Staging accuracy in patients with clinical T2N0 gastric cancer: Implications for treatment sequencing.

BACKGROUND: Patients with clinical T2N0 (cT2N0) gastric adenocarcinoma are recommended to undergo either perioperative chemotherapy or upfront resection. If T2N0 disease is pathologically confirmed, patients may be observed without chemotherapy. These guidelines create the possibility of both systemic therapy overuse and underuse depending on clinical staging accuracy. Our objectives were to define factors associated with upstaging after upfront resection and describe the association between postoperative chemotherapy and survival. METHODS: Patients with cT2N0 gastric adenocarcinoma were identified using the National Cancer Database. Factors associated with upstaging were assessed by logistic regression. Survival was assessed using Kaplan-Meier and Cox proportional hazard analyses. RESULTS: Of 4,076 patients undergoing upfront resection for cT2N0 gastric cancer, 1,933 (47.4%) were pathologically upstaged. Patients were more likely to be upstaged if they had >3.0-cm (adjusted odds ratio [aOR] 2.31, 95% confidence interval [CI] 1.97-2.70; P < .001) or poorly differentiated tumors (aOR 2.22, 95% CI 1.89-2.60; P < .001). Patients were less likely to be upstaged if they had distal tumors (aOR 0.77, 95% CI 0.64-0.93; P = .006). Of those pathologically upstaged (n = 1,933), 1,111 (57.4%) received adjuvant chemotherapy that was associated with improved survival (HR 0.55, 95% CI 0.47-0.63; P < .001). Among those not upstaged (n = 2,143), 247 (11.5%) received adjuvant chemotherapy that was not associated with improved survival (HR 0.92, 95% CI 0.70-1.21; P = .54). CONCLUSIONS: Pathologic upstaging after upfront resection in patients with cT2N0 gastric cancer is associated with patient and tumor characteristics. Adjuvant chemotherapy is associated with improved survival only in the patients upstaged at surgery. An upfront surgical approach may be preferred in select patients, especially if avoiding chemotherapy is desired.

Spatial transcriptomic analysis of primary and metastatic pancreatic cancers highlights tumor microenvironmental heterogeneity.

Although the spatial, cellular and molecular landscapes of resected pancreatic ductal adenocarcinoma (PDAC) are well documented, the characteristics of its metastatic ecology remain elusive. By applying spatially resolved transcriptomics to matched primary and metastatic PDAC samples, we discovered a conserved continuum of fibrotic, metabolic and immunosuppressive spatial ecotypes across anatomical regions. We observed spatial tumor microenvironment heterogeneity spanning beyond that previously appreciated in PDAC. Through comparative analysis, we show that the spatial ecotypes exhibit distinct enrichment between primary and metastatic sites, implying adaptability to the local environment for survival and progression. The invasive border ecotype exhibits both pro-tumorigenic and anti-tumorigenic cell-type enrichment, suggesting a potential immunotherapy target. The ecotype heterogeneity across patients emphasizes the need to map individual patient landscapes to develop personalized treatment strategies. Collectively, our findings provide critical insights into metastatic PDAC biology and serve as a valuable resource for future therapeutic exploration and molecular investigations.

Surgical Outcome After Distal Pancreatectomy With and Without Portomesenteric Venous Resection in Patients with Pancreatic Adenocarcinoma: A Transatlantic Evaluation of Patients in North America, Germany, Sweden, and The Netherlands (GAPASURG).

