Long-Term Kidney and Cardiovascular Complications in Pediatric Cancer Survivors.

OBJECTIVE: The objective of this study was to describe the burden of adverse kidney and hypertension outcomes in patients evaluated by pediatric nephrology in a multidisciplinary survivorship clinic. STUDY DESIGN: Retrospective chart review of all patients followed up by nephrology in our multidisciplinary survivorship clinic from August 2013 to June 2021. Data included clinic blood pressure, longitudinal ambulatory blood pressure monitoring (ABPM), echocardiography, serum creatinine, and first-morning urine protein/creatinine ratios. For patients with multiple ABPMs, results of initial and most recent ABPMs were compared. RESULTS: Of 422 patients followed in the multidisciplinary cancer survivorship clinic, 130 were seen by nephrology. The median time after therapy completion to first nephrology visit was 8 years. The most common diagnoses were leukemia/myelodysplastic syndrome (27%), neuroblastoma (24%), and Wilms tumor (15%). At the last follow-up, 68% had impaired kidney function, 38% had a clinical diagnosis of hypertension, and 12% had proteinuria. There were 91 ABPMs performed in 55 (42%) patients. Patients with multiple ABPMs (n = 21) had statistically significant reductions in overall median blood pressure loads: systolic initial load 37% vs most recent 10% (P = .005) and diastolic load 36% vs 14% (P = .017). Patients with impaired kidney function were more likely to have received ifosfamide. Patients with hypertension were more likely to have received total body irradiation or allogeneic stem cell transplant. CONCLUSIONS: History of leukemia/myelodysplastic syndrome, neuroblastoma, and Wilms tumor was frequent among survivors seen by nephrology. There was significant improvement in cardiovascular measures with increased recognition of hypertension and subsequent treatment.

Late effects in survivors of high-risk neuroblastoma following stem cell transplant with and without total body irradiation.

BACKGROUND: Neuroblastoma is the most common extracranial solid tumor in children. Those with high-risk disease are treated with multimodal therapy, including high-dose chemotherapy, stem cell transplant, radiation, and immunotherapy that have led to multiple long-term complications in survivors. In the late 1990s, consolidation therapy involved myeloablative conditioning including total body irradiation (TBI) with autologous stem cell rescue. Recognizing the significant long-term toxicities of exposure to TBI, more contemporary treatment protocols have removed this from conditioning regimens. This study examines an expanded cohort of 48 high-risk neuroblastoma patients to identify differences in the late effect profiles for those treated with TBI and those treated without TBI. PROCEDURE: Data on the study cohort were collected from clinic charts, provider documentation in the electronic medical record of visits to survivorship clinic, including all subspecialists, and ancillary reports of laboratory and diagnostic tests done as part of risk-based screening at each visit. RESULTS: All 48 survivors of BMT for high-risk neuroblastoma had numerous late effects of therapy, with 73% having between five and 10 late effects. TBI impacted some late effects significantly, including growth hormone deficiency (GHD), bone outcomes, and cataracts. CONCLUSION: Although high-risk neuroblastoma survivors treated with TBI have significant late effects, those treated without TBI also continue to have significant morbidity related to high-dose chemotherapy and local radiation. A multidisciplinary care team assists in providing comprehensive care to those survivors who are at highest risk for significant late effects.

Improved Survival With Extracorporeal Cardiopulmonary Resuscitation Despite Progressive Metabolic Derangement Associated With Prolonged Resuscitation.

