Is there a relationship between morphokinetic parameters and obstetrical complications? An analysis of singleton live births after single fresh embryo transfer.

BACKGROUND: With the advancement in embryology and the introduction of time-lapse monitoring system, the embryologists' goal might be to find not only the embryo with the highest probability of live birth, but also the embryo with the highest probability to progress to a healthy full-term delivery. Thus, we aimed to investigate the association between morphokinetic time-lapse parameters and obstetrical and perinatal complications. METHODS: A cohort study reviewing fertility and delivery files of all singletone births from IVF patients whose embryos were cultured in a time-lapse monitoring system and had a single fresh embryo transfer at our center between 2013-2019. We conducted multiple comparisons between complicated and uncomplicated pregnancies of each perinatal complication, including: gestational diabetes mellitus (GDM); small for gestational age (SGA); pre-eclamptic toxemia (PET); preterm labor < 37 weeks of gestation (PTL); and third stage of labor complications. A comparison between pregnancies with and without a composite outcome of placental complications including GDM, SGA, PET and PTL was also conducted. Baseline characteristics, treatment and morphokinetic parameters in complicated and uncomplicated gestations were compared. Logistic regression analysis was utilized to adjust results for potential confounders. RESULTS: One hundred seventy-six single embryo transfers resulted in 176 live births. Morphokinetic time-lapse parameters were similar between the groups, except for a shorter time to full blastulation in the SGA group (tB-tPNf = 75.5 ± 1.3 h vs. 79.5 ± 4.8 in the non-SGA group, p < 0.001), and shorter third cell cycle duration in the PET group (CC3 = 12.4 ± 1.1 h vs. 13.6 ± 2.9 in the non-PET group, p = 0.02). On multivariate regression analysis, none of the morphokinetic parameters were found to be significantly correlated with any of the perinatal complications. CONCLUSION: Time-lapse morphokinetic parameters of the embryo transferred are not associated with adverse obstetric and perinatal outcomes.

Anatomic Location Influences Duration of Local Lidocaine Anesthesia in Dermatologic Surgery.

BACKGROUND: Although the onset and duration of local anesthetics are well-defined, how the anatomic site influences the duration of local anesthetics has not been well characterized in dermatology. OBJECTIVE: To define the duration of local anesthesia by anatomic site. MATERIALS AND METHODS: This was a prospective study. Adult healthy volunteers and patients undergoing Mohs micrographic surgery were invited to participate. The nose and the shin were chosen to represent highly and poorly vascularized anatomic sites, respectively. A total of 0.5 mL of buffered 1% lidocaine hydrochloride with 1:100,000 epinephrine was injected subcutaneously into each anatomic site of each participant. A pinprick test was used to assess adequate anesthesia until return of baseline sensation or visit completion. RESULTS: This study enrolled 25 participants. Time to return of sensation was significantly shorter on the nose compared with the shin ( p < .0001). On the nose, there was an association between male sex and shorter time to return of sensation. CONCLUSION: Time to return of sensation is significantly shorter on the nasal ala compared with the shin, suggesting that patients may regain sensation sooner on highly vascularized sites. Defining the duration of local anesthetics based on anatomic regions is important for treatment planning in dermatologic procedures.

Arterial and Venous Thromboembolism in ALK-Rearrangement-Positive Non-small Cell Lung Cancer: A Population-Based Cohort Study.

INTRODUCTION: There is scarce data regarding the incidence of venous thromboembolism (VTE) and arterial thromboembolism (ATE) in the molecular subtypes of non-small cell lung cancer (NSCLC). We aimed to investigate the association between Anaplastic Lymphoma Kinase (ALK)-positive NSCLC and thromboembolic events. METHODS: A retrospective population-based cohort study of the Clalit Health Services database, included patients with NSCLC diagnosed between 2012 and 2019. Patients exposed to ALK-tyrosine-kinase inhibitors (TKIs) were defined as ALK-positive. The outcome was VTE (at any site) or ATE (stroke or myocardial infarction) 6 months prior to the diagnosis of cancer, until 5 years post-diagnosis. The cumulative incidence of VTE and ATE and hazard-ratios (HR) with 95% CIs were calculated (at 6- 12- 24 and 60-months), using death as a competing risk. Cox proportional hazards multivariate regression was performed, with the Fine and Gray correction for competing risks. RESULTS: The study included 4762 patients, of which 155 (3.2%) were ALK-positive. The overall 5-year VTE incidence was 15.7% (95% CI, 14.7-16.6%). ALK-positive patients had a higher VTE risk compared to ALK-negative patients (HR 1.87 [95% CI, 1.31-2.68]) and a 12-month VTE incidence of 17.7% (13.9-22.7%) compared to 9.9% (9.1-10.9%) in ALK-negative patients. The overall 5-year ATE incidence was 7.6% [6.8-8.6%]. ALK positivity was not associated with ATE incidence (HR 1.24 [0.62-2.47]). CONCLUSIONS: In this study, we observed a higher VTE risk, but not ATE risk, in patients with ALK-rearranged NSCLC relative to those without ALK rearrangement. Prospective studies are warranted to evaluate thromboprophylaxis in ALK-positive NSCLC.