BACKGROUND: Pancreatic adenocarcinoma located in the pancreatic body might require a portomesenteric venous resection (PVR), but data regarding surgical risks after distal pancreatectomy (DP) with PVR are sparse. Insight into additional surgical risks of DP-PVR could support preoperative counseling and intraoperative decision making. This study aimed to provide insight into the surgical outcome of DP-PVR, including its potential risk elevation over standard DP. METHODS: We conducted a retrospective, multicenter study including all patients with pancreatic adenocarcinoma who underwent DP ± PVR (2018-2020), registered in four audits for pancreatic surgery from North America, Germany, Sweden, and The Netherlands. Patients who underwent concomitant arterial and/or multivisceral resection(s) were excluded. Predictors for in-hospital/30-day major morbidity and mortality were investigated by logistic regression, correcting for each audit. RESULTS: Overall, 2924 patients after DP were included, of whom 241 patients (8.2%) underwent DP-PVR. Rates of major morbidity (24% vs. 18%; p = 0.024) and post-pancreatectomy hemorrhage grade B/C (10% vs. 3%; p = 0.041) were higher after DP-PVR compared with standard DP. Mortality after DP-PVR and standard DP did not differ significantly (2% vs. 1%; p = 0.542). Predictors for major morbidity were PVR (odds ratio [OR] 1.500, 95% confidence interval [CI] 1.086-2.071) and conversion from minimally invasive to open surgery (OR 1.420, 95% CI 1.032-1.970). Predictors for mortality were higher age (OR 1.087, 95% CI 1.045-1.132), chronic obstructive pulmonary disease (OR 4.167, 95% CI 1.852-9.374), and conversion from minimally invasive to open surgery (OR 2.919, 95% CI 1.197-7.118), whereas concomitant PVR was not associated with mortality. CONCLUSIONS: PVR during DP for pancreatic adenocarcinoma in the pancreatic body is associated with increased morbidity, but can be performed safely in terms of mortality.

The Five Periampullary Cancers, not Just Different Siblings but Different Families: An International Multicenter Cohort Study.

BACKGROUND: Cancer arising in the periampullary region can be anatomically classified in pancreatic ductal adenocarcinoma (PDAC), distal cholangiocarcinoma (dCCA), duodenal adenocarcinoma (DAC), and ampullary carcinoma. Based on histopathology, ampullary carcinoma is currently subdivided in intestinal (AmpIT), pancreatobiliary (AmpPB), and mixed subtypes. Despite close anatomical resemblance, it is unclear how ampullary subtypes relate to the remaining periampullary cancers in tumor characteristics and behavior. METHODS: This international cohort study included patients after curative intent resection for periampullary cancer retrieved from 44 centers (from Europe, United States, Asia, Australia, and Canada) between 2010 and 2021. Preoperative CA19-9, pathology outcomes and 8-year overall survival were compared between DAC, AmpIT, AmpPB, dCCA, and PDAC. RESULTS: Overall, 3809 patients were analyzed, including 348 DAC, 774 AmpIT, 848 AmpPB, 1,036 dCCA, and 803 PDAC. The highest 8-year overall survival was found in patients with AmpIT and DAC (49.8% and 47.9%), followed by AmpPB (34.9%, P < 0.001), dCCA (26.4%, P = 0.020), and finally PDAC (12.9%, P < 0.001). A better survival was correlated with lower CA19-9 levels but not with tumor size, as DAC lesions showed the largest size. CONCLUSIONS: Despite close anatomic relations of the five periampullary cancers, this study revealed differences in preoperative blood markers, pathology, and long-term survival. More tumor characteristics are shared between DAC and AmpIT and between AmpPB and dCCA than between the two ampullary subtypes. Instead of using collective definitions for "periampullary cancers" or anatomical classification, this study emphasizes the importance of individual evaluation of each histopathological subtype with the ampullary subtypes as individual entities in future studies.

Pathological Complete Response in Patients With Resected Pancreatic Adenocarcinoma After Preoperative Chemotherapy.

Importance: Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma, leading to pathological complete response (pCR) in a small subset of patients. However, multicenter studies with in-depth data about pCR are lacking. Objective: To investigate the incidence, outcome, and risk factors of pCR after preoperative chemo(radio)therapy. Design, Setting, and Participants: This observational, international, multicenter cohort study assessed all consecutive patients with pathology-proven localized pancreatic adenocarcinoma who underwent resection after 2 or more cycles of chemotherapy (with or without radiotherapy) in 19 centers from 8 countries (January 1, 2010, to December 31, 2018). Data collection was performed from February 1, 2020, to April 30, 2022, and analyses from January 1, 2022, to December 31, 2023. Median follow-up was 19 months. Exposures: Preoperative chemotherapy (with or without radiotherapy) followed by resection. Main Outcomes and Measures: The incidence of pCR (defined as absence of vital tumor cells in the sampled pancreas specimen after resection), its association with OS from surgery, and factors associated with pCR. Factors associated with overall survival (OS) and pCR were investigated with Cox proportional hazards and logistic regression models, respectively. Results: Overall, 1758 patients (mean [SD] age, 64 [9] years; 879 [50.0%] male) were studied. The rate of pCR was 4.8% (n = 85), and pCR was associated with OS (hazard ratio, 0.46; 95% CI, 0.26-0.83). The 1-, 3-, and 5-year OS rates were 95%, 82%, and 63% in patients with pCR vs 80%, 46%, and 30% in patients without pCR, respectively (P < .001). Factors associated with pCR included preoperative multiagent chemotherapy other than (m)FOLFIRINOX ([modified] leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) (odds ratio [OR], 0.48; 95% CI, 0.26-0.87), preoperative conventional radiotherapy (OR, 2.03; 95% CI, 1.00-4.10), preoperative stereotactic body radiotherapy (OR, 8.91; 95% CI, 4.17-19.05), radiologic response (OR, 13.00; 95% CI, 7.02-24.08), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76; 95% CI, 1.79-7.89). Conclusions and Relevance: This international, retrospective cohort study found that pCR occurred in 4.8% of patients with resected localized pancreatic adenocarcinoma after preoperative chemo(radio)therapy. Although pCR does not reflect cure, it is associated with improved OS, with a doubled 5-year OS of 63% compared with 30% in patients without pCR. Factors associated with pCR related to preoperative chemo(radio)therapy regimens and anatomical and biological disease response features may have implications for treatment strategies that require validation in prospective studies because they may not universally apply to all patients with pancreatic adenocarcinoma.