BACKGROUND: The likelihood of neurologically favorable survival declines with prolonged resuscitation. However, the ability of extracorporeal cardiopulmonary resuscitation (ECPR) to modulate this decline is unknown. Our aim was to examine the effects of resuscitation duration on survival and metabolic profile in patients who undergo ECPR for refractory ventricular fibrillation/ventricular tachycardia out-of-hospital cardiac arrest. METHODS: We retrospectively evaluated survival in 160 consecutive adults with refractory ventricular fibrillation/ventricular tachycardia out-of-hospital cardiac arrest treated with the University of Minnesota (UMN) ECPR protocol (transport with ongoing cardiopulmonary resuscitation [CPR] to the cardiac catheterization laboratory for ECPR) compared with 654 adults who had received standard CPR in the amiodarone arm of the ALPS trial (Amiodarone, Lidocaine, or Placebo Study). We evaluated the metabolic changes and rate of survival in relation to duration of CPR in UMN-ECPR patients. RESULTS: Neurologically favorable survival was significantly higher in UMN-ECPR patients versus ALPS patients (33% versus 23%; P=0.01) overall. The mean duration of CPR was also significantly longer for UMN-ECPR patients versus ALPS patients (60 minutes versus 35 minutes; P<0.001). Analysis of the effect of CPR duration on neurologically favorable survival demonstrated significantly higher neurologically favorable survival for UMN-ECPR patients compared with ALPS patients at each CPR duration interval <60 minutes; however, longer CPR duration was associated with a progressive decline in neurologically favorable survival in both groups. All UMN-ECPR patients with 20 to 29 minutes of CPR (8 of 8) survived with neurologically favorable status compared with 24% (24 of 102) of ALPS patients with the same duration of CPR. There were no neurologically favorable survivors in the ALPS cohort with CPR ≥40 minutes, whereas neurologically favorable survival was 25% (9 of 36) for UMN-ECPR patients with 50 to 59 minutes of CPR and 19% with ≥60 minutes of CPR. Relative risk of mortality or poor neurological function was significantly reduced in UMN-ECPR patients with CPR duration ≥60 minutes. Significant metabolic changes included decline in pH, increased lactic acid and arterial partial pressure of carbon dioxide, and thickened left ventricular wall with prolonged professional CPR. CONCLUSIONS: ECPR was associated with improved neurologically favorable survival at all CPR durations <60 minutes despite severe progressive metabolic derangement. However, CPR duration remains a critical determinate of survival.

Kidney Outcomes and Hypertension in Survivors of Wilms Tumor: A Prospective Cohort Study.

OBJECTIVE: To assess the prevalence of therapy-related kidney outcomes in survivors of Wilms tumor (WT). STUDY DESIGN: This prospective cohort study included survivors of WT who were ≥5 years old and ≥1 year from completing therapy, excluding those with preexisting hypertension, prior dialysis, or kidney transplant. Participants completed 24-hour ambulatory blood pressure monitoring (ABPM). Abnormal blood pressure (BP) was defined as ≥90th percentile. Masked hypertension was defined as having normal office BP and abnormal ABPM findings. Urine was analyzed for kidney injury molecule-1, interleukin-18, epidermal growth factor, albumin, and creatinine. The estimated glomerular filtration rate (eGFR) was calculated using the bedside chronic kidney disease in children equation. Recent kidney ultrasound examinations and echocardiograms were reviewed for contralateral kidney size and left ventricular hypertrophy, respectively. Clinical follow-up data were collected for approximately 2 years after study enrollment. RESULTS: Thirty-two participants (median age, 13.6 years [IQR, 10.5-16.3 years]; 75% stage 3 or higher WT) were evaluated at a median of 8.7 years (IQR, 6.5-10.8 years) after therapy; 29 participants underwent unilateral radical nephrectomy, 2 bilateral partial nephrectomy, and 1 radical and contralateral partial nephrectomy. In this cohort, 72% received kidney radiotherapy and 75% received doxorubicin. Recent median eGFR was 95.6 mL/min/1.73 m2 (IQR, 84.6-114.0; 11 [34%] had an eGFR of <90 mL/min/1.73 m2). Abnormal ABPM results were found in 22 of 29 participants (76%), masked hypertension in 10 of 29 (34%), and microalbuminuria in 2 of 32 (6%). Of the 32 participants, 22 (69%) had abnormal epidermal growth factor; few had abnormal kidney injury molecule-1 or interleukin-18. Seven participants with previous unilateral nephrectomy lacked compensatory contralateral kidney hypertrophy. None had left ventricular hypertrophy. CONCLUSIONS: In survivors of WT, adverse kidney outcomes were common and should be closely monitored.