Rituximab versus obinutuzumab-based first-line chemoimmunotherapy for follicular lymphoma-a real-world multicenter retrospective cohort study.

The GALLIUM study showed a progression-free survival advantage of 7% in favor of obinutuzumab vs. rituximab-based immunochemotherapies as first-line therapy in follicular lymphoma (FL) patients. Yet, the toxicity appears to be increased with obinutuzumab-based therapy. This is a multicenter retrospective-cohort study including adult FL patients comparing the toxicity of first-line rituximab vs. obinutuzumab-based chemo-immunotherapies (R and O groups, respectively). We compared the best standard-of-care therapy used per time period, before and after obinutuzumab approval. The primary outcome was any infection during induction and 6 months post-induction. Secondary outcomes included rates of febrile neutropenia, severe and fatal infections, other adverse events, and all-cause mortality. Outcomes were compared between groups. A total of 156 patients were included in the analysis, 78 patients per group. Most patients received bendamustine (59%) or CHOP (31.4%) as adjacent chemotherapy. Half of the patients received growth-factor prophylaxis. Overall, 69 patients (44.2%) experienced infections, and a total of 106 infectious episodes were recorded. Patients in the R and O groups had similar rates of any infection (44.8% and 43.5%, p = 1), severe infections (43.3% vs. 47.8%, p = 0.844), febrile neutropenia (15% vs. 19.6%, p = 0.606), and treatment discontinuation, as well as similar types of infections. No covariate was associated with infection in multivariable analysis. No statistically significant difference was evident in adverse events of grades 3-5 (76.9% vs. 82%, p = 0.427). To conclude, in this largest real-life study of first-line treated FL patients comparing R- to O-based therapy, we did not observe any difference in toxicity during the induction and 6 months post-induction period.

A Longitudinal Assessment of the Natural Change in Haemoglobin, Haematocrit, and Mean Corpuscular Volume with Age.

INTRODUCTION: We aimed to assess the natural annual trends in the levels of haemoglobin, haematocrit, and mean corpuscular volume (MCV) in a population of adults, together with the influence of different clinical parameters on these trends. METHODS: A retrospective analysis was carried out on data from a large cohort of subjects attending a screening centre in Israel. For each subject, the yearly average change of haemoglobin, haematocrit, and MCV was calculated. Statistical analysis was performed for the whole cohort and for different subgroups. RESULTS: The study included 3,551 subjects. The average annual rates of decline were found to be -0.0550 g/dL (95% confidence interval [CI] -0.0590 g/dL to -0.0503 g/dL) and -0.097% (95% CI -0.112% to -0.083%) for haemoglobin and haematocrit, respectively. An average annual increase in the MCV level by 0.184 fL (95% CI 0.168 fL-0.200 fL) was found. Among men, the rate of decline in haemoglobin was found to be twice as high compared with women -0.06 g/dL versus -0.03 g/dL, respectively (p = 0.0063). In a multivariate analysis, gender remained the only parameter significantly associated with the annual decline of haemoglobin (p = 0.0001). CONCLUSION: An annual average decrease in the levels of haemoglobin and haematocrit together with an annual increase in MCV was found. These changes were more prominent in men.

Bedside Durable Tunneled Femoral Central Venous Catheter is Feasible and Safe in High-Risk Infants in the Pediatric Cardiac Intensive Care Unit.

