: A total of 208 CROSS patients and 173 post-CROSS patients were included in this study. Patients from the post-CROSS cohort were older, had more co morbidities, and had poorer performance status. Clinical N stage, but not cT stage, was worse in the post-CROSS cohort. There were no statistically significant differences in adverse events (pulmonary, cardiac, or anastomotic complications) or survival between the comparison cohorts. CONCLUSION: The outcomes of patients treated with nCRT plus esophagectomy for cancer have a high external consistency and can be extrapolated to the daily practice of physicians involved in the treatment and care of esophageal cancer patients.

Extent of lymph node removal during esophageal cancer surgery and survival.

BACKGROUND: It is unclear how the extent of surgical lymph node clearance influences prognosis after surgery for esophageal cancer. METHODS: This nationwide, population-based cohort study included 1044 esophageal cancer patients who had undergone esophagectomy between 1987 and 2010 in Sweden, with follow-up until 2012. The independent role of lymph node removal in relation to survival was analyzed using Cox proportional hazards regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs), adjusted for age, sex, comorbidity, tumor (T) stage, neo-adjuvant treatment, surgeon volume, and calendar period. Statistical tests were two-sided, except tests for trend. RESULTS: Analyzed as a linear variable, a higher number of lymph nodes removed did not influence the overall five-year mortality (adjusted HR = 1.00, 95% CI = 0.99 to 1.01). Patients in the third (7-15 nodes) and fourth (16-114 nodes) quartiles of removed nodes did not demonstrate any decreased overall five-year mortality compared with those in the lowest two quartiles (<7 nodes) (HR = 1.13, 95% CI = 0.95 to 1.35 and HR = 1.17, 95% CI = 0.94 to 1.46, respectively). In early T stages (Tis-T1) the hazard ratios indicated a worse survival with more lymphadenectomy using the median as cutoff (HR = 1.53, 95% CI = 1.13 to 2.06). Increased lymph node removal did not decrease mortality in any specific T stage. A greater number of metastatic nodes and a higher positive-to-negative node ratio were associated with strongly increased mortality. All results were similar when disease-specific mortality was analyzed. CONCLUSION: This population-based study indicates that more extensive lymph node clearance during surgery for esophageal cancer may not improve survival. These results challenge current clinical guidelines, and further research is needed to change clinical practice.

Reoperation after oesophageal cancer surgery in relation to long-term survival: a population-based cohort study.

OBJECTIVES: The influence of reoperation on long-term prognosis is unknown. In this large population-based cohort study, it was aimed to investigate the influence of a reoperation within 30 days of oesophageal cancer resection on survival even after excluding the initial postoperative period. DESIGN: This was a nationwide population-based retrospective cohort study. SETTING: All hospitals performing oesophageal cancer resections during the study period (1987-2010) in Sweden. PARTICIPANTS: Patients operated for oesophageal cancer with curative intent in 1987-2010. PRIMARY AND SECONDARY OUTCOMES: Adjusted HRs of all cause, early and late mortality up to 5 years after reoperation following oesophageal cancer resection. RESULTS: Among 1822 included patients, the 200 (11%) who were reoperated had a 27% increased HR of all-cause mortality (adjusted HR 1.27, 95% CI 1.05 to 1.53) and 28% increased HR of disease-specific mortality (adjusted HR 1.28, 95% CI 1.04 to 1.59), compared to those not reoperated. Reoperation for anastomotic insufficiency in particular was followed by an increased mortality (adjusted HR 1.82, 95% CI 1.19 to 2.76). CONCLUSIONS: This large and population-based nationwide cohort study shows that reoperation within 30 days after primary oesophageal resection was associated with increased mortality, even after excluding the initial 3 months after surgery. This finding stresses the need to consider any actions that might prevent complications and reoperation after oesophageal cancer resection.

The influence of preoperative weight loss on the postoperative course after esophageal cancer resection.

OBJECTIVE: Preoperative weight loss might increase the risk of postoperative morbidity and mortality after esophagectomy for cancer. We hypothesized that patients with esophageal cancer with >10% weight loss during the 3 months before their diagnosis would be at an increased risk of postoperative complications, have a longer length of stay, and have worse overall survival. METHODS: In the present hospital-based cohort study, all patients who had undergone surgery for esophageal cancer in 1990 to 2010 at the Erasmus University Medical Center Rotterdam were included. Weight loss was defined as "no, or limited" (≤10%) or "severe" (>10%). Logistic regression analysis was used to estimate the relative risk of complications, expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Hazard ratios were calculated to assess the length of hospital stay and survival. The risk estimates were adjusted for potential confounding factors. RESULTS: Of 922 included patients, 155 (17%) had experienced severe weight loss. These patients had no increased risk of early surgical, early nonsurgical, or late surgical complications (OR, 0.83 and 95% CI, 0.54-1.24; OR, 0.90 and 95% CI, 0.63-1.30; OR, 1.14 and 95% CI, 0.79-1.66, respectively) and had no increased length of stay (hazard ratio, 1.09; 95% CI, 0.89-1.35). Preoperative weight loss was followed by increased 5-year mortality (hazard ratio, 1.34; 95% CI, 1.02-1.74). CONCLUSIONS: A >10% preoperative weight loss was followed by decreased 5-year survival after esophageal cancer surgery but no increased risk of postoperative complications.

Surgical prevention of reflux after esophagectomy for cancer.

