Pregnancy Outcomes in Patients Enrolled in the Healthy Beginnings Plus Program.

OBJECTIVE: To evaluate the effectiveness of enrollment in the Healthy Beginnings Plus Program (HB) on pregnancy outcomes. DESIGN: Retrospective cohort study of 12,299 singleton pregnancies birthed between January 2007 and December 2018. SETTING/LOCAL PROBLEM: Individuals of low socioeconomic status are at increased risk for adverse pregnancy outcomes, such as preterm birth (PTB) and low-birth-weight (LBW) neonates. Pennsylvania offers HB to pregnant individuals with Medical Assistance insurance to provide additional psychosocial and obstetric resources to routine prenatal care to minimize risk. PARTICIPANTS: Individuals with Medical Assistance insurance enrolled in HB (n = 4,645), individuals with Medical Assistance insurance not enrolled in HB (n = 2,874), and individuals with private insurance (n = 4,780). MEASUREMENTS: Primary outcomes were rates of PTB and LBW neonates. Secondary outcomes included rates of gestational diabetes, gestational hypertension, small-for-gestational-age neonates, and admission to the NICU. RESULTS: There were no differences in PTB (adjusted OR [aOR] = 0.93, 95% confidence interval [CI] [0.76, 1.13]) or LBW neonates (aOR = 1.06, 95% CI [0.86, 1.31]) between individuals with Medical Assistance enrolled in HB versus those with Medical Assistance insurance not enrolled in HB. Individuals with Medical Assistance enrolled in HB were less likely to develop gestational hypertension compared to individuals with Medical Assistance insurance not enrolled in HB (aOR = 1.41, 95% CI [1.25, 1.59]) and individuals with private insurance (aOR = 0.85, 95% CI [0.76, 0.96]). They also attended more prenatal visits than individuals with Medical Assistance insurance not enrolled in HB (12.0 vs. 14.0, p < .01). CONCLUSION: Although there was no significant difference between groups for the primary outcomes studied, individuals with Medical Assistance insurance enrolled in HB attended more prenatal visits than those who did not enroll in HB. Similar programs should evaluate outcomes and consider whether changes are needed.

Malic Enzyme 1 Absence in Synovial Sarcoma Shifts Antioxidant System Dependence and Increases Sensitivity to Ferroptosis Induction with ACXT-3102.

PURPOSE: To investigate the metabolism of synovial sarcoma (SS) and elucidate the effect of malic enzyme 1 absence on SS redox homeostasis. EXPERIMENTAL DESIGN: ME1 expression was measured in SS clinical samples, SS cell lines, and tumors from an SS mouse model. The effect of ME1 absence on glucose metabolism was evaluated utilizing Seahorse assays, metabolomics, and C13 tracings. The impact of ME1 absence on SS redox homeostasis was evaluated by metabolomics, cell death assays with inhibitors of antioxidant systems, and measurements of intracellular reactive oxygen species (ROS). The susceptibility of ME1-null SS to ferroptosis induction was interrogated in vitro and in vivo. RESULTS: ME1 absence in SS was confirmed in clinical samples, SS cell lines, and an SS tumor model. Investigation of SS glucose metabolism revealed that ME1-null cells exhibit higher rates of glycolysis and higher flux of glucose into the pentose phosphate pathway (PPP), which is necessary to produce NADPH. Evaluation of cellular redox homeostasis demonstrated that ME1 absence shifts dependence from the glutathione system to the thioredoxin system. Concomitantly, ME1 absence drives the accumulation of ROS and labile iron. ROS and iron accumulation enhances the susceptibility of ME1-null cells to ferroptosis induction with inhibitors of xCT (erastin and ACXT-3102). In vivo xenograft models of ME1-null SS demonstrate significantly increased tumor response to ACXT-3102 compared with ME1-expressing controls. CONCLUSIONS: These findings demonstrate the translational potential of targeting redox homeostasis in ME1-null cancers and establish the preclinical rationale for a phase I trial of ACXT-3102 in SS patients. See related commentary by Subbiah and Gan, p. 3408.

Do gynecologic oncology patients with severely diminished renal function and urinary tract obstruction benefit from ureteral stenting or percutaneous nephrostomy?