Total Pancreatectomy with Percutaneous Islet Autotransplant after Remote Islet Processing: A Viable Paradigm?

OBJECTIVES: Total pancreatectomy with islet autotransplant (TPIAT) is important therapy for select chronic pancreatitis (CP) patients. The specialized technique of islet isolation limits widespread TPIAT use. We hypothesized that remote islet isolation provides satisfactory islet yield and perioperative outcomes. METHODS: Retrospective review of TPIAT patients between 2020 and 2022. Islet isolation was performed off-site, with percutaneous intraportal islet autotransplant (IAT) completed the morning following pancreatectomy. Demographics and perioperative outcomes were analyzed. RESULTS: Fourteen patients underwent TPIAT; median age was 43 [interquartile range 12.5] years. Operation occurred 7.5 [14.8] years after pancreatitis diagnosis. The most common pancreatitis etiology was genetic (50%). All patients underwent preoperative endoscopic therapy; three underwent prior pancreatectomy. Operative time was 236 [51] minutes; subsequent percutaneous IAT time was 87 [35] minutes. The islet equivalent (IEQ)/kilogram (kg) yield was 3,456 [3,815] IEQ/kg. Nine patients had positive islet cultures. Two thromboembolic events and one bacteremia occurred. One perihepatic hematoma occurred after percutaneous portal venous access. Median postoperative length of stay was 14.5 days, and five patients (36%) were readmitted within 90 days. All patients were discharged home on insulin. No mortality occurred. CONCLUSION: Total pancreatectomy with remote islet isolation provides excellent islet yield for autotransplant and satisfactory perioperative outcomes.

The road to tailored adjuvant chemotherapy for all four non-pancreatic periampullary cancers: An international multimethod cohort study.

BACKGROUND: Despite differences in tumour behaviour and characteristics between duodenal adenocarcinoma (DAC), the intestinal (AmpIT) and pancreatobiliary (AmpPB) subtype of ampullary adenocarcinoma and distal cholangiocarcinoma (dCCA), the effect of adjuvant chemotherapy (ACT) on these cancers, as well as the optimal ACT regimen, has not been comprehensively assessed. This study aims to assess the influence of tailored ACT on DAC, dCCA, AmpIT, and AmpPB. PATIENTS AND METHODS: Patients after pancreatoduodenectomy for non-pancreatic periampullary adenocarcinoma were identified and collected from 36 tertiary centres between 2010 - 2021. Per non-pancreatic periampullary tumour type, the effect of adjuvant chemotherapy and the main relevant regimens of adjuvant chemotherapy were compared. The primary outcome was overall survival (OS). RESULTS: The study included a total of 2866 patients with DAC (n = 330), AmpIT (n = 765), AmpPB (n = 819), and dCCA (n = 952). Among them, 1329 received ACT, and 1537 did not. ACT was associated with significant improvement in OS for AmpPB (P = 0.004) and dCCA (P < 0.001). Moreover, for patients with dCCA, capecitabine mono ACT provided the greatest OS benefit compared to gemcitabine (P = 0.004) and gemcitabine - cisplatin (P = 0.001). For patients with AmpPB, no superior ACT regime was found (P > 0.226). ACT was not associated with improved OS for DAC and AmpIT (P = 0.113 and P = 0.445, respectively). DISCUSSION: Patients with resected AmpPB and dCCA appear to benefit from ACT. While the optimal ACT for AmpPB remains undetermined, it appears that dCCA shows the most favourable response to capecitabine monotherapy. Tailored adjuvant treatments are essential for enhancing prognosis across all four non-pancreatic periampullary adenocarcinomas.