BACKGROUND: Reflux frequently occurs after a gastric conduit has replaced the resected esophagus. In this Swedish population-based cohort study, the potential antireflux effects of using cervical anastomosis, intrathoracic antireflux anastomosis, or pyloric drainage, and a risk of dysphagia due to cervical anastomosis and intrathoracic antireflux anastomosis were studied. METHODS: Patients undergoing esophagectomy with gastric conduit reconstruction in 2001-2005 were included. Reflux symptoms and dysphagia were assessed 6 months and 3 years postoperatively using a validated questionnaire (EORTC QLQ-OES18). The study exposures were cervical anastomosis, antireflux anastomosis, and pyloric drainage procedure. Multivariable logistic regression and propensity-adjusted analyses based on multinomial logistic regression estimated odds ratios (OR) with 95 % confidence intervals (CI), adjusted for potential confounding. RESULTS: A total of 304 patients were included in the study. Adjusted ORs for reflux symptoms were 0.9 (95 % CI 0.3-2.2) for patients with a cervical anastomosis compared to patients with an intrathoracic anastomosis, 0.9 (95 % CI 0.4-2.0) for patients with an antireflux anastomosis versus patients with a conventional anastomosis, and 1.5 (95 % CI 0.9-2.6) for patients after pyloric drainage versus patients without such a pyloric drainage procedure. Dysphagia was not statistically significantly increased after cervical anastomosis or antireflux anastomosis. ORs were virtually similar 3 years after surgery. No interactions were identified. The propensity analyses rendered similar results as the logistic regression models, except for a possibly increased dysphagia with a cervical anastomosis. CONCLUSIONS: Cervical anastomosis, antireflux anastomosis, and pyloric drainage do not seem to prevent reflux symptoms 6 months or 3 years after esophagectomy for cancer with a gastric conduit.

The influence of surgical factors on persisting symptoms 3 years after esophageal cancer surgery: a population-based study in Sweden.

BACKGROUND: Little is known about the long-term effects of surgical approach and type of anastomosis in the surgical treatment of esophageal cancer on patient-reported outcomes. METHODS: A Swedish nationwide, population-based cohort study included patients undergoing esophagectomy for esophageal cancer in 2001-2005. The predefined exposures included surgical approach (transhiatal or transthoracic) and anastomotic technique (hand-sewn or mechanical). The outcomes were esophageal-specific symptoms 3 years after the surgery. Symptoms were measured using the cancer-specific quality of life questionnaire, the QLQ-C30, supplemented by an esophageal cancer-specific module (QLQ-OES18), both developed by the European Organisation for Research and Treatment of Cancer. Logistic regression models were used to estimate relative risk, expressed as odds ratios (OR) with 95 % confidence intervals (CI), of experiencing symptoms as assessed by the questionnaires. RESULTS: Among the 178 included patients, there was an 84 % participation rate. No statistically significant differences were found regarding surgical approach. However, point estimates indicate that patients operated on with a transhiatal approach had a lower risk for symptoms of nausea and vomiting (OR = 0.5, 95 % CI 0.1-1.9), diarrhea (OR = 0.5, 95 % CI 0.2-1.8), and trouble swallowing (OR = 0.4, 95 % CI 0-3), and a slightly higher risk for loss of appetite (OR = 2, 95 % CI 0.7-5.6) compared with patients operated on with a transthoracic approach. Anastomotic technique did not seem to influence the risk for any of the selected symptoms. CONCLUSIONS: Surgical approach and type of anastomosis do not seem to influence the risk of general and esophageal-specific cancer symptoms 3 years after surgery for esophageal cancer.

Reference values for the EORTC QLQ-C30 quality of life questionnaire in a random sample of the Swedish population.

AIM: To obtain reference values for health-related quality of life (HRQL) measured with the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) in a random sample of the adult Swedish population. METHODS: A population-based survey of a random sample of 7002 Swedish adults aged 40-79 years, frequency-matched to reflect the age and sex distribution of upper gastrointestinal cancer patients. Scales were scored on a 0-100 metric according to standard procedures. Functions and symptoms were dichotomized into "poor" versus "good" function, and "symptomatic" and "no or minor symptoms", respectively. The results were stratified for age and gender. RESULTS: The questionnaire was completed by 4910 (70.5%) of 6969 eligible participants. Missing values were limited. HRQL was found to vary according to age and sex. Generally, men reported better functioning and fewer symptoms than women. The most common symptoms were fatigue, pain, and insomnia. CONCLUSION: The reference values provided can be used as a surrogate baseline measure in HRQL research, and when evaluating the effect of interventions on HRQL in cancer patients.

Reference values of oesophago-gastric symptoms (EORTC QLQ-OG25) in a population-based setting.

AIM: Health-related quality of life (HRQL) has been recognised as an important outcome in clinical cancer research. A problem in HRQL studies is the lack of true baseline measures since patients already suffer from symptoms at time of diagnosis. The aim of this study is to provide valid reference values regarding symptoms common among oesophageal and gastric cancer patients, based on an unselected adult population. METHODS: In 2008 the EORTC QLQ-OG25 questionnaire was sent to randomly selected people in the adult Swedish population. Mean scores with standard deviation were calculated. Frequencies of symptoms were categorised into 'symptoms' or 'no symptoms'. The analyses were subcategorised for age groups, gender, and cancer diagnosis. RESULTS: In total, 4910 (70.5%) people responded to the questionnaire. Reflux was reported by 22.5% of the population, 25.6% reported pain and discomfort in the stomach area, 25.5% dry mouth and 32.0% had trouble with coughing. Other symptoms were dysphagia (3.5%), odynophagia (5.1%), and trouble eating with others (2.9%). Reflux, pain and discomfort and dry mouth were more often reported among women, while trouble with coughing was overrepresented among men. The symptoms dry mouth and trouble with coughing increased with age in both sexes. CONCLUSION: This comprehensive study is the first to provide reference values for the EORTC QLQ-OG25 questionnaire. These can be used as baseline surrogate in clinical research in oesophago-gastric cancer patients.