Determining Risk Factors for Endovenous Heat-induced Thrombosis after Radiofrequency Ablation.

BACKGROUND: The objective of this study was to evaluate risk factors, incidence, management, and outcome of endovenous heat-induced thrombosis (EHIT) related to radiofrequency ablation (RFA). METHODS: This was a single-center retrospective analysis of patients over the age of 18 who underwent RFA between 2016 and 2019. Demographics, comorbidities, medications, severity scores, vascular anatomy, procedural details, and outcome data were collected. EHIT-related data included occurrence, grade, laterality, management, and outcome. RESULTS: During the study period, 672 RFA procedures were performed at our institution. Of these, 642 (median age 57 (21-93), 62.3% female) met study inclusion criteria. EHIT was observed in 43 (6.6%) cases. Concurrent left common femoral vein (CFV) or right femoral vein (FV) incompetence was found to be more prevalent in the EHIT group (P = 0.024 and P = 0.011, respectively). Compared with performing RFA alone, concurrent performance of stab phlebectomy and sclerotherapy with RFA on the left side was found to be associated with possible increased risk for EHIT (P = 0.021). Furthermore, patients with diabetes mellitus (DM) (P = 0.05) and those with median diameter of the treated left vein of 1.2 cm (P = 0.02) were more likely to have a higher EHIT grade (III and IV) than those without DM and those with smaller vein diameter, respectively. Management included aspirin (44%), anticoagulant (28%), both (10%), or neither (18%). EHIT either resolved or regressed (64%), did not change (5%), or propagated (8%) at follow-up. CONCLUSIONS: Left CFV or right FV incompetence was found to be more prevalent in the total EHIT group. Furthermore, DM and the median size of the treated vein on the left (1.2 cm) were more prevalent in the high (III-IV) versus low grade (I-II) EHIT group. More than 50% of EHIT improved (regressed or resolved) at follow-up regardless of the management option. Further analysis with larger patient samples are needed to confirm the association between these variables and the development of EHIT.

Ovarian tissue cryopreservation (OTC) in prepubertal girls and young women: an analysis of parents' and patients' decision-making.

PURPOSE: The purpose of this study was to explore the decision-making influences, perceived level of control over decision-making, and mood states of parents and patients who were offered OTC prior to gonadotoxic therapy. METHODS: Parents and patients, at least 12 years old, who required gonadotoxic therapy and were offered OTC prior to therapy, were asked to complete questionnaires. Two validated instruments were also used: the Decision-Making Control Instrument (DMCI) and the Profile of Mood States (POMS). The factors that influenced decision-making were compared using Student's t test, and the scores of DMCI and POMS were compared using the Mann-Whitney test. RESULTS: Thirty-six parents and 16 patients who elected ovarian tissue cryopreservation (OTC) completed questionnaires. Five parents who declined OTC also completed questionnaires. Accepters thought OTC was a good idea and that, in the future, science would enable cryopreserved ovarian tissue to be used to restore fertility (100% parents, 93.8% patients). Among accepters, the desire for genetically related children and prevention of the stress of infertility drove parents' and patients' decisions (90.9 and 100%, respectively). The desire to prevent the stress of infertility was important to parents, but patients were less likely to report that a desire to prevent the stress of infertility factored into their decision-making (66.7 vs. 50.0%; p < 0.001). All respondents felt in control of their decision and displayed low levels of mood disturbance. CONCLUSIONS: Though the decision to undergo experimental OTC is difficult and often urgent, this study suggests that families feel in control of their decision-making and report little emotional disturbance.

Analysis of semen parameters in a young cohort of cancer patients.