Evaluating the safety and efficacy of a novel polysaccharide hemostatic system during surgery: A multicenter multispecialty prospective randomized controlled trial.

Background: Operative blood loss is associated with postoperative morbidity and mortality in surgery. Hemostatic agents are used as adjuncts for hemostasis during surgery and help to prevent postoperative bleeding. We evaluated the safety and efficacy of an investigational polysaccharide hemostatic (PH) topical product compared to a U.S. Food and Drug Administration (FDA)-approved control in clinical use comprising microporous polysaccharide hemospheres (MPH) to achieve hemostasis of bleeding surfaces during surgery. Study design: This prospective multicenter trial enrolled patients undergoing open elective cardiac, general, or urologic surgery. Patients were stratified by bleeding severity and therapeutic area, then randomized 1:1 to receive PH or MPH. Bleeding assessments occurred intraoperatively using a novel bleeding assessment methodology. Primary endpoint was noninferiority as compared with control via effective hemostasis at 7 min. Patients were monitored and followed daily in the postoperative period until time of discharge and again at 6 weeks. Overall survival was assessed in oncology patients at 24 months. Safety of PH vs. MPH was determined by comparing relative incidence of adverse events. Results: Across 19 centers, 324 (161 PH, 163 MPH) patients were randomized (48 % general surgery, 27 % cardiac surgery, and 25 % urologic surgery). PH was noninferior to MPH and met the primary endpoint of hemostatic success at 7 min at a non-inferiority margin of 10 %. No significant differences were found in adverse event rates. Six deaths were reported within the 6-week follow-up period. No difference in overall survival was observed at 2 years (76 % PH vs. 74 % MPH, P = .66) for patients undergoing cancer operations. Conclusion: Across three therapeutic areas, PH was noninferior to MPH at all hemostasis assessment time points with no safety concerns. PH is an effective alternative to MPH for hemostasis during surgery.ClinicalTrials.gov Identifier: NCT02359994.

Uterus and cervix anatomical changes and cervix stiffness evolution throughout pregnancy.

The coordinated biomechanical performance, such as uterine stretch and cervical barrier function, within maternal reproductive tissues facilitates healthy human pregnancy and birth. Quantifying normal biomechanical function and detecting potentially detrimental biomechanical dysfunction (e.g., cervical insufficiency, uterine overdistention, premature rupture of membranes) is difficult, largely due to minimal data on the shape and size of maternal anatomy and material properties of tissue across gestation. This study quantitates key structural features of human pregnancy to fill this knowledge gap and facilitate three-dimensional modeling for biomechanical pregnancy simulations to deeply explore pregnancy and childbirth. These measurements include the longitudinal assessment of uterine and cervical dimensions, fetal weight, and cervical stiffness in 47 low-risk pregnancies at four time points during gestation (late first, middle second, late second, and middle third trimesters). The uterine and cervical size were measured via 2-dimensional ultrasound, and cervical stiffness was measured via cervical aspiration. Trends in uterine and cervical measurements were assessed as time-course slopes across pregnancy and between gestational time points, accounting for specific participants. Patient-specific computational solid models of the uterus and cervix, generated from the ultrasonic measurements, were used to estimate deformed uterocervical volume. Results show that for this low-risk cohort, the uterus grows fastest in the inferior-superior direction from the late first to middle second trimester and fastest in the anterior-posterior and left-right direction between the middle and late second trimester. Contemporaneously, the cervix softens and shortens. It softens fastest from the late first to the middle second trimester and shortens fastest between the late second and middle third trimester. Alongside the fetal weight estimated from ultrasonic measurements, this work presents holistic maternal and fetal patient-specific biomechanical measurements across gestation.

Prenatal aneuploidy screening in a low-risk Hispanic population: price elasticity and cost-effectiveness.