OBJECTIVE: Ultrasound (US)-guided durable tunneled femoral central venous catheters (TF-CVCs) are a safe central venous access option in infants and neonates. Studies have shown, however, that femoral central venous access has the potential for high central line-associated bloodstream infection (CLABSI) rates with a significant increase in risk for line-related thrombosis. Our aims were to describe the bedside insertion technique and evaluate the safety and complication rates of TF-CVCs in high-risk, young, pediatric cardiac intensive-care unit (PCICU) population. DESIGN: A retrospective observational cohort study. SETTING: University affiliated, tertiary-care hospital, PCICU. PATIENTS: All PCICU patients that underwent bedside TF-CVC insertion were enrolled. Data was collected from the electronic medical record system. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During April 2016 to October 2021, 103 TF-CVC lines were inserted into 94 pediatric cardiac critical care patients, at the bedside. Patients' characteristics were median (IQR) age of 47.5 days (22.6, 120.5), weight 3.3 kg (2.9, 4.3), 33% prevalence of genetic anomalies, need for ECMO support in 20.4%, and STAT category 4-5 in 53.4%. All procedures were performed by intensivists. There were no immediate procedure-related complications. TF-CVCs were inserted on average on post-operative day (POD) 14, median line indwell duration was 25 days (16.3, 42.3) and total TF-CVC dwell duration for the entire cohort of 3442.7 days. During the study period eight CLABSI events were recorded (2.3/1000 line-days). Line obstruction rate was 1.16/1000 line-days and six lines were dislodged in the intermediate-care unit. There was no symptomatic line-related thrombosis. CONCLUSIONS: We show that US-guided durable tunneled femoral central venous catheter (TF-CVC) insertion by an intensivist at the bedside is a technically feasible and safe prolonged central venous access option in critically ill, high-risk infants and neonates in the PCICU.

Preceding Clinical Events in High-risk, Postoperative, Pediatric Cardiac Patients-A Novel Association With Bacteremia.

Objective: Blood stream infections (BSIs) are well described in pediatric cardiac intensive care units (PCICU). We noted that postoperative high-risk patients may develop BSI after a preceding clinical event (PCE). The study aim was to investigate whether high-risk patients who developed bacteremia experienced more PCEs than a similar group of high-risk patients. Design: Retrospective case-control study. Setting: Referral pediatric center. Patients: We enrolled patients who developed bacteremia from March 2010 to November 2019, after undergoing open-heart surgery at a pediatric center. The control group was comprised of case-matched patients with immediate consecutive same surgery. Interventions: None. Measurements: We recorded operative data, common risk factors, postoperative indicators of organ dysfunction, mortality, and PCEs 72 to 24 h before bacteremia emerged. Main results: A total of 200 patients were included (100 with bacteremia and 100 controls). Key demographic and operative parameters were matched. Bacteremia emerged on average on postoperative day 12.8. Skin-associated Gram-positive bacteria were cultured in 10% and Gram-negative bacteria in 84% of the patients. Average central-venous lines (CVL) duration was 9.5 ± 8.4 days. Postoperatively (72 h), indicators of organ dysfunction were significantly worse in patients with bacteremia, with a higher rate of postoperative complications during PCICU length-of-stay (LOS). In the bacteremia group, 72 to 24 h prior to the development of bacteremia, 92 (92%) PCEs were recorded, as compared to 21 (21%) in controls during their entire LOS (odds ratio [OR] 43.3, confidence interval [CI] 18.2-103.1, P < .0001). Conclusions: We propose a 3-hit model demonstrating that high-risk patients undergoing open-heart surgery have significantly higher risk for bacteremia after a PCE.

Extracorporeal photopheresis induces NETosis in neutrophils derived from patients with chronic graft-vs-host disease.

