Maintenance proton pump inhibitor use and risk of colorectal cancer: a Swedish retrospective cohort study.

OBJECTIVES: We aimed to evaluate the risk of colorectal adenocarcinoma (CRA) associated with long-term use of proton pump inhibitors (PPIs) in a large nationwide cohort. DESIGN: Retrospective cohort study. SETTING: This research was conducted at the national level, encompassing the entire population of Sweden. PARTICIPANTS: This study utilised Swedish national registries to identify all adults who had ≥180 days of cumulative PPI use between July 2005 and December 2012, excluding participants who were followed up for less than 1 year. A total of 754 118 maintenance PPI users were included, with a maximum follow-up of 7.5 years. INTERVENTIONS: Maintenance PPI use (cumulative≥180 days), with a comparator of maintenance histamine-2 receptor antagonist (H2RA) use. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was the risk of CRA, presented as standardised incidence ratios (SIRs) with 95% confidence intervals (CIs). Subgroup analyses were performed to explore the impact of indications, tumour locations, tumour stages and the duration of follow-up. A multivariable Poisson regression model was fitted to estimate the incidence rate ratios (IRRs) and 95% CIs of PPI versus H2RA use. RESULTS: Maintenance PPI users exhibited a slightly elevated risk of CRA compared to the general population (SIR 1.10, 95% CI=1.06 to 1.13) for both men and women. Individuals aged 18-39 (SIR 2.79, 95% CI=1.62 to 4.47) and 40-49 (SIR 2.02, 95% CI=1.65 to 2.45) had significantly higher risks than the general population. Right-sided CRA showed a higher risk compared to the general population (SIR 1.26, 95% CI=1.20 to 1.32). There was no significant difference in the risk of CRA between maintenance PPI users and maintenance H2RA users (IRR 1.05, 95% CI=0.87 to 1.27, p<0.05). CONCLUSIONS: Maintenance PPI use may be associated with an increased risk of CRA, but a prolonged observation time is needed.

Endoscopic enhanced-view totally extraperitoneal prosthetic (eTEP) versus open Rives-Stoppa repair as a treatment of midline abdominal wall hernias with rectus diastasis: comparison of postoperative pain and length of hospital stay in a single-centre surgical cohort.

The Rives-Stoppa (RS) procedure is a gold standard treatment of midline abdominal wall hernias. Comparability of pain control and outcomes to the enhanced-view totally extraperitoneal prosthetic (eTEP) repair remain unclear. A single-centre retrospective surgical cohort was selected including 30 RS repairs (January 2019-November 2021) and 30 consecutive eTEP procedures (September 2021-August 2022) for midline abdominal wall hernia(s) with rectus abdominis diastasis. Postoperative pain and outcomes were compared up to 1 month. Presence and median duration of patient-controlled analgesia were, respectively, 90% and 3 nights with RS, versus 30% and 0 nights with eTEP. Median switch to only oral analgesics occurred at postoperative day (POD) 3 after RS and at POD 2 after eTEP. Postoperative analgesics and opioid prescription at discharge were comparable. Median length of hospital stay was six nights after RS versus 3 nights after eTEP. Median duration of surgery was 110.5 and 164.5 min for RS and eTEP, respectively. After RS, 30 patients had postoperative drain(s) compared to 3 patients after eTEP. Conversion was needed in 3 eTEP procedures. Postoperative complications were comparable. No early recurrences were observed. Minimal residual diastasis was seen at postoperative consultation in 11 patients after eTEP. Compared to RS, eTEP is a minimally invasive alternative treatment of midline abdominal wall hernias with rectus abdominis diastasis and is associated with a shorter length of hospital stay, less postoperative pain and a comparable risk of short-term complications. At 1 month after eTEP, minimal residual diastasis can be present. ClinicalTrials.gov: NCT05446675. Secondary identifying number: EC/EH/220608-SK. Date of Registration: June 24, 2022.

Accuracy and diagnostic performance of the Bethesda system for reporting thyroid cytopathology in a tertiary endocrine surgical referral center in Belgium.

BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology is a commonly used classification for fine needle aspiration (FNA) cytology of suspicious thyroid nodules. The risk of malignancy (ROM) for each category has recently been analyzed in three international databases. This paper compares the diagnostic performance of the Bethesda classification in a high-volume referral center in Belgium. METHODS: All consecutive thyroid procedures were registered in a prospective database from January 2010 till August 2022. Patient and surgical characteristics, preoperative Bethesda categories, and postoperative pathology results were analyzed. RESULTS: Out of 2219 consecutive thyroid procedures, 1226 patients underwent preoperative FNA. Papillary thyroid cancer was the most prevalent malignancy (N = 119, 70.4%), followed by follicular (N = 17, 10.1%) and medullary thyroid cancer (N = 15, 8.9%). Micropapillary thyroid cancer was incidentally found in 46 (3.8%) patients. Bethesda categories I, II, III, IV, V, and VI, respectively, represented 250 (20.4%; ROM 4.4%), 546 (44.5%; ROM 3.8%), 96 (7.8%; ROM 20.8%), 231 (18.8%; ROM 15.2%), 62 (5.1%; ROM 72.6%), and 41 (3.3%; ROM 90.2%) patients. Overall ROM was 13.8%. An negative predictive value (NPV) of 96.2% was found. Overall specificity was 64.2% with a positive predictive value (PPV) of 31.9%. Diagnostic accuracy was 67.8%. Compared to international databases (CESQIP, EUROCRINE, and UKRETS), ROM in this study appeared lower for Bethesda category IV (15.2 vs. 26.7% and p = 0.612). CONCLUSION: Despite being validated in numerous studies, ROM based on preoperative FNA cytology classified according to the Bethesda classification may vary among surgical centers and countries as this study reveals a higher NPV and lower PPV.

Clostridioides difficile recurrence in individuals with and without cancer: a Swedish population-based cohort study.

PURPOSE: Patients with cancer are vulnerable to Clostridioides difficile infection (CDI) due to their disease, treatment and regular hospital contact, yet if CDI-recurrence is more common remains unclear, and differences among cancer types remain unexplored. METHODS: This Swedish nationwide population-based cohort included all 43,150 individuals with recorded CDI (2006-2019) to assess CDI-recurrence in individuals with and without cancer, with binary multivariable logistic regression, stratified by anatomical location, and survival status. RESULTS: Compared to those without cancer (N = 29,543), ongoing cancer (diagnosis < 12 months; N = 3,882) was associated with reduced recurrence (OR = 0.81, 95% CI 0.73-0.89), while there was no association with cancer history (diagnosis ≥ 12 months; N = 9,725). There was an increased 8-week all-cause mortality (Ongoing cancer: OR = 1.58, 95% CI 1.43-1.74; Cancer history: OR = 1.45, 95% CI 1.36-1.55) compared to those without cancer. Among CDI-survivors, those with ongoing cancer presented with a decreased odds of recurrence (OR = 0.84, 95% CI 0.76-0.94), compared to those without cancer history, with no association for those with cancer history (OR = 1.04, 95% CI 0.97-1.1). Large variations were seen across cancer types, with the highest observed proportion of recurrence in oral and mesothelial cancer, and the lowest for esophageal cancer, although no statistically significant OR were found. CONCLUSION: The population-based study indicates that individuals with cancer may have fewerrecurrences than expected, yet variations by cancer type were large, and mortality was high.

Prognostic impact of lymph node characteristics after therapeutic neck dissection for classic N1 papillary thyroid cancer.