BACKGROUND: Infertility can be the result of some common cancer treatments and can significantly impact quality of life. Semen cryopreservation allows for fertility preservation. We analyzed the semen parameters of specimens collected from pubertal males from the Children's Hospital of Philadelphia (CHOP) in order to expand current knowledge on the quality of these specimens and inform a standard clinical practice. PROCEDURE: Males who were at least Tanner stage III and newly diagnosed with cancer at CHOP were approached regarding sperm banking. The success and quality of the samples collected were analyzed and compared in relation to prior treatment, age, and diagnosis. RESULTS: From 399 patients approached for semen collection, 339 (85%) attempted to bank sperm, of which 265 (78%) were successful and 60 (15%) refused to participate. Therapy prior to sperm banking significantly impacted a successful collection (P < 0.01). Only 16.9% of the untreated patients were azoospermic, whereas 84.0% of the treated subjects were azoospermic. Older patients were less likely to be azoospermic and have a greater quality collection when compared with younger patients (P < 0.01). However, 65% of our youngest patients still were able to cryopreserve semen. There was no difference in azoospermia across diagnostic groups (P = 0.35), though there were differences in quality of semen parameters across diagnoses. CONCLUSION: Our data support that sperm banking pubertal males prior to the initiation of therapy is feasible. While there were differences in quality of semen parameters across age and diagnostic groups, most males, regardless of age or diagnosis, had adequate specimens for cryopreservation.

Histology of Testicular Biopsies Obtained for Experimental Fertility Preservation Protocol in Boys with Cancer.

PURPOSE: Cryopreservation of testicular tissue with subsequent reimplantation after therapy has the potential to preserve fertility for prepubertal boys with cancer. We present the histology and feasibility of testicular tissue procurement for this novel approach. MATERIALS AND METHODS: We performed a prospective cohort study of boys at significant risk for treatment associated gonadotoxicity who were eligible for an experimental research protocol between 2008 and 2011. Open testicular biopsy was performed while the patients were anesthetized for another treatment related procedure. Half of the specimen was reserved for cryopreservation, while the other half was used for research purposes. Semithin sections of the biopsy specimens were evaluated for histological features and compared to age adjusted reference values. RESULTS: A total of 34 boys underwent biopsy between March 2008 and October 2011. Of the patients 29 had solid tumors and 5 underwent hematopoietic stem cell transplantation for benign disease. A total of 27 patients had adequate tissue for histological analysis. Median patient age was 8.7 years (IQR 2.2 to 11.5). All children had either normal (81.5% of patients) or increased (18.5%) numbers of germ cells per tubule for their age. However, 5 of 26 patients (19%) older than 6 months had no evidence of adult dark spermatogonia and 9 of 16 (56%) older than 6 years had no evidence of primary spermatocytes on biopsy, which would be expected based on age norms. These findings are suggestive of abnormal germ cell maturation. CONCLUSIONS: The preliminary histological findings of abnormal spermatogenesis maturation in the testes of prepubertal boys with cancer warrants further investigation.

Testicular tissue cryopreservation in prepubertal male children: an analysis of parental decision-making.

BACKGROUND: Infertility is an unfortunate treatment-related consequence for some pediatric malignancies as well as some non-malignant conditions treated with stem cell transplant. Unlike pubertal males, prepubertal males cannot produce semen for cryopreservation. This manuscript reports on the acceptability and safety of a multi-institutional protocol for offering testicular tissue cryopreservation to families of prepubertal male children at highest risk for infertility. Data on decision influences, decision-making control, and emotional state when considering this option are described. PROCEDURE: Prepubertal males facing gonadotoxic therapy were offered testicular cryopreservation. Post-biopsy, patients were followed for acute side effects. In addition, parents and patients were asked to complete questionnaires, whether or not they chose to cryopreserve tissue. RESULTS: Seventy-four prepubertal male children were approached. Fifty-seven families (77%) consented to the testicular biopsy; 48 of 57 underwent the procedure. There was one post-operative side effect. Parents who agreed to testicular cryopreservation and those that did not felt in control of this decision. Parents who consented to the biopsy and refusers were not deterred by the experimental nature of the protocol. An important decision-making influence was the risk of the biopsy. CONCLUSION: Biopsy and cryopreservation of testicular tissue from prepubertal male children was performed successfully and safely at three institutions. Parents faced with this option at diagnosis can make an informed decision and weigh carefully the risks and benefits. Although asked to make a decision soon after they were given a difficult diagnosis, parents uniformly felt in control of this decision.