INTRODUCTION: Extracorporeal photopheresis (ECP) is considered an effective treatment for patients with chronic graft vs host disease (cGVHD) and demonstrates efficacy in ameliorating GVHD. The mechanism by which ECP acts against cGVHD is not fully understood. Preliminary observations have hinted at the potential involvement of neutrophil extracellular traps (NETs) formation in the pathogenesis of cGVHD. We aimed to assess the influence of ECP on the formation of NETs in patients with cGVHD as a potential mechanism in this setting. METHODS: Patients treated with ECP for cGVHD at the Rabin Medical Center were included in this study. Blood samples were obtained at three different time points: before starting an ECP cycle, at the end of the first day of treatment, and 24 h following the initiation of the ECP treatment cycle. Neutrophils were harvested from all blood samples. NET formation was assessed by measurement of NET-bound specific neutrophil elastase activity and by immunofluorescence staining. RESULTS: Six patients (two females and four males) with cGVHD were included in the study. We observed a significant increase in NET formation among all six patients following ECP. Net-bound specific neutrophil elastase activity was elevated from a median value of 2.23 mU/mL (interquartile range [IQR] 2.06-2.47 mU/mL) at baseline to a median value of 13.06 mU/mL (IQR 10.27-15.97 mU/mL) immediately after the treatment and to a peak median value of 14.73 mU/mL (IQR 9.6-22.38 mU/mL) 24 h following the initiation of the ECP cycle. A qualitative assessment of NET formation using immunofluorescence staining has demonstrated markedly increased expression of citrullinated histone H3, a marker of NET formation, following ECP treatment. CONCLUSIONS: Our preliminary data indicate that ECP induces NET formation among patients with cGVHD. The contribution of increased NET formation to the therapeutic effect of cGVHD should be further investigated.

Pulmonary function tests for evaluating the severity of Duchenne muscular dystrophy disease.

AIM: In Duchenne muscular dystrophy (DMD), lung disease contributes significantly to morbidity and mortality. This study aimed to assess the usefulness of various pulmonary function tests in evaluating DMD severity. METHODS: This retrospective study analysed lung function tests of patients with DMD-treated in the multidisciplinary respiratory neuromuscular clinic at Schneiders' Children Medical Center of Israel. Data were analysed according to age, ambulatory status and glucocorticoid treatment. RESULTS: Among 90 patients with DMD, 40/63 (63.5%) ambulatory patients and 22/27 (81.5%) nonambulatory patients successfully performed spirometry. Significant annual declines were demonstrated among nonambulatory patients, in percentile predicted forced vital capacity (3.8%) and in total lung capacity (5.5%) per year. The decline correlated with age and loss of ambulation but not with steroid treatment. Peak cough flow values were randomly distributed and did not correlate with age, ambulation or treatment. In nonambulatory patients, transcutaneous carbon dioxide measurement correlated significantly with age (r = 0.55, p = 0.02). CONCLUSION: Forced vital capacity, total lung capacity and transcutaneous carbon dioxide correlated with the clinical severity of disease in children with DMD. These measures may be useful in follow-up and clinical trials. A comparable correlation was not found for peak cough flow.

Clinical Outcomes of Hospitalized Patients with SARS-CoV-2 Omicron Variant vs. Influenza A During Influenza Season 2021 to 2022: A Retrospective Observational Study.

BACKGROUND: Influenza and coronavirus disease 2019 (COVID-19) are respiratory diseases with similar modes of transmission. In December 2021, influenza re-emerged after it had been undetected since March 2020 and the Omicron variant replaced the Delta variant. Data directly comparing the two diseases are scarce. OBJECTIVES: To compare the outcomes of patients with both the Omicron variant and influenza during 2021-2022. METHODS: We performed a retrospective study conducted in Beilinson hospital, Israel, from December 2021 to January 2022. We included all hospitalized patients with either laboratory-confirmed COVID-19 or influenza. The primary outcome was 30-day mortality. RESULTS: We identified 167 patients diagnosed with Omicron and 221 diagnosed with Influenza A. The median age was 71 years for Omicron and 65 years for influenza. Patients with Omicron had a significantly higher Charlson Comorbidity Index score (4 vs. 3, P < 0.001). Patients with Omicron developed more respiratory failure that needed mechanical ventilation (7% vs. 2%, P = 0.05) and vasopressors (14% vs. 2%, P < 0.001) than patients with influenza. In a multivariate model, 30-day mortality was lower in patients diagnosed with influenza than in patients diagnosed with Omicron (19/221 [9%] vs. 44/167 [26%], hazard ratio 0.45, 95% confidence interval 0.25-0.81). CONCLUSIONS: Patients diagnosed with Omicron had higher mortality than patients diagnosed with seasonal influenza. This finding could be due to differences in co-morbidities, the virus pathogenicity, and host responses to infection.

Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission after 5-azacitidine and venetoclax: a multicenter retrospective study.