BACKGROUND: In October 2015, the Massachusetts Medicaid program temporarily stopped reimbursement for procedures in which the International Classification of Diseases, Tenth Edition, code for serum aneuploidy screening used by certain communities was stipulated. This change led to a substantial number of patients who went without aneuploidy screening for approximately 3 years. OBJECTIVE: This study aimed to determine the change in use and cost-effectiveness of prenatal aneuploidy serum screening in a low-risk Hispanic Medicaid population in Massachusetts. STUDY DESIGN: We conducted a retrospective chart review of Spanish-speaking pregnant patients younger than 35 years of age who underwent aneuploidy serum screening at a Massachusetts community health center. The study compared the aneuploidy serum screening rates for the periods before and after May 2016 when the Massachusetts Medicaid program, MassHealth, temporarily discontinued reimbursement for the screening. Based on these rates, we developed a Markov cohort simulation model to assess the economic value of reimbursed aneuploidy screening vs nonreimbursed or limited screening. Clinical outcomes included trisomy 21, live births, and therapeutic abortions for a trisomy 21 diagnosis. Economic outcomes included discounted quality-adjusted life years and lifetime medical costs, net health benefit, and incremental cost-effectiveness ratios. RESULTS: Before the MassHealth policy change, 69% (55/80) of pregnant individuals selected quad or sequential screens in comparison with only 9% (10/112) who selected screens after the policy change. Traditional aneuploidy serum screening in a low-risk (aged <35 years) Hispanic population was considered to be cost-saving (ie, led to lower incremental costs and higher incremental benefits when compared with nonreimbursed or limited screening). CONCLUSION: From a United States healthcare payer perspective, aneuploidy serum screening for Hispanic pregnant individuals under 35 years of age is economically advantageous when compared with limited screening.

Contemporary Outcomes of Transduodenal Sphincteroplasty: the Importance of Surgical Quality.

BACKGROUND: Sphincter of Oddi dysfunction (SOD) is managed primarily by endoscopic sphincterotomy (ES); however, surgical transduodenal sphincteroplasty (TDS) is a treatment option for select patients. In our high-volume pancreatico-biliary practice, we have observed variable outcomes among TDS patients; therefore, we sought to determine preoperative predictors of durable improvement in quality of life. METHODS: SOD patients treated by TDS between January 2006 and December 2015 were studied. The primary outcome measure was long-term changes in quality of life after sphincteroplasty. The secondary outcome measure examined postoperative outcomes, including postoperative complications, need for repeat procedures, and readmission rates. Perioperative data were abstracted, and the SF-36 quality-of-life (QoL) survey was administered. Standard statistical analysis included non-parametric methods to examine bivariate associations. RESULTS: Eighty-eight patients had an average follow-up duration of 6.7 (± 2.9) years. Thirty (34%) patients were naïve to endoscopic therapy. Patients with prior endoscopy averaged 2.1 procedures (range 1 to 13) prior to surgery. Perioperative morbidity was 27%; one postoperative death was caused by severe acute pancreatitis. Twenty-nine (33%) patients required subsequent biliary-pancreatic procedures. QoL analysis from available patients showed that 66% were improved or much improved. With multivariable analysis including SOD type and prior endoscopic instrumentation, freedom from surgical complication was the only variable that correlated significantly with a good outcome (p < 0.02). CONCLUSION: Surgical transduodenal sphincteroplasty provides durable symptom management for select patients with sphincter of Oddi dysfunction. Minimizing surgical complications optimizes long-term outcomes.

Do Weekend Discharges Impact Readmission Rate in Patients Undergoing Pancreatic Surgery?

BACKGROUND: Weekend readmissions have been previously associated with increased mortality after pancreatic resection, but the effect of weekend discharge is less understood. In this study, we aim to determine the impact of weekend discharges on 30-day readmission rate after pancreatic surgery. METHODS: All patients who underwent pancreatic surgery at a single, high-volume institution between 2013 and 2021 were retrospectively reviewed from a targeted, institutional ACS-NSQIP database. Patients who died prior to discharge were excluded. Multivariable logistic regression was used to assess the relationship between readmission and weekend discharge. RESULTS: Out of 2042 patients who underwent pancreatectomy, 418 patients (20.5%) were discharged on the weekend. Weekend discharge was associated with fewer Whipple surgeries, fewer open surgical approaches, and shorter operative time. Patients discharged on the weekend were also less likely to have had postoperative complications such as delayed gastric emptying (DGE) (6.7% vs 12.6%, p < 0.01) and were more frequently discharged to home (91.1% vs. 85.3%, p < 0.01). Thirty-day readmission rate was almost identical between groups (14.8% vs 14.8%, p = 0.997). On multivariable analysis, 30-day readmission was independently associated with DGE (OR (95% CI): 3.48 (2.31-5.23), p < 0.01), postoperative pancreatic fistula (3.36 (2.34-4.83), p < 0.01), myocardial infarction, and perioperative blood transfusion, but not weekend discharge (1.02 (0.72-1.43), p = 0.93). Readmission rate also did not differ significantly when including Friday discharges in the weekend group (15.2% vs 14.6%, p = 0.72). CONCLUSIONS: With careful clinical decision making, patients may safely be discharged on the weekend after pancreatic surgery without increasing 30-day readmission rate.