OBJECTIVE: To assess the renal outcomes of gynecologic oncology patients who present with hydronephrosis and acute kidney injury (AKI), have <20% renal function on diuretic renal scintigraphy, and undergo placement of a ureteral stent or percutaneous nephrostomy (PCN) tube. METHODS: This is a single-institution case series of gynecologic oncology patients who underwent diuretic renal scintigraphy from January 1, 2007, to June 1, 2017. Univariate and multivariate logistic analyses were used to assess predictors of <20% renal function. Recovery from AKI or elevated creatinine was reported for women with <20% renal function who received a unilateral ureteral stent or PCN tube on the same side as their more compromised kidney. RESULTS: Among 353 gynecologic oncology patients who underwent diuretic renal scintigraphy, 58 (16%) had renal function <20%. Mean age was 59.6 years, 17% had preexisting chronic kidney disease, and 44% had a diagnosis of cervical cancer. Renal atrophy on computed tomography scan (aOR 18.24, 95% CI 1.21-274.92) predicted renal function <20%. Of 10 women with <20% renal function who received a stent or PCN tube, 7 recovered from AKI or elevated creatinine. CONCLUSIONS: Gynecologic oncology patients with <20% renal function may recover from AKI after placement of a stent or PCN tube, indicating that a diuretic renal scintigraphy cutoff of <20% renal function may be overly conservative. Future studies are warranted to determine optimal renal function cutoffs for stent/PCN tube placement in gynecologic oncology patients.

Arginine Deprivation Inhibits the Warburg Effect and Upregulates Glutamine Anaplerosis and Serine Biosynthesis in ASS1-Deficient Cancers.

Targeting defects in metabolism is an underutilized strategy for the treatment of cancer. Arginine auxotrophy resulting from the silencing of argininosuccinate synthetase 1 (ASS1) is a common metabolic alteration reported in a broad range of aggressive cancers. To assess the metabolic effects that arise from acute and chronic arginine starvation in ASS1-deficient cell lines, we performed metabolite profiling. We found that pharmacologically induced arginine depletion causes increased serine biosynthesis, glutamine anaplerosis, oxidative phosphorylation, and decreased aerobic glycolysis, effectively inhibiting the Warburg effect. The reduction of glycolysis in cells otherwise dependent on aerobic glycolysis is correlated with reduced PKM2 expression and phosphorylation and upregulation of PHGDH. Concurrent arginine deprivation and glutaminase inhibition was found to be synthetic lethal across a spectrum of ASS1-deficient tumor cell lines and is sufficient to cause in vivo tumor regression in mice. These results identify two synthetic lethal therapeutic strategies exploiting metabolic vulnerabilities of ASS1-negative cancers.

Development of 89Zr-Ontuxizumab for in vivo TEM-1/endosialin PET applications.

PURPOSE: The complexity of sarcoma has led to the need for patient selection via in vivo biomarkers. Tumor endothelial marker-1 (TEM-1) is a cell surface marker expressed by the tumor microenvironment. Currently MORAb-004 (Ontuxizumab), an anti-TEM-1 humanized monoclonal antibody, is in sarcoma clinical trials. Development of positron emission tomography (PET) for in vivo TEM-1 expression may allow for stratification of patients, potentially enhancing clinical outcomes seen with Ontuxizumab. RESULTS: Characterization of cell lines revealed clear differences in TEM-1 expression. One high expressing (RD-ES) and one low expressing (LUPI) cell line were xenografted, and mice were injected with 89Zr-Ontuxizumab. PET imaging post-injection revealed that TEM-1 was highly expressed and readily detectable in vivo only in RD-ES. In vivo biodistribution studies confirmed high radiopharmaceutical uptake in tumor relative to normal organs. EXPERIMENTAL DESIGN: Sarcoma cell lines were characterized for TEM-1 expression. Ontuxizumab was labeled with 89Zr and evaluated for immunoreactivity preservation. 89Zr-Ontuxizumab was injected into mice with high or null expressing TEM-1 xenografts. In vivo PET imaging experiments were performed. CONCLUSION: 89Zr-Ontuxizumab can be used in vivo to determine high versus low TEM-1 expression. Reliable PET imaging of TEM-1 in sarcoma patients may allow for identification of patients that will attain the greatest benefit from anti-TEM-1 therapy.