The combination of hypomethylating agents and venetoclax has revolutionized the therapeutic landscape of acute myeloid leukemia (AML), especially for patients previously deemed unfit for curative-intent treatment. Some of these patients undergo allogeneic hematopoietic cell transplant (alloHCT); yet, there are scarce data regarding transplantation outcomes. We conducted a multicenter nationwide retrospective cohort study, including patients with AML who underwent alloHCT in CR1 after frontline treatment with azacitidine plus venetoclax only (aza-ven group). We collected a historical control group of patients who achieved CR1 after first-line intensive chemotherapy only, followed by alloHCT (intensive group). Patients in the aza-ven group (n = 24) were transplanted between 2019 and 2021. Compared to the intensive group, patients in the aza-ven group were older (median age 71.7 vs. 58.4 years), had higher incidence of therapy-related AML and AML with antecedent hematologic disorder and had more often adverse cytogenetics. They had a higher percentage of allografts from matched-unrelated donors, and reduced intensity conditioning was more commonly used. The estimated 12 months non relapse mortality was 19.1% in the aza-ven group and 11.8% in the intensive group. The estimated 12 months relapse-free survival and overall survival were 58% and 63% in the aza-ven group and 54% and 70% in the intensive group, respectively. The cumulative incidence of acute GVHD at 6 months and of chronic GVHD at 12 months were 58% and 40% in the aza-ven group and 62% and 42% in the intensive group, respectively. Analysis of the aza-ven group revealed that HCT-CI score and ELN risk category were predictive of RFS in both univariate analysis as well as multivariate analysis. Our data suggests that alloHCT for AML patients achieving first CR with aza-ven appears feasible, with short-term post-transplant outcomes similar to those expected after traditional intensive chemotherapy.

Comparisons of Continuous-wave Doppler Ultrasound Monitor and Echocardiography in Cardiac Postoperative Pediatric Patients.

RATIONAL AND OBJECTIVES: Non-invasive cardiac output (CO) measurements are essential during the immediate post-operative course of young, congenital heart repaired patients. The use of the Ultrasonic Cardiac Output Monitor (USCOM) in pediatric intensive care units (PICU) is increasing. The literature on accuracy of USCOM in young, critically ill, mechanically ventilated, hemodynamically supported patients is scarce. We aimed to assess agreement between the USCOM device and echocardiography for measurements of CO in this population. MATERIALS (PATIENTS) AND METHODS: A prospective observational study in a pediatric cardiac intensive care unit (PCICU). Paired CO measurements were taken in young, mechanically ventilated, immediate post-operative patients with exclusion of unrepaired or residual intra-cardiac shunt, using USCOM and echocardiography, by two separate senior performers. Agreement between echocardiography and USCOM was assessed by percentage error and Bland-Altman analysis. RESULTS: One hundred and thirteen comparison scans were performed on 61 patients: mean age 94 ± 111 d, weight 4.7 ± 2.1 kg, vaso-inotropic score 15.3 ± 11, and STAT score 3-4 (46%). Mean USCOM cardiac index (CI) percent difference was -9.6% (45.6) and velocity-time-integral (VTI) 8.9% (34.7). Bland-Altman analyzes demonstrated poor agreement comparing USCOM to echocardiography with regard to CI, stroke volume (SV), VTI and aortic diameter (AO) measurements. CONCLUSION: Our study shows that USCOM underestimates CI in comparison with echocardiography; therefore USCOM should be used with great caution as an absolute estimate or surrogate of CI in neonates and infants in the immediate post-operative, congenital heart surgery period.

Exacerbation of immune thrombocytopenia following initial and booster vaccination with Pfizer-BioNTech COVID-19 vaccine.

As the immune thrombocytopenia exacerbation rate after booster COVID-19 vaccines is unknown, we explore the rates after first, second and booster Pfizer-BioNTech COVID-19 vaccines. A retrospective study of adult ITP patients, receiving 1-3 vaccines was performed. The primary outcome was clinical ITP exacerbation defined as platelet count decrease requiring initiation/escalation of ITP treatment and/or new medical attention due to bleeding, within 3 months. Secondary outcome was any clinically relevant platelet decrease during the 3 months post-vaccination. The study included 93 ITP patients receiving 1 (n = 2), 2 (n = 22) or 3 (n = 69) vaccines. ITP exacerbation occurred in 2/93 (2.2%) patients following initial vaccination and in 3/69 (4.3%) following booster dose. Clinically relevant platelet decreases after initial doses occurred in 8/72 (11.1%) patients and in 8/39 (20.5%) after the booster. Clinical ITP exacerbation after booster doses did not follow clinical exacerbation after initial doses. Half of patients with clinically relevant platelet decreases after booster dose also had clinically relevant decreases following initial vaccination. We concluded that clinical ITP exacerbation is infrequent following Pfizer-BioNTech COVID-19 vaccine. Clinical exacerbation after booster doses was not preceded by clinical exacerbation after initial doses. Clinically relevant platelet decreases after booster doses occur frequently in patients with clinically relevant decreases after initial doses.