The validity of hospital diagnostic and procedure codes reflecting morbidity in preterm neonates born <32 weeks gestation.

OBJECTIVE: To determine the validity of diagnostic hospital billing codes for complications of prematurity in neonates <32 weeks gestation. STUDY DESIGN: Retrospective cohort data from discharge summaries and clinical notes (n = 160) were reviewed by trained, blinded abstractors for the presence of intraventricular hemorrhage (IVH) grades 3 or 4, periventricular leukomalacia (PVL), necrotizing enterocolitis (NEC), stage 3 or higher, retinopathy of prematurity (ROP), and surgery for NEC or ROP. Data were compared to diagnostic billing codes from the neonatal electronic health record. RESULTS: IVH, PVL, ROP and ROP surgery had strong positive predictive values (PPV > 75%) and excellent negative predictive values (NPV > 95%). The PPVs for NEC (66.7%) and NEC surgery (37.1%) were low. CONCLUSION: Diagnostic hospital billing codes were observed to be a valid metric to evaluate preterm neonatal morbidities and surgeries except in the instance of more ambiguous diagnoses such as NEC and NEC surgery.

Prepubertal human spermatogonia and mouse gonocytes share conserved gene expression of germline stem cell regulatory molecules.

In the human testis, beginning at approximately 2 months of age, gonocytes are replaced by adult dark (Ad) and pale (Ap) spermatogonia that make up the spermatogonial stem cell (SSC) pool. In mice, the SSC pool arises from gonocytes approximately 6 days after birth. During puberty in both species, complete spermatogenesis is established by cells that differentiate from SSCs. Essentially pure populations of prepubertal human spermatogonia and mouse gonocytes were selected from testis biopsies and validated by confirming the presence of specific marker proteins in cells. Stem cell potential of germ cells was demonstrated by transplantation to mouse testes, following which the cells migrated to the basement membrane of the seminiferous tubule and were maintained similar to SSCs. Differential gene expression profiles generated between germ cells and testis somatic cells demonstrated that expression of genes previously identified as SSC and spermatogonial-specific markers (e.g., zinc-finger and BTB-domain containing 16, ZBTB16) was greatly elevated in both human spermatogonia and mouse gonocytes compared to somatic cells. Several genes were expressed at significantly higher levels in germ cells of both species. Most importantly, genes known to be essential for mouse SSC self-renewal (e.g., Ret proto-oncogene, Ret; GDNF-family receptor alpha1, Gfr alpha1; and B-cell CLL/lymphoma 6, member B, Bcl6b) were more highly expressed in both prepubertal human spermatogonia and mouse gonocytes than in somatic cells. The results indicate remarkable conservation of gene expression, notably for self-renewal genes, in these prepubertal germline cells between two species that diverged phylogenetically approximately 75 million years ago.

Ovarian tissue cryopreservation for fertility preservation in cancer patients: successful establishment and feasibility of a multidisciplinary collaboration.