Recent advances in the treatment of sarcomas in gynecology.

Uterine sarcomas are a heterologous group of rare malignancies accounting for 8-10% of all uterine malignancies, but are significantly more aggressive and have worse prognoses. Management of uterine sarcomas including leiomyosarcoma and endometrial stromal sarcoma are reviewed here, with additional discussions regarding high-grade undifferentiated sarcoma and adenosarcoma. Uterine carcinosarcomas are currently staged and treated similar to high-grade epithelial endometrial carcinomas, thus will not be discussed in this review. Gemcitabine/docetaxel with adriamycin holds promise for the treatment of leiomyosarcoma, but currently, limited advancements have been made in discovering targeted therapies to these tumors. Continued translational research in both medical oncology and gynecologic oncology is necessary to forward the development of novel and targeted therapeutic agents in the treatment of sarcoma. Enrollment of these patients in clinical trials is encouraged, and will allow for the development of safer and more effective therapies.

Dialysis exercise team: the way to sustain exercise programs in hemodialysis patients.

Patients affected by end-stage renal disease (ESRD) show quite lower physical activity and exercise capacity when compared to healthy individuals. In addition, a sedentary lifestyle is favoured by lack of a specific counseling on exercise implementation in the nephrology care setting. Increasing physical activity level should represent a goal for every dialysis patient care management. Three crucial elements of clinical care may contribute to sustain a hemodialysis exercise program: a) involvement of exercise professionals, b) real commitment of nephrologists and dialysis professionals, c) individual patient adaptation of the exercise program. Dialysis staff have a crucial role to encourage and assist patients during intra-dialysis exercise, but other professionals should be included in the ideal "exercise team" for dialysis patients. Evaluation of general condition, comorbidities (especially cardiovascular), nutritional status and physical exercise capacity are mandatory to propose an exercise program, in either extra-dialysis or intra-dialysis setting. To this aim, nephrologist should lead a team of specialists and professionals including cardiologist, physiotherapist, exercise physiologist, renal dietician and nurse. In this scenario, dialysis nurses play a pivotal role since they guarantee a constant and direct approach. Unfortunately dialysis staff may often lack of information and formation about exercise management while they take care patients during the dialysis session. Building an effective exercise team, promoting the culture of exercise and increasing physical activity levels lead to a more complete and modern clinical care management of ESRD patients.

Obstetric and gynecologic challenges in women with Ehlers-Danlos syndrome.

OBJECTIVE: To determine how often women with Ehlers-Danlos syndrome experience obstetric and gynecologic issues both compared with the general population and within the three most common subtypes of Ehlers-Danlos syndrome. METHODS: An anonymous, prospective, online questionnaire in English was posted to the Ehlers-Danlos National Foundation web site (http://ednf.org). RESULTS: Of the 1,769 of those who completed the survey, 1,225 reported a typed diagnosis of Ehlers-Danlos syndrome. Further stratification to the three most common types and reproductive-aged women (n=775) allowed conclusions to be made about differences in rates of obstetric complications and gynecologic dysfunction compared with the general population and between types of Ehlers-Danlos syndrome. Rates of obstetric outcomes for women who reported at least one pregnancy included term pregnancy in 69.7%, preterm birth in 25.2%, spontaneous abortion in 57.2%, and ectopic pregnancy in 5.1%. Infertility was reported by 44.1% of survey respondents. Normal menstrual cycles were reported by only 32.8% with intermenstrual bleeding occurring in 18.6%. Heavy menstrual bleeding was reported by 32.9% survey participants. Gynecologic pain reported included dysmenorrhea by 92.5% and dyspareunia by 77.0%. CONCLUSION: There is a much greater prevalence of obstetric and gynecologic issues reported by women with Ehlers-Danlos syndrome than in the general population. Additionally, rates differed significantly among the three most common types of Ehlers-Danlos syndrome with vascular type having the highest rates of adverse pregnancy outcomes and menstrual abnormalities. Physician providers should be aware of these challenges and should counsel patients with Ehlers-Danlos syndrome about relevant options and risks.

Oncofertility: an emerging discipline in obstetrics and gynecology.