Accurate Diagnosis of Adnexal Torsion-Not Only for Expert Sonographers: A Retrospective Cohort Analysis.

OBJECTIVES: The aim of the study was to evaluate the clinical and sonographic parameters associated with a correct or incorrect diagnosis of adnexal torsion made by resident/attending physicians who are not expert sonographers. METHODS: A retrospective study design included women who presented to the Emergency Department (ED) of a tertiary medical center between 2010 and 2019 with acute lower abdominal pain, who were subsequently diagnosed laparoscopically with adnexal torsion. Women who were correctly diagnosed in the ED by an obstetrician-gynecologist who was not an expert sonographer were compared for clinical and sonographic parameters with women who were initially incorrectly diagnosed and underwent a second ultrasound examination by an expert sonographer following admission. RESULTS: Of 118 women with surgically proven adnexal torsion, 76 were correctly diagnosed in the ED and 42 were initially incorrectly diagnosed. The correctly diagnosed group was characterized by a significantly shorter mean time from admission to surgery, higher rate of vomiting, shorter duration of abdominal pain, and higher rate of prior torsion (P < .05). Physicians who made the correct diagnosis utilized more sonographic parameters than those who did not, namely ovarian size, ovarian edema, and Doppler flow. The correctly diagnosed group had a higher rate of bluish-black (ischemic) adnexa at laparoscopy, but a higher rate of recovery following detorsion. CONCLUSIONS: Physicians in the ED should be alerted to the need to address some basic sonographic features when adnexal torsion is suspected. The diagnostic accuracy of adnexal torsion can be improved by utilizing simple sonographic markers, even in the ED setting.

Alternative nivolumab duration and scheduling in advanced nonsmall cell lung cancer: A real-world evidence.

In advanced nonsmall cell lung cancer (aNSCLC), stopping nivolumab after 12 months negatively affects outcomes. We performed a world data-based analysis assessing the value of nivolumab continuation and optimal dosing beyond 24 months. Out of 697 consecutive patients with aNSCLC in whom nivolumab was initiated between 2015 and 2018, 45 patients receiving nivolumab for ≥24 months were selected. These were divided into Groups A: nivolumab administered at a dose 3 mg/kg q2 weeks/240 mg q2 weeks/480 mg q4 weeks, n = 25; B: nivolumab re-scheduled to a nonstandard dose 3 mg/kg q3 weeks-q8 weeks, n = 13; C: nivolumab stopped after 24 months, n = 7; (in Groups B and C-for reasons other than progressive disease or intolerable toxicity). Progression-free survival (PFS) (Revised Response Evaluation Criteria in Solid Tumors, version 1.1) and safety (Common Terminology Criteria for Adverse Events, version 4.03) were assessed. With median follow-up of 35.6 months (interquartile range 28.4-41.8), 4%, 31%, 29% and 30% of patients progressed in Groups A, B, C and B+C, respectively. PFS at 36 months since nivolumab initiation comprised 100%, 67%, 67% and 67%, in Groups A, B, C and B+C, respectively. PFS at 40 months since nivolumab initiation comprised 83%, 67%, 67% and 67%, in Groups A, B, C and B+C, respectively. Allocation to Group A vs Group B, C and B+C was associated with hazard ratio for PFS-0.20 (95% confidence interval [CI], 0.02-1.77, P-.15), 0.20 (95% CI, 0.02-2.25, P-.19) and 0.20 (95% CI, 0.02-1.66, P-.14), respectively. No differences in newly occurring or worsening adverse events between the groups were observed. A trend for worse PFS was observed with alternative nivolumab scheduling or quitting 24 months after initiation. Continuing nivolumab at a standard dose until disease progression or intolerable toxicity remains the standard treatment option.