BACKGROUND: The impact of lymph node characteristics on mortality and recurrence remains controversial. This study evaluated the prognostic impact of lymph node characteristics in a large, homogenous cohort of patients with therapeutic neck dissection for clinically N1 classic papillary thyroid cancer (PTC). METHODS: All consecutive adult patients with therapeutic central and lateral neck dissection for PTC at a French referral centre were prospectively enrolled from January 2000 until June 2021. The primary outcome was the impact of lymph node characteristics in predicting a disease event (persistence or recurrence), using univariable and multivariable logistic regression modelling. RESULTS: A total of 462 patients were included. Lymph node capsular rupture was seen in 260 patients (56.3 per cent). Median maximum lymph node size was 15 (i.q.r. 9-23) mm. The median central, lateral, and total lymph node ratio (LNR) was 0.50 (i.q.r. 0.22-0.75), 0.15 (i.q.r. 0.07-0.29), and 0.26 (i.q.r. 0.14-0.41), respectively. After a median follow-up of 93 (i.q.r. 50-149) months, 182 (39.4 per cent) patients had a disease event. After multivariable analysis, the number of harvested lymph node >35 (OR 2.33 (95 per cent c.i. 1.10-4.95)), presence of lymph node capsular rupture (OR 1.92 (1.17-3.14)), and total LNR >0.20 (OR 2.37 (1.08-5.19)) and >0.40 (OR 4.92 (1.61-15.03)) predicted a disease event. An LNR of 0.20 predicted a disease event with a sensitivity of 80.8 per cent and a specificity of 50.4 per cent. CONCLUSION: Disease persistence or recurrence after thyroidectomy with therapeutic neck dissection for classic PTC with preoperative nodal disease appears to depend on number of harvested lymph node, presence of lymph node capsular rupture, and total LNR.

Combining PD-1/PD-L1 blockade with type I interferon in cancer therapy.

PD-1 and PD-L1 are crucial regulators of immunity expressed on the surface of T cells and tumour cells, respectively. Cancer cells frequently use PD-1/PD-L1 to evade immune detection; hence, blocking them exposes tumours to be attacked by activated T cells. The synergy of PD-1/PD-L1 blockade with type I interferon (IFN) can improve cancer treatment efficacy. Type I IFN activates immune cells boosts antigen presentation and controls proliferation. In addition, type I IFN increases tumour cell sensitivity to the blockade. Combining the two therapies increases tumoral T cell infiltration and activation within tumours, and stimulate the generation of memory T cells, leading to prolonged patient survival. However, limitations include heterogeneous responses, the need for biomarkers to predict and monitor outcomes, and adverse effects and toxicity. Although treatment resistance remains an obstacle, the combined therapeutic efficacy of IFNα/ß and PD-1/PD-L1 blockade demonstrated considerable benefits across a spectrum of cancer types, notably in melanoma. Overall, the phases I and II clinical trials have demonstrated safety and efficiency. In future, further investigations in clinical trials phases III and IV are essential to compare this combinatorial treatment with standard treatment and assess long-term side effects in patients.

Thyroid surgery in the elderly: a surgical cohort.

PURPOSE: The need for thyroid surgery in the elderly is rising due to an ageing population, the liberal use of imaging studies, and the increasing prevalence of thyroid nodules and cancer with age. Data on surgical outcomes in this population are scarce and conflicting, but essential to assess safety of short-stay surgery. This study aims to compare surgical outcomes by age. METHODS: All consecutive patients undergoing thyroid surgery from January 2010 to July 2021 in a large tertiary referral centre for endocrine surgery were included in this surgical cohort. The indication for surgery, surgical morbidity (hypocalcaemia, bleeding, recurrent laryngeal nerve (RLN) palsy), and length of hospital stay were assessed in three age groups (young: 18-64y, older: 65-74y, and the elderly: 75 years and older). RESULTS: A total of 2,030 patients (1,499 young, 370 older, and 161 elderly) were included. The indication for surgery was significantly different, with the main indications in the elderly being multinodular goitre (70.2% vs. 47.7% in young patients) and thyroid cancer (9.9% vs. 7.0%). Reintervention for bleeding was more often required in the older (4.6%) and the elderly (2.5%) patients (vs. 1.4%). There was no difference in the proportion of hypocalcaemia or RLN palsy. The length of hospital stay was significantly longer in the elderly (length of stay longer than one day 43.5% vs. 9.8%). CONCLUSION: Thyroid surgery in patients aged 75 years and older is a safe procedure with morbidity comparable to younger patients. However, the risk of reintervention for bleeding is higher, rendering ambulatory surgery not advisable. TRIAL REGISTRATION: Researchregistry6182 on October 29th 2020, retrospectively registered.

Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome.