BACKGROUND: As advancements in cancer therapies have led to dramatic improvements in long term survival, there has been increasing interest in methods to expand fertility preservation options for cancer patients. METHODS: An experimental protocol for ovarian tissue cryopreservation was developed at the University of Pennsylvania for patients requiring gonadotoxic therapies. The protocol for adults was implemented at the Hospital of the University of Pennsylvania and for children at the Children's Hospital of Philadelphia in collaboration with the Oncofertility Consortium and the National Physicians Cooperative (NPC). RESULTS: A total of twenty-one patients (age range: 8-36 years) have cryopreserved ovarian tissue as part of this study. While patients had a variety of diagnoses and treatment exposures, 10/21 (48 %) patients suffered from hematologic disorders and 43 % were anticipating stem cell transplantation. No patients have requested that the tissue be used for clinical purposes. CONCLUSIONS: Ovarian tissue cryopreservation protocols can be implemented at pediatric and adult institutions through multi-disciplinary collaboration. While more research is needed to determine the safety and efficacy of ovarian tissue cryopreservation, this procedure provides hope for preserving the ability to have biological offspring to patients facing gonadotoxic therapies for a variety of medical conditions.

Progesterone receptor-Src kinase signaling pathway mediates neuroprogesterone induction of the luteinizing hormone surge in female rats.

Neural circuits in female rats are exposed to sequential estradiol and progesterone to regulate the release of luteinizing hormone (LH) and ultimately ovulation. Estradiol induces progesterone receptors (PGRs) in anteroventral periventricular nucleus (AVPV) kisspeptin neurons, and as estradiol reaches peak concentrations, neuroprogesterone (neuroP) synthesis is induced in hypothalamic astrocytes. This local neuroP signals to PGRs expressed in kisspeptin neurons to trigger the LH surge. We tested the hypothesis that neuroP-PGR signaling through Src family kinase (Src) underlies the LH surge. As observed in vitro, PGR and Src are co-expressed in AVPV neurons. Estradiol treatment increased the number of PGR immunopositive cells and PGR and Src colocalization. Furthermore, estradiol treatment increased the number of AVPV cells that had extranuclear PGR and Src in close proximity (< 40 nm). Infusion of the Src inhibitor (PP2) into the AVPV region of ovariectomized/adrenalectomized (ovx/adx) rats attenuated the LH surge in trunk blood collected 53 h post-estradiol (50 µg) injection that induced neuroP synthesis. Although PP2 reduced the LH surge in estradiol benzoate treated ovx/adx rats, activation of either AVPV PGR or Src in 2 µg estradiol-primed animals significantly elevated LH concentrations compared to dimethyl sulfoxide infused rats. Finally, antagonism of either AVPV PGR or Src blocked the ability of PGR or Src activation to induce an LH surge in estradiol-primed ovx/adx rats. These results indicate that neuroP, which triggers the LH surge, signals through an extranuclear PGR-Src signaling pathway.

Development and validation of the health competence beliefs inventory in young adults with and without a history of childhood cancer.

BACKGROUND: Adolescent and young adult survivors of childhood cancer are a vulnerable population. Health beliefs may be related to necessary follow-up care. PURPOSE: This study seeks to develop a measure of health beliefs for adolescents and young adults with and without a history of cancer. METHODS: Inductive and deductive methods and focus groups were used to develop the Health Competence Beliefs Inventory. Cancer survivors (n = 138) and comparison participants (n = 130) completed the Health Competence Beliefs Inventory and other measures. Healthcare providers reported current medical problems. RESULTS: A series of iterative exploratory factor analyses generated a 21-item four-factor solution: (1) Health Perceptions; (2) Satisfaction with Healthcare; (3) Cognitive Competence; and (4) Autonomy. Survivors reported significantly different Health Competence Beliefs Inventory scale scores than comparisons (p < .05). The Health Competence Beliefs Inventory was associated with beliefs, affect, quality of life, posttraumatic stress symptoms, and medical problems. CONCLUSIONS: The Health Competence Beliefs Inventory is a promising measure of adolescent and young adult perceptions of health and well-being.

Prevalence of advanced bone age in a cohort of patients who received cis-retinoic acid for high-risk neuroblastoma.