Taxane versus vinorelbine in combination with trastuzumab and pertuzumab for first-line treatment of metastatic HER2-positive breast cancer: a retrospective two-center study.

BACKGROUND: The combination of a taxane with trastuzumab and pertuzumab is standard of care for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The combination of vinorelbine with trastuzumab and pertuzumab showed anti-tumor activity in a phase 2 trial. PATIENTS AND METHODS: The databases of two tertiary medical centers were retrospectively searched for patients with HER2-positive metastatic breast cancer who underwent first-line treatment in 2013-2019 with a taxane or vinorelbine in combination with trastuzumab and pertuzumab. Groups were compared for progression-free survival (PFS), overall survival (OS), and toxicity profile. RESULTS: The study included 87 patients in the taxane group and 65 in the vinorelbine group. Overall median PFS was significantly longer in the taxane group [HR 0.56 (0.36-0.88), P = 0.01], but on multivariate analysis the difference was not statistically significant [HR 0.68 (0.4-1.1, P = 0.11)]. PFS was comparable in both groups of patients with recurrent disease [HR 0.94 (0.5-1.79), P = 0.85]. However, in patients with de novo metastatic disease, the difference in favor of the taxane group was pronounced [HR 0.4 (0.2-0.78), P = 0.007] and maintained significance on multivariate analysis [HR 0.46 (0.2-0.97, P = 0.04)]. There was no statistical significant difference in OS in the whole cohort [HR 0.69 (0.39-1.23)] or the subgroups. CONCLUSIONS: Patients with HER2-positive metastatic breast cancer had similar survival with first-line treatment of taxane or vinorelbine combined with trastuzumab and pertuzumab. When the analysis was adjusted for prognostic factors, there was no PFS benefit for taxanes except in the subgroup with de novo disease.

The Impact of Exogenous Estrogen Exposure on the Characteristics and Outcome of Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early-Stage Breast Cancer.

INTRODUCTION: The impact of exogenous estrogen exposure on breast cancer characteristics and outcomes is not well described. We aimed to investigate the effect of prior treatment with oral contraceptives (OCT), hormone replacement therapy (HRT), and fertility treatments on early-stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. METHODS: This is a single-center retrospective cohort study comprising all women with ER-positive, HER2-negative, early breast cancer whose tumors were sent to Oncotype DX analysis between 2005 and 2012. Data on prior exposures to OCT, HRT, and fertility treatments were collected. The impact of these exposures on prespecified histopathological features was assessed including tumor size, nodal status, intensity of the hormonal receptors, grade, Oncotype recurrence score, Ki67, and lymphovascular and perineural invasion. The impact of these exposures on disease-free survival (DFS) and overall survival (OS) was also evaluated. RESULTS: A total of 620 women were included, of which 19% had prior exposure to OCT, 30% to HRT, and 11% to fertility treatments. OCT use was associated with smaller (≤1 cm) tumors (p = 0.023) and were less likely to have grade 3 disease (p = 0.049). No other associations were found between exogenous estrogen exposure and tumor characteristics. Median follow-up was 10.4 years. Ten-year DFS was 85.7%, and it was not influenced by exogenous exposure. Ten-year OS was 90.2%, and OCT was associated with improved OS in univariate analysis (HR = 0.31, 95% CI: 0.11-0.85), but this difference did not remain significant in multivariate analysis (p = 0.275). CONCLUSION: The impact of exogenous estrogen exposure on ER-positive, HER2-negative early breast cancer characteristics is limited. In the long term, none of the evaluated exposures had negative effect on DFS and OS.

Features and long-term outcomes of patients hospitalized for diabetic ketoacidosis.