The transgenerational maternal effects of polycystic ovary syndrome (PCOS) in female progeny are being revealed. As there is evidence that a male equivalent of PCOS may exists, we ask whether sons born to mothers with PCOS (PCOS-sons) transmit reproductive and metabolic phenotypes to their male progeny. Here, in a register-based cohort and a clinical case-control study, we find that PCOS-sons are more often obese and dyslipidemic. Our prenatal androgenized PCOS-like mouse model with or without diet-induced obesity confirmed that reproductive and metabolic dysfunctions in first-generation (F1) male offspring are passed down to F3. Sequencing of F1-F3 sperm reveals distinct differentially expressed (DE) small non-coding RNAs (sncRNAs) across generations in each lineage. Notably, common targets between transgenerational DEsncRNAs in mouse sperm and in PCOS-sons serum indicate similar effects of maternal hyperandrogenism, strengthening the translational relevance and highlighting a previously underappreciated risk of transmission of reproductive and metabolic dysfunction via the male germline.

The Local Tumor Microbiome Is Associated with Survival in Late-Stage Colorectal Cancer Patients.

The gut microbiome is associated with survival in colorectal cancer. Single organisms have been identified as markers of poor prognosis. However, in situ imaging of tumors demonstrate a polymicrobial tumor-associated community. To understand the role of these polymicrobial communities in survival, we conducted a nested case-control study in late-stage cancer patients undergoing resection for primary adenocarcinoma. The microbiome of paired tumor and adjacent normal tissue samples was profiled using 16S rRNA sequencing. We found a consistent difference in the microbiome between paired tumor and adjacent tissue, despite strong individual microbial identities. Furthermore, a larger difference between normal and tumor tissue was associated with prognosis: patients with shorter survival had a larger difference between normal and tumor tissue. Within the tumor tissue, we identified a 39-member community statistic associated with survival; for every log2-fold increase in this value, an individual's odds of survival increased by 20% (odds ratio survival 1.20; 95% confidence interval = 1.04 to 1.33). Our results suggest that a polymicrobial tumor-specific microbiome is associated with survival in late-stage colorectal cancer patients. IMPORTANCE Microbiome studies in colorectal cancer (CRC) have primarily focused on the role of single organisms in cancer progression. Recent work has identified specific organisms throughout the intestinal tract, which may affect survival; however, the results are inconsistent. We found differences between the tumor microbiome and the microbiome of the rest of the intestine in patients, and the magnitude of this difference was associated with survival, or, the more like a healthy gut a tumor looked, the better a patient's prognosis. Our results suggest that future microbiome-based interventions to affect survival in CRC will need to target the tumor community.

High-fat diet and estrogen modulate the gut microbiota in a sex-dependent manner in mice.

A high-fat diet can lead to gut microbiota dysbiosis, chronic intestinal inflammation, and metabolic syndrome. Notably, resulting phenotypes, such as glucose and insulin levels, colonic crypt cell proliferation, and macrophage infiltration, exhibit sex differences, and females are less affected. This is, in part, attributed to sex hormones. To investigate if there are sex differences in the microbiota and if estrogenic ligands can attenuate high-fat diet-induced dysbiosis, we used whole-genome shotgun sequencing to characterize the impact of diet, sex, and estrogenic ligands on the microbial composition of the cecal content of mice. We here report clear host sex differences along with remarkably sex-dependent responses to high-fat diet. Females, specifically, exhibited increased abundance of Blautia hansenii, and its levels correlated negatively with insulin levels in both sexes. Estrogen treatment had a modest impact on the microbiota diversity but altered a few important species in males. This included Collinsella aerofaciens F, which we show correlated with colonic macrophage infiltration. In conclusion, male and female mice exhibit clear differences in their cecal microbial composition and in how diet and estrogens impact the composition. Further, specific microbial strains are significantly correlated with metabolic parameters.

Maintenance Proton Pump Inhibitor Use Associated with Increased All-Cause and Cause-Specific Mortality in Sweden.