Oncofertility is an exciting new interdisciplinary field that encompasses the obstetrician gynecologist, gynecologic oncologist, reproductive endocrinologist, and primary care physician in a common goal to provide fertility preservation options for cancer patients. Maintaining their fertility is of the upmost importance for many oncology patients diagnosed during their childbearing years. This review addresses the common types of cancers in reproductive-age patients and how the treatment of these cancers may impact reproductive potential. Fertility preservation treatments will also be discussed to assist health care providers in appropriately counseling patients about options after a diagnosis of cancer. The goal of oncofertility is to provide both physicians and patients with the knowledge and resources to make fertility an ongoing opportunity for all patients who desire a future with children.

Upper limb disability in hemodialysis patients: evaluation of contributing factors aside from amyloidosis.

This cross-sectional case-control study evaluated upper limb muscle strength and shoulder mobility in hemodialysis (HD) patients with arteriovenous fistula or graft. Twenty-five adult patients on thrice-a-week HD treatment for 6 months at least, were selected for the study. In all the patients and control subjects, handgrip tests and tests of range of motion in the upper extremities were evaluated by physiotherapy tests. Patients on HD showed lower muscle strength than age and sex matched subjects without severe chronic kidney disease (right: 30.1 ± 11.6 vs 40.5 ± 15.1 kg, P < 0.001; left 29.1 ± 12.9 vs 40.7 ± 11.1 kg, P < 0.01), and a reduced range of shoulder mobility. The presence of fistula or graft was associated with a greater limitation of both active (74.0 ± 18.3 vs 85.2 ± 8.8 °, P < 0.01) and passive (82.2 ± 9.9 vs 87.2 ± 6.6 °, P < 0.05) extra-rotation than the contralateral limb, with a higher prevalence of impingement (72 vs 36%, P < 0.05). Muscle strength was related to albumin and inversely to age; whereas ß(2) -microglobulin and CRP serum levels were associated with impairment of passive and active extra-rotation of the shoulder that was free from the fistula or graft. In summary, patients on HD have a reduced range of shoulder mobility and marked reduction of muscle strength. The abnormalities are more prevalent in upper limbs with fistula or grafts. The arteriovenous fistula or graft may worsen the disability of the patient's upper limbs presumably due to the obligate position required during the HD sessions. Proper pre- and post-dialysis exercise programs should be implemented to maintain mobility and strength of the upper limbs.

Endodermal sinus tumor of the ovary in an 86 year old woman.

► Oldest reported patient with endodermal sinus tumor of the ovary. ► Chemotherapy for endodermal sinus tumor. ► BEP chemotherapy in an elderly patient.

Implementation of exercise training programs in a hemodialysis unit: effects on physical performance.

INTRODUCTION: Exercise training is beneficial for hemodialysis patients, but it should be tailored to individual abilities and willingness to participate. This study evaluated the effects of different 6-month programs of physical activity in 18 patients of a single hemodialysis unit. METHODS: Before and after a 12-month control period (T0), and following 3 (T3) and 6 (T6) months of training, the patients underwent the 6-minute walk test (6MWT) and constant treadmill test at 3 km/hour speed and 10% grade; spontaneous physical activity was assessed by pedometers. All patients trained for coordination, flexibility and muscular strengthening for 30 minutes within the first 2 hours of hemodialysis sessions: 9 patients underwent home exercise walking training (advised walking group [AWG]); the other 9 patients underwent the advised home training program plus an additional supervised gym training session, twice weekly (supervised walking group [SWG]). RESULTS: In both AWG and SWG, no changes occurred during the control period (232 ± 204 m and 248 ± 187 m at T0). In contrast, endurance performance at treadmill increased at T3 and T6 in the AWG (377 ± 272 m and 615 ± 413 m; p<0.01) and in the SWG (424 ± 272 m and 890 ± 364 m; p<0.001). No unwanted side effects occurred. CONCLUSION: This study shows that physical exercise programs can safely increase physical performance in hemodialysis patients. The training program should be continued for at least 6 months to increase muscle strength and endurance. Intradialytic exercise and home-based, pedometer-based regimens may be a useful and easy approach, whereas supervised programs can give additional benefits in motivated, selected patients.