BACKGROUND: Diabetic ketoacidosis (DKA) is an acute metabolic complication characterized by hyperglycaemia, ketones in blood or urine, and acidosis. OBJECTIVE: The aim of this study was to characterize features of patients hospitalized for DKA, to identify triggers for DKA and to evaluate the long-term effects of DKA on glycaemic control, complications of diabetes, re-hospitalizations, and mortality. METHODS: Historical prospectively collected data of patients hospitalized to medical wards for DKA between 2011 and 2017. Data regarding comorbidities, mortality, triggers, and re-hospitalizations for DKA were also collected. RESULTS: The cohort consisted of 160 patients (mean age 38 ± 18 years, 43% male). One fifth of the patients (34 patients, 21%) were newly diagnosed with diabetes, and DKA was their first presentation of the disease. Among the 126 patients with pre-existing diabetes, the common identified triggers for DKA were poor compliance to treatment (22%) and infectious diseases (18%). During over 7 years of follow-up, mortality rate was 9% (15 patients), and re-hospitalization for DKA rate was 31% (50 patients). Risk factors for re-hospitalization for DKA included young age (OR = 1.02, 95% CI, 1.00-1.04), pre-existing diabetes compared to DKA as the first presentation (OR = 5.4, 95% CI, 1.7-18), and poorer glycaemic control before initial hospitalization (10.5 ± 2.5% vs. 9.4 ± 2.2%; OR = 0.8, 95% CI [0.68-0.96]) and after discharge (10.3 ± 2.4% vs. 9.0 ± 1.9%; OR = 0.73, 95% CI [0.61-0.87]). Laboratory tests during the initial hospitalization, smoking, alcohol, or comorbidities did not increase the risk for re-hospitalization for DKA. CONCLUSIONS: The risk for readmission for DKA is higher for young patients with long duration of diabetes, poor compliance of insulin treatment and poorly controlled diabetes.

Consecutive ovarian stimulation is beneficial in patients with a poor response to high-dose follicle-stimulating hormone.

OBJECTIVE: To investigate if an immediate additional IVF-ET cycle bear an advantage to patients with poor ovarian response in comparison to a cycle performed at some delay. METHODS: A cohort study including 632 patients who underwent a fresh IVF-ET cycle with high-dose (≥300 IU/d) FSH stimulation that yielded ≤4 oocytes and did not achieve a clinical pregnancy. All underwent a second stimulation and oocyte pick-up (OPU), either consecutively or separately within 180 days (nonconsecutive OPU). The oocyte yield, number of embryos available for transfer, pregnancy live birth rates of the second OPU were compared between patients who had consecutive and nonconsecutive cycles. RESULTS: Consecutive OPU was associated with more mature follicles in the second cycle compared to nonconsecutive OPU (p = .03) in addition to higher peak estradiol level (p < .0001), and more aspirated oocytes (p = .03) and available embryos (p = .023). There was no between-group difference in ongoing pregnancy and live birth rates. In a multivariate analysis of variance controlling for potential confounders, the difference in the number of aspirated oocytes and available embryos was associated significantly only with consecutive performance of the second cycle. CONCLUSION: Immediate sequential stimulation (without an intervening menstrual cycle) in poor responders is advantageous over delayed stimulation in terms of number of aspirated oocytes and available embryos. The administration of high-dose FSH in the first cycle may benefit follicular recruitment also in the subsequent cycle. Although the effect is modest, given that each additional oocyte aspirated contributes to the outcome, it might be of significance especially in younger patients.

Sex Differences in Folate Levels: A Cross Sectional Study of a Large Cohort from Israel.

BACKGROUND: Low folate levels are associated with megaloblastic anemia, neural tube defects, and an increased risk of cancer. Data are scarce regarding the sex aspect of this deficiency. OBJECTIVES: To assess sex differences in folate levels in a large cohort of patients and to investigate the effect of low folate levels on homocysteine concentrations. METHODS: Data were collected from medical records of patients examined at a screening center in Israel between 2000 and 2014. Cross sectional analysis was conducted on 9214 males and 4336 females. RESULTS: The average age was 48.4 ± 9.5 years for males and 47.6 ± 9.4 years for females. Average folate levels were 19.2 ± 8.6 and 22.4 ±10.3 nmol/L in males and females, respectively (P < 0.001). The prevalence of folate levels below 12.2 nmol/L was 19.5% in males compared to 11.6% in females (P < 0.001). In patients with low folate levels and normal B12 levels, homocysteine levels above 15 µmol/L were found in 32.4% of males and 11.4% of females (P < 0.001). Males had a significantly higher odds ratio (OR) of having folate levels below 12.2 nmol/L: OR 1.84 (95% confidence interval [95%CI] 1.66-2.05) in a non-adjusted model, and OR 2.02 (95%CI 1.82-2.27) adjusted for age, smoking status, body mass index, kidney function, albumin, and triglycerides levels. CONCLUSIONS: Folate levels are lower in males compared to females, which may contribute to the higher homocysteine levels found in males and thus to their increased risk of developing atherosclerosis and coronary artery disease.