BACKGROUND: Proton pump inhibitor (PPI) use has increased over the last decades and has been associated with multiple adverse events and potentially even overall survival. AIMS: We aimed to investigate the association between proton pump inhibitor maintenance use and all-cause and cause-specific mortality, addressing confounding by indication and duration of use. METHODS: This Swedish population-based cohort study included all adult (N = 935,236) PPI and histamine-2 receptor antagonist maintenance users (≥ 180 days use) during 2005-2014. Standardised mortality ratios (SMRs) and 95% confidence intervals were calculated for all-cause and cause-specific mortality comparing the risk among PPI/H2RA users to that of the Swedish background population, stratified by age, sex, calendar period, indication and duration of use. Multivariable Poisson regression models were used to compare PPI use to H2RA use, expressed as incidence rate ratios and 95% confidence intervals. RESULTS: PPI and histamine-2 receptor antagonist use were associated with an increased risk of all-cause mortality (SMR = 1.35; 1.34-1.36; SMR = 1.31; 1.27-1.36, respectively). The highest SMRs were found in the youngest age groups. In direct comparison, PPI use showed a higher mortality risk than histamine-2 receptor antagonist use (incidence rate ratios = 1.42; 1.38-1.46). PPIs were related to increased cancer (SMR = 1.21; 1.20-1.22), and cardiovascular mortality (SMR = 1.36; 1.35-1.37). Increased SMRs were observed for most indications. Longer duration of use was associated with a higher mortality among PPI users but not among histamine-2 receptor antagonist users. CONCLUSION: Maintenance PPI use was associated with an increased risk of all-cause and cause-specific mortality, and the risk increased with prolonged duration.

Cohort profile: the Swedish Maternal Microbiome project (SweMaMi) - assessing the dynamic associations between the microbiome and maternal and neonatal adverse events.

PURPOSE: The Swedish Maternal Microbiome (SweMaMi) project was initiated to better understand the dynamics of the microbiome in pregnancy, with longitudinal microbiome sampling, shotgun metagenomics, extensive questionnaires and health registry linkage. PARTICIPANTS: Pregnant women were recruited before the 20th gestational week during 2017-2021 in Sweden. In total, 5439 pregnancies (5193 unique women) were included. For 3973 pregnancies (73%), samples were provided at baseline, and for 3141 (58%) at all three timepoints (second and third trimester and postpartum). In total, 38 591 maternal microbiome samples (vaginal, faecal and saliva) and 3109 infant faecal samples were collected. Questionnaires were used to collect information on general, reproductive and mental health, diet and lifestyle, complemented by linkage to the nationwide health registries, also used to follow up the health of the offspring (up to age 10). FINDINGS TO DATE: The cohort is fairly representative for the total Swedish pregnant population (data from 2019), with 41% first-time mothers. Women with university level education, born in Sweden, with normal body mass index, not using tobacco-products and aged 30-34 years were slightly over-represented. FUTURE PLANS: The sample and data collection were finalised in November 2021. The next steps are the characterisation of the microbial DNA and linkage to the health and demographic information from the questionnaires and registries. The role of the microbiome on maternal and neonatal outcomes and early-childhood diseases will be explored (including preterm birth, miscarriage) and the role and interaction of other risk factors and confounders (including endometriosis, polycystic ovarian syndrome, diet, drug use). This is currently among the largest pregnancy cohorts in the world with longitudinal design and detailed and standardised microbiome sampling enabling follow-up of both mothers and children. The findings are expected to contribute greatly to the field of reproductive health focusing on pregnancy and neonatal outcomes.

Long-term outcome of surgical techniques for sporadic primary hyperparathyroidism in a tertiary referral center in Belgium.