Cerclage prevents ascending intrauterine infection in pregnant mice.

BACKGROUND: The treatment for cervical insufficiency is cerclage surgery. Although cerclage is a common therapy for prevention of preterm birth, there is no consensus about its mechanism of efficacy. Previous investigators have hypothesized that cerclage prevents preterm birth by improving the cervical barrier to ascending infection. However, this hypothesis is difficult to study in human pregnancy. OBJECTIVE: In a mouse model of ascending infection, we hypothesized that a cerclage improves the cervical barrier leading to decreased ascending intrauterine infection and inflammation. An abdominal cerclage was studied because a vaginal cerclage is not feasible in mice. STUDY DESIGN: To perform an abdominal cerclage, laparotomy was performed on timed, pregnant C57BL/6 mice on gestational day 10 (E10). A 6-0 silk suture was placed around the cervix just below the junction of the 2 uterine horns. Sham controls received the same surgery, but no cerclage was placed. To track ascending infection nonpathogenic E coli K12 was genetically modified to express bioluminescence. On E15, bioluminescent E coli K12 (20 µL of 1×109 bacteria) was inoculated into the vagina. Whole-body bioluminescence imaging was performed 0.5 hours and 24 hours after inoculation. To assess intrauterine inflammation, pathogenic E coli K1 was used. On E15, bacterial inoculums of E coli K1 (20 µL of 1×104 bacteria) were vaginally administered. Samples of uterus, placenta, and fetal membranes were collected 24 hours after inoculation. Gene expression of inflammation-related proteins was compared between 3 groups: (1) sham control surgery + inoculation of phosphate-buffered saline (PBS), (2) sham control surgery + inoculation of E coli K1, and (3) cerclage surgery + inoculation of E coli K1. RESULTS: Abdominal cerclage was well tolerated. No cases of preterm birth were seen following abdominal cerclage. Whole-body bioluminescent imaging performed 0.5 hours post inoculation showed a strong luminescence signal in the vaginal region of mice in both control and experimental groups indicating successful bacteria inoculation. Twenty-four hours after inoculation, bioluminescent signal was seen ascending into the uterine horns in all control mice. However, in mice with abdominal cerclages, no bioluminescent signal was seen after 24 hours. When the reproductive tissues were imaged separately in control mice, strong bioluminescence signal was detected in the placenta, fetal membranes, and uterus. Gene expression studies showed that cerclage significantly decreased the expression of inflammatory proteins induced by E coli K1 in the uterus, placenta, and fetal membranes. CONCLUSION: In this mouse model of ascending intrauterine infection, abdominal cerclage prevented ascending infection of E coli. In addition, abdominal cerclage prevented expression of inflammatory cytokines in the uterus, placenta, and membranes of mice. The study provides evidence for a potential mechanism of cerclage success in human pregnancy.

Ferroportin expression and regulation in human placenta/fetal membranes: Implications for ferroptosis and adverse pregnancy outcomes.