In the last decade, 13-cis-retinoic acid (13-cis-RA) has been added to the treatment of patients with high-risk neuroblastoma. In survivors of neuroblastoma, short stature is consistently observed. Causes include growth hormone deficiency and poor growth of irradiated long bones. Within the survivorship program at CHOP, we have observed that a number of these patients also have advanced bone ages. Children treated with 13-cis-RA are at risk for advanced bone age that may dramatically impact their linear growth. Ongoing evaluation is necessary to examine the effect of 13-cis-RA on final adult height and to inform clinical practice in this cohort.

Outcomes associated with delayed enteral feeding after cardiac arrest treated with veno-arterial extracorporeal membrane oxygenation and targeted temperature management.

INTRODUCTION: While early enteral nutrition is generally preferred in critically ill patients, the optimal timing of feeding among refractory cardiac arrest patients is unknown. We examined the association between timing of enteral nutrition and patient survival and safety outcomes in patients with refractory out-of-hospital cardiac arrest (OHCA) who were treated with extracorporeal cardiopulmonary resuscitation (ECPR). METHODS: We performed a retrospective analysis of 142 consecutive patients presenting with OHCA due to ventricular fibrillation or ventricular tachycardia treated with ECPR and targeted temperature management (TTM). Neurologically favorable survival and clinical outcomes were compared between patients who received early enteral nutrition (<48 h after admission to the intensive care unit) and patients receiving delayed enteral nutrition (initiated >48 h after admission). RESULTS: Enteral nutrition was initiated in 90/142 (63%) patients. Early enteral nutrition was provided in 34/90 (38%) while delayed nutrition occurred in 56/90 (62%). In adjusted analysis including patients who received nutrition, delayed enteral feeding was associated with increased odds of neurologically favorable survival (29 vs 54%, CI 1.04-7.25, p = 0.04). There were no significant differences in the incidence of pneumonia (18 vs 27%, p = 0.16), gastrointestinal bleeding (5.9 vs 3.6%, p = 0.42), intestinal ischemia (5.9 vs 5.4%, p = 0.90), ileus (12 vs 11%, p = 0.98), or need for tracheostomy (15 vs 20%, p = 0.81) between early and late feeding groups. CONCLUSION: In patients with refractory OHCA treated with ECPR and TTM, delayed enteral nutrition was associated with improved neurologically favorable survival. Adverse events related to enteral feeding were not associated with timing of feeding initiation.

Early cardiovascular structural and functional abnormalities as a guide to future morbid events.

AIMS: Our aim was to evaluate the predictive value of a battery of 10 non-invasive tests of cardiovascular structural and functional health on the future risk of cardiovascular morbid events. METHODS AND RESULTS: A total of 1900 asymptomatic adults concerned about their risk for cardiovascular disease underwent non-invasive assessment with 10 tests of vascular and cardiac structure and function. A disease score (DS) was calculated for each individual based on these 10 tests. Follow-up (mean 9.2 years) for cardiovascular morbidity and mortality was available for 1442 individuals (mean age 53.2 years, 48.2% women). Those in the lowest DS tertile (0-2) experienced 0.16 cardiovascular events per 100 patient-years (PY), those in the middle tertile (3-5) experienced 0.86 events per 100 PY, and those in the highest tertile (6+) experienced 1.3 events per 100 PY (p < .001). Sensitivity analysis, assuming a neutral effect of DS on projected events in subjects not followed, did not alter statistical significance. Risk assessment using the Framingham risk score (FRS) also predicted morbid events but the two methods differed in identifying individuals at high risk. The net reclassification index was improved by 0.11 (p = 0.01) when DS was added to FRS. CONCLUSIONS: Assessing the biological disease process in the arteries and heart of asymptomatic adults provides a guide to the risk of a future cardiovascular morbid event. Larger and longer studies are needed to determine whether risk factor algorithms, the severity of the biological process or some combination is the optimal method for identifying individuals in need of intervention to delay morbid events.