PURPOSE: Surgery remains the only permanent treatment option for primary hyperparathyroidism (pHPT). To date, the number of long-term outcome studies of parathyroidectomy is limited. This study aims to compare different surgical approaches and evaluate the importance of preoperative localization imaging in the treatment of pHPT. METHODS: All 200 consecutive patients with a parathyroidectomy for sporadic pHPT without planned concomitant surgery between 09/2009 and 04/2021 in a Belgian tertiary referral hospital were enrolled. All patients underwent at least two preoperative localization imaging studies (neck ultrasound, CT, SPECT, and/or Sestamibi scintigraphy) of the parathyroid glands. The main outcomes were the (long-term) cured proportion and postoperative morbidity (hypocalcemia, recurrent laryngeal nerve palsy, return to theater for bleeding, and wound morbidity). RESULTS: Most patients were referred with concordant positive imaging (82%, n = 164). Only nine patients (4.5%) had double negative imaging, not revealing a possible adenoma. The remaining 27 (13.5%) were referred with discordant imaging. Parathyroidectomy was performed via traditional cervicotomy (30%), mini-open approach (39.5%), or endoscopic approach (30.5%). Morbidity was low with no persistent hypocalcemia, one return to theater for bleeding, and no 30-day mortality. In the concordant imaging population, 13 patients (8%) had multiglandular disease. Overall, 97.5% was considered cured. Long-term recurrence was 12% with a minimal follow-up of 5 years. CONCLUSION: This consecutive, single-surgeon, single-center cohort with extensive data collection and long-term follow-up confirms the safety and excellent cured proportions of minimally invasive parathyroidectomy. Disease recurrence becomes more important long after surgery.

Feasibility and Safety of Ambulatory Transoral Endoscopic Thyroidectomy via Vestibular Approach (TOETVA).

BACKGROUND: In search of an ideal cosmesis, transoral endoscopic thyroidectomy via vestibular approach (TOETVA) has recently been introduced to avoid a visible scar. Although ambulatory thyroid surgery is considered safe in carefully selected patients, this remains unclear for TOETVA. METHODS: All consecutive adult patients who underwent ambulatory TOETVA or open thyroid surgery at a French university hospital were prospectively enrolled from 12/2020 until 11/2021. The primary outcome was postoperative morbidity (recurrent laryngeal nerve (RLN) palsy, re-intervention for bleeding, wound morbidity, or hospital readmission). The secondary outcome was quality of life (QoL), measured by a survey including a validated questionnaire (SF-12) and a modified thyroid surgery questionnaire six weeks after surgery. RESULTS: Throughout the study period, 374 patients underwent a unilateral lobectomy or isthmectomy in ambulatory setting, of which 34 (9%) as TOETVA (including 21 (62%) for a possible malignancy). In the TOETVA group, younger age (median 40 (IQR 35-50) vs. 51 (40-60) years, P < 0.001) and lower BMI (median 23.1 (20.9-25.4) vs. 24.9 (22.1-28.9) kg/m2, P = 0.001) were noted. No cases were converted to open cervicotomy. TOETVA was at least as good as open cervicotomy with nil versus four (1%) re-interventions for bleeding, one temporary (5%) versus 13 (4%) (temporary) RLN palsies, and one (<1%) wound infection (open cervicotomy group). No hospital readmissions occurred in all ambulatory surgery patients. No differences were found in physical (P = 0.280) and mental (P = 0.569) QoL between TOETVA and open surgery. CONCLUSIONS: In carefully selected patients, the feasibility and safety of ambulatory TOETVA are comparable to open surgery.

Association between menopausal hormone therapy use and mortality risk: a Swedish population-based matched cohort study.

BACKGROUND: The net effect of menopausal hormone therapy on the risk of death is understudied, and current evidence is conflicting. Our aim was to investigate the association between menopausal hormones and risk of all-cause, cardiovascular, and cancer-specific mortality, based on the Swedish Prescribed Drug Registry and National Patient Registry. METHODS: This Swedish population-based matched cohort study included all women, 40 years or older, who had received at least one prescription of systemic menopausal hormone therapy between 2005-2014 (n = 290,186), group level matched 1:3 to non-users (n = 870,165). Multivariable conditional logistic regression models estimated the relative risk of all-cause and cause-specific mortality, adjusting for several clinical factors and comorbidities. RESULTS: Ever-use of menopausal hormones was associated with a slightly lower overall odds of all-cause (OR = 0.97, 95%CI 0.95-0.98) and cardiovascular (OR = 0.97, 95%CI 0.95-0.99) mortality, whilst 30% lower overall odds of cancer-related mortality (OR = 0.70, 95%CI 0.68-0.72) was shown. The odds of all-cause and cancer-related mortality were consistently reduced among women who began menopausal hormone therapy ≤60 years, whereas the association with cardiovascular mortality was inconsistent. In contrast, oestrogen-only therapy was associated with elevated odds of all-cause (OR = 1.14, 95%CI 1.11-1.16) and cardiovascular mortality (OR = 1.04, 95%CI 1.01-1.06) among women who began treatment at ≥70 years. Among current users, oestrogen-only therapy was associated with higher odds of all-cause (OR = 1.48, 95%CI 1.44-1.52) and cardiovascular mortality (OR = 1.24, 95%CI 1.20-1.28), whereas past use of oestrogen-only therapy suggested lower odds of mortality. CONCLUSIONS: Our generalisable data suggest that early menopausal hormone treatment initiation does not increase the odds of mortality. However, the role of oestrogens in particularly cardiovascular mortality remains to be investigated.