Iron overload is associated with pregnancy complications. Ferroportin (FPN) is the only known iron exporter in mammalian cells. We hypothesize that FPN is functionally important in ferrotopsis, a process of iron-dependent non-apoptotic programmed cell death, and may have a critical role to play in pregnancy success. We investigated the expression of FPN in placenta/fetal membranes by immunohistochemistry in tissues collected from pregnancies with/without preeclampsia (PE) and spontaneous preterm birth (SPTB). FPN was highly expressed in both trophoblasts and decidual cells found in placenta/fetal membranes. Staining was significantly reduced in fetal membranes from SPTB versus healthy pregnancies (P = 0.046). FPN expression in immortalized human endometrial stromal cells (HESC) increased with in vitro decidualization induction using 1 µM of medroxyprogesterone acetate and 0.5 mM of dibutyryl-cAMP. In addition, both HESC cells and immortalized extravillous trophoblast SW71 cells with FPN knockdown showed significant sensitivity to ferroptosis inducer, erastin (P < 0.001 and P = 0.009, respectively). The survival of both HESC and SW71 cells was not negatively affected by iron supplementation with ferric ammonium citrate in the medium. However, SW71 cells were more sensitive than HESC cells to physiologic iron in the presence of a non-lethal dose of erastin (P < 0.001). Taken together, our data demonstrating increased sensitivity of FPN knockdown HESC and SW71 cells to erastin and increased sensitivity of trophoblasts to iron overload under ferroptotic stress support the hypothesis that FPN protects against ferroptosis during pregnancy.

Urgent Follow-up after Outpatient Nonstress Tests and the Potential for Fetal Monitoring at Home.

OBJECTIVE: This study aimed to measure the proportion of patients needing urgent clinical follow-up after an abnormal outpatient nonstress test (NST). We further sought to capture the patient perspective on the acceptability of performing NSTs at home. STUDY DESIGN: A retrospective cohort study was performed over a 2-year period to determine the frequency of abnormal NSTs in a hospital-based, antepartum testing unit in patients greater than or equal to 32 weeks' gestation. The proportion of patients who delivered within 24 hours of an abnormal NST was also determined. A cross-sectional, web-based patient survey was conducted to obtain insight into the patient's comfort level with potentially performing NSTs at home. RESULTS: The chart review yielded 665 patients who underwent 2,122 NSTs at greater than or equal to 32 weeks. Of the 2,122 NSTs, 111 were categorized as abnormal and required urgent clinical follow-up, or 5.2% (95% confidence interval [CI] 4.3, 6.3%). Of the 665 patients, 13 delivered within 24 hours of an abnormal NST, or 2.0% (95% CI 1.0, 3.3%). In the web-based survey, the proportion of respondents who would feel comfortable or very comfortable conducting NSTs at home was 87/125, or 69.6% (95% CI 60.9, 77.1%). CONCLUSION: This study revealed that 5.2% of NSTs performed in a hospital-based antepartum testing unit were abnormal and required urgent clinical follow-up. Of the patients being followed in the antepartum testing unit, 2.0% delivered within 24 hours of an abnormal NST. The majority of the survey respondents indicated they would feel comfortable performing NSTs at home. The present study adds important information regarding the risks and benefits of NSTs at home. KEY POINTS: · Telehealth for NSTs offers advantages over in-person NSTs.. · The proportion of NSTs that need urgent follow-up was 5.2%.. · A majority of patients are interested in telehealth for NSTs.. · Guidelines are needed before adoption of telehealth for NSTs..

Patients with deleterious germline mutations: A heterogeneous population for pancreatic cancer screening?

BACKGROUND AND OBJECTIVES: Modest data exist on the benefits of screening and surveillance for pancreatic cancer (PC) in high-risk individuals. Intraductal papillary mucinous neoplasms (IPMN) are known precursors to PC. We hypothesized that patients with high-risk deleterious germline mutations have a higher prevalence of IPMN. METHODS: All patients undergoing prospective screening at a single institution from 2013 to 2019 were reviewed. RESULTS: Of 1166 patients screened, 358 (31%) possessed germline mutations and/or family history of PC (mutations n = 201/358, 56%, family history n = 226/358, 63%) (median follow-up 2.7 years). IPMN was found in 127 patients (35.5%). The prevalence of IPMN in mutation carriers (18%) was higher than in the general population (p < 0.01). Germline mutation was an independent predictor of IPMN (odds ratio [OR] = 3.2; p < 0.01), while family history was not (p = 0.22). IPMN prevalence was distributed unevenly between mutation types (67%-Peutz-Jeghers; 43%-HNPCC, 24%-BRCA2; 17%-ATM; 9%-BRCA1; 0%-CDKN2A and PALB2). CONCLUSION: In this series, 18% of mutation carriers harbored IPMN, higher than the general population. Germline mutation, but not a family history of PC, was independently associated with IPMN. This prevalence varied across mutation subtypes, suggesting not all mutation carriers develop precancerous lesions. Genetic testing for patients with a positive family history may improve screening modalities for this high-risk population.