Patients treated with venoarterial extracorporeal membrane oxygenation have different baseline risk and outcomes dependent on indication and route of cannulation.

OBJECTIVES: To investigate the baseline risk of patients treated with Extracorporeal Cardiopulmonary Membrane Oxygenation (ECMO) in relation to cannulation strategy and indication for ECMO as well as the relation of cannulation strategy with survival and secondary hospitalization outcomes. METHODS: Severity of illness and predicted mortality risk were assessed in 317 patients. Central cannulation was used in 52 patients unable to wean off cardiopulmonary bypass after cardiac surgery. Peripheral cannulation was used in 179 patients for extracorporeal cardiopulmonary resuscitation (eCPR) and in 86 patients who received ECMO for refractory cardiogenic shock (RCS). RESULTS: Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were significantly worse (P < 0.01) for peripheral ECMO eCPR (23.2) vs central ECMO (14.6) and vs peripheral ECMO for RCS (18.9). Survival After Venoarterial ECMO (SAVE) scores were significantly worse for peripheral ECMO for eCPR (-7.85) and RCS (-10.38) vs central ECMO (-3.97), and P < 0.01. Peripherally cannulated patients had significantly worse renal function. No significant difference existed for survival to discharge (peripheral ECMO for eCPR, 31%; central ECMO, 44%; peripheral ECMO for refractory cardiac shock, 39.5%; and P = 0.176), although centrally cannulated patients had significantly longer treatment durations compared with peripheral ECMO for eCPR. CONCLUSIONS: Peripherally cannulated patients with eCPR had significantly worse APACHE II and SAVE scores compared to peripherally cannulated RCS or patients with central ECMO, despite having similar mortality.

Relationship of menopausal symptoms and ovarian reserve in reproductive-aged cancer survivors.

PURPOSE: This study sought to evaluate the prevalence of menopausal symptoms in a population of reproductive-aged women remote from cancer therapy compared with a group of healthy similar-aged controls and with a cohort of late reproductive-aged (LR) controls. METHODS: Participants were assessed for symptoms of menopause, early follicular phase hormones, and ultrasound examinations. Menopausal symptoms were analyzed in exposed participants and controls using χ2 analyses, Wilcoxon-Mann Whitney tests, and multivariable logistic regression models. RESULTS: One hundred seventy cancer survivors, 135 similar-aged controls, and 71 LR controls were followed prospectively for an average of 38 months. Compared with similar-aged controls, a greater proportion of survivors reported vasomotor symptoms at some point over the study period (35% vs 19%, p < 0.01), and this proportion was similar to LR controls (44%, p = 0.22). Survivors were more likely to be bothered by vaginal dryness (27%) than similar-aged controls (16%, p = 0.02) or LR controls (14%, p = 0.02). FSH levels were 38.4% higher in those with vasomotor symptoms compared with those without symptoms (p = 0.021). CONCLUSIONS: Reproductive-aged cancer survivors have a higher prevalence of vasomotor symptoms and vaginal dryness than their similar-aged peers. IMPLICATIONS FOR CANCER SURVIVORS: Providers should be attuned to the high prevalence of menopausal symptoms in cancer survivors.

Sodium Nitroprusside-Enhanced Cardiopulmonary Resuscitation Improves Blood Flow by Pulmonary Vasodilation Leading to Higher Oxygen Requirements.

Sodium nitroprusside-enhanced cardiopulmonary resuscitation has shown superior resuscitation rates and neurologic outcomes in large animal models supporting the need for a randomized human clinical trial. This study is the first to show nonselective pulmonary vasodilation as a potential mechanism for the hemodynamic benefits. The pulmonary shunting that is created requires increased oxygen treatment, but the overall improvement in blood flow increases minute oxygen delivery to tissues. In this context, hypoxemia is an important safety endpoint and a 100% oxygen ventilation strategy may be necessary for the first human clinical trial.