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.

Long-term survival of metastatic small intestine neuroendocrine tumors: a meta-analysis.

This meta-analysis aims to evaluate the long-term survival and prognostic factors in patients with metastatic small intestine neuroendocrine tumors (siNETs). Patients with siNETs usually present with advanced disease, limiting curative treatment options. The overall survival seems favorable compared to other cancers, but differences in terminology, lack of consistent coding, conflicting results from smaller cohorts, and recent developments of new treatment options make (reliable) survival data difficult to achieve. Nevertheless, accurate survival data are essential for many facets of health care. A systematic literature search was performed using MEDLINE®(PubMed), EMBASE®, Web of Science, and Cochrane Library up to June 30, 2021. Studies were included if the overall survival data in patients with metastatic siNETs were reported. The results were pooled in a random-effects meta-analysis and are reported as hazard ratios and 95% CIs. Subgroup analyses and meta-regression were performed to assess the observed heterogeneity and the impact of important prognostic factors. After screening 9065 abstracts, there were 23 studies, published between 1995 and 2021, that met the inclusion criteria, with a total of 8636 patients. The weighted 5- and 10-year overall survival was 67 and 37%, respectively. Meta-regression identified younger age and primary tumor resection to be associated with better prognosis. Subgroup analyses showed similar results. This study confirms that in an advanced, metastatic setting, the weighted 5- and 10-year overall survival reveal a favorable prognosis, improving over the last few decades. Meta-regression showed that age at diagnosis is an important prognostic factor.

Aspirin, Statins, Non-aspirin NSAIDs, Metformin, and the Risk of Biliary Cancer: A Swedish Population-Based Cohort Study.

BACKGROUND: Chemoprevention for biliary tract cancers (BTC), which comprise intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), and gallbladder cancer, is controversial. We examined associations between low-dose aspirin, statins, NSAIDs, and metformin with BTC risk. METHODS: We used a population-based cohort of 5.7 million persons over age 18 without personal history of cancer (except nonmelanoma skin cancer), receiving at least one commonly prescribed drug between July 1, 2005, and December 31, 2012, from the Swedish Prescribed Drug Registry. Hazard ratios (HR) were calculated using age-scaled multivariable-adjusted Cox models. RESULTS: 2,160 individuals developed BTC. Low-dose aspirin was not associated with BTC risk [HR, 0.93; 95% confidence interval (CI), 0.81-1.07], iCCA (HR, 1.21; 95% CI, 0.93-1.57), eCCA (HR, 0.80; 95% CI, 0.60-1.07), or gallbladder cancer (HR, 0.87; 95% CI, 0.71-1.06). Statins were associated with lower risk of BTC (HR, 0.66; 95% CI, 0.56-0.78), iCCA (HR, 0.69; 95% CI, 0.50-0.95), eCCA (HR 0.54; 95% CI, 0.38-0.76), and gallbladder cancer (HR, 0.72; 95% CI, 0.57-0.91). For all BTC subtypes, combined low-dose aspirin and statins were not associated with lower risk than statins alone. NSAIDs were associated with higher risk of BTC and its subtypes. Metformin was not associated with BTC risk (HR, 0.98; 95% CI, 0.82-1.18), iCCA (HR, 1.06; 95% CI, 0.77-1.48), eCCA (HR, 1.15; 95% CI, 0.82-1.61), or gallbladder cancer (HR, 0.84; 95% CI, 0.63-1.11). CONCLUSIONS: Statins were associated with a decreased risk of BTC and its subtypes. Low-dose aspirin alone was not associated with a decreased risk, and use of both was not associated with further decrease in risk beyond statins alone. IMPACT: Statins were most consistently associated with a decreased risk of BTC and its subtypes.

Effect of primary tumour resection without curative intent in patients with metastatic neuroendocrine tumours of the small intestine and right colon: meta-analysis.

BACKGROUND: Patients with small intestinal neuroendocrine tumours (siNETs) usually present with advanced disease. Primary tumour resection without curative intent is controversial in patients with metastatic siNETs. The aim of this meta-analysis was to investigate survival after primary tumour resection without curative intent compared with no resection in patients with metastatic siNETs. METHODS: A systematic literature search was performed, using MEDLINE® (PubMed), Embase®, Web of Science, and the Cochrane Library up to 25 February 2021. Studies were included if survival after primary tumour resection versus no resection in patients with metastatic siNETs was reported. Results were pooled in a random-effects meta-analysis, and are reported as hazard ratios (HRs) with 95 per cent confidence intervals. Sensitivity analyses were undertaken to enable comment on the impact of important confounders. RESULTS: After screening 3659 abstracts, 16 studies, published between 1992 and 2021, met the inclusion criteria, with a total of 9428 patients. Thirteen studies reported HRs adjusted for important confounders and were included in the meta-analysis. Median overall survival was 112 (i.q.r. 82-134) months in the primary tumour resection group compared with 60 (74-88) months in the group without resection. Five-year overall survival rates were 74 (i.q.r. 67-77) and 44 (34-45) per cent respectively. Primary tumour resection was associated with improved survival compared with no resection (HR 0.55, 95 per cent c.i. 0.47 to 0.66). This effect remained in sensitivity analyses. CONCLUSION: Primary tumour resection is associated with increased survival in patients with advanced, metastatic siNETs, even after adjusting for important confounders.

Association between proton-pump inhibitors and the risk of gastric cancer: a systematic review with meta-analysis.

INTRODUCTION: The use of proton-pump inhibitors (PPI) may be associated with an increased risk of gastric cancer (GC). OBJECTIVE: To review and meta-analyse available literature investigating the association between PPI use and GC risk. METHODS: Two independent reviewers systematically searched Ovid MEDLINE, EMBASE, and Cochrane Library (inception to July 2020) for case-control and cohort studies assessing the association between PPI use and GC according to a predefined protocol in PROSPERO (CRD42018102536). Reviewers independently assessed study quality, extracted data, and meta-analysed available and newly calculated odds ratios (ORs) using a random-effects model, and stratified for GC site (cardia versus non-cardia) and PPI duration (<1 year, 1-3 years, >3 years). RESULTS: We screened 2,396 records and included five retrospective cohort and eight case-control studies comprising 1,662,881 individuals in our meta-analysis. In random-effect models, we found an increased GC risk in PPI users [OR: 1.94, 95% confidence interval (95% CI): 1.47-2.56] with high statistical heterogeneity (I 2 = 82%) and overall moderate risk of bias. Stratified analyses indicated a significant risk increase in non-cardia (OR: 2.20, 95% CI: 1.44-3.36, I 2 = 77%) with a similar non-significant trend in cardia regions (OR: 1.77, 95% CI: 0.72-4.36, I 2 = 66%). There was no GC increase with longer durations of PPI exposure (<1 year: OR: 2.29, 95% CI: 2.13-2.47, I 2 = 0%; 1-3 years: OR: 1.46, 95% CI: 0.53-4.01, I 2 = 35%; >3 years: OR: 2.08, 95% CI: 0.56-7.77, I 2 = 61%). CONCLUSION: We found a twofold increased GC risk among PPI users, but this association does not confirm causation and studies are highly heterogeneous. PPI should only be prescribed when strictly indicated.