Fertility Potential and Gonadal Function in Survivors of Reduced-Intensity Hematopoietic Stem Cell Transplantation.

The use of reduced-intensity conditioning (RIC) regimens has increased in an effort to minimize hematopoietic stem cell transplantation (HCT) end-organ toxicity, including gonadal toxicity. We aimed to describe the incidence of fertility potential and gonadal function impairment in adolescent and young adult survivors of HCT and to identify risk factors (including conditioning intensity) for impairment. We performed a multi-institutional, international retrospective cohort study of patients age 10 to 40 years who underwent first allogeneic HCT before December 1, 2019, and who were alive, in remission, and available for follow-up at 1 to 2 years post-HCT. For females, an AMH level of ≥.5 ng/mL defined preserved fertility potential; an AMH level of ≥.03 ng/mL was considered detectable. Gonadal failure was defined for females as an elevated follicle-stimulating hormone (FSH) level >30 mIU/mL with an estradiol (E2) level <17 pg/mL or current use of hormone replacement therapy (regardless of specific indication or intent). For males, gonadal failure was defined as an FSH level >10.4 mIU/mL or current use of hormone replacement therapy. A total of 326 patients (147 females) were available for analysis from 17 programs (13 pediatric, 4 adult). At 1 to 2 years post-HCT, 114 females (77.6%) had available FSH and E2 levels and 71 (48.3%) had available AMH levels. FSH levels were reported for 125 males (69.8%). Nearly all female HCT recipients had very low levels of AMH. One of 45 (2.2%) recipients of myeloablative conditioning (MAC) and four of 26 (15.4%) recipients of reduced-intensity conditioning (RIC) (P = .06) had an AMH ≥.5 ng/m, and 8 of 45 MAC recipients (17.8%) and 12 of 26 RIC recipients (46.2%) (P = .015) had a detectable AMH level. Total body irradiation (TBI) dose and cyclophosphamide equivalent dose (CED) were not associated with detectable AMH. The incidence of female gonadal hormone failure was 55.3%. In univariate analysis, older age at HCT was associated with greater likelihood of gonadal failure (median age, 17.6 versus 13.9; P < .0001), whereas conditioning intensity (RIC versus MAC), TBI, chronic graft-versus-host disease requiring systemic therapy, and CED were not significantly associated with gonadal function. In multivariable analysis, age remained statistically significant (odds ratio [OR]. 1.11; 95% confidence interval [CI], 1.03 to 1.22) for each year increase; P = .012), Forty-four percent of the males had gonadal failure. In univariate analysis, older age (median, 16.2 years versus 14.4 years; P = .0005) and TBI dose (P = .002) were both associated with gonadal failure, whereas conditioning intensity (RIC versus MAC; P = .06) and CED (P = .07) were not statistically significant. In multivariable analysis, age (OR, 1.16; 95% CI, 1.06-1.27 for each year increase; P = .0016) and TBI ≥600 cGy (OR, 6.23; 95% CI, 2.21 to 19.15; P = .0008) remained significantly associated with gonadal failure. Our data indicate that RIC does not significantly mitigate the risk for gonadal failure in females or males. Age at HCT and (specifically in males) TBI use seem to be independent predictors of post-transplantation gonadal function and fertility status. All patients should receive pre-HCT infertility counseling and be offered appropriate fertility preservation options and be screened post-HCT for gonadal failure.

Quality-of-Life Trajectories in Adolescent and Young Adult versus Older Adult Allogeneic Hematopoietic Cell Transplantation Recipients.

Hematopoietic cell transplantation (HCT) is physically and psychologically challenging, potentially exposing patients to quality-of-life (QoL) impairments. Adolescent and young adults (AYAs, aged 15 to 39 years) are a vulnerable cohort facing multiple hurdles due to dynamic changes in several aspects of their lives. The AYA population may be particularly prone to QoL issues during HCT. We hypothesized that due to the unique psychosocial challenges faced by AYAs, they would have an inferior quality of life. We studied QoL differences between AYA (aged 15 to 39 years) and older adult (aged 40 to 60 years) allogeneic HCT recipients before and after HCT. Additionally, we determined if pre-HCT QoL for AYA transplant recipients changed over time. QoL data were collected prospectively before and after transplant on 431 recipients aged 15 to 60 years from June 2003 through December 2017 using the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) questionnaire. Repeated-measures analysis of variance was used to assess differences among age groups. Pearson correlation (r) was used to determine if baseline QoL had improved after HCT from June 2003 through December 2017 in the AYA cohort. QoL did not differ among younger AYAs, older AYAs, or older adults at any time in the first year after allogeneic HCT. At 1 year post-HCT, total FACT-BMT score and all FACT-BMT domains except physical well-being improved from pre-HCT in all age groups. From 2003 to 2017, AYA allogeneic recipients experienced modest improvement in additional concerns (r = 0.26, P = .003), trial outcome index (r = 0.23, P = .008), and total FACT-BMT score (r = 0.19, P = .031), although no improvements were seen in physical, social, emotional, or functional well-being. Contrary to our hypothesis, we found that QoL in the AYA population is similar to that of older adults before and after HCT. Improvements in QoL of AYA allogeneic patients since 2003 were driven by the additional concerns domain, which addresses multiple psychosocial aspects such as vocation, hobbies, and acceptance of illness. Continued efforts to tailor treatment and support for AYA HCT recipients is critical to improving QoL outcomes.

To D or not to D: vitamin D in hematopoietic cell transplantation.

Vitamin D plays an essential role in bone health, immune tolerance, and immune modulation. Autologous and allogeneic hematopoietic cell transplantation (HCT) recipients are at increased risk of vitamin D deficiency, which may increase risks of bone loss and fracture, graft-versus-host disease (GVHD), and relapse, and can delay hematologic and immune recovery following HCT. Growing evidence indicates that vitamin D may have a role as an immunomodulator, and supplementation during HCT may decrease the risk of GVHD, infection, relapse, and mortality. In this paper, we review the role of vitamin D and its association with HCT outcomes and discuss prevention and treatment of vitamin D deficiency after HCT in adult recipients. We review the role of monitoring of vitamin D levels pre- and post-HCT and its supplementation in appropriate patients. We also review the use of bone densitometry prior to HCT and in long-term follow-up and the treatment of osteoporosis in this high-risk population.

Breath analysis in gastrointestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Volatile organic compounds (VOCs) are generated during pathologic processes, and their assessment can be used to diagnose and monitor a variety of diseases. Given the role of the microbiome in graft-versus-host disease (GVHD), we hypothesized that microorganisms producing volatile metabolites may alter VOCs expelled in breath in patients with gastrointestinal (GI) GVHD. In this pilot study, exhaled breath samples were obtained from 19 patients with grade 2 to 4 acute GI GVHD, 10 patients with no GVHD at day 100, and 10 healthy control subjects; the samples were analyzed by using mass spectrometry. Overall, nine (47%) patients had grade 2 GVHD, eight (42%) patients had grade 3 GVHD, and two (11%) patients had grade 4 GVHD; 26% had upper GI, 21% had lower GI, and 53% had both upper and lower GI manifestations. Stepwise canonical discriminant analysis identified 5 VOCs distinguishing patients with and without GI GVHD: 2-propanol, acetaldehyde, dimethyl sulfide, isoprene, and 1-decene (Wilks' Λ, 0.43; F statistic, 6.08; P = .001). The model correctly classified 89% (17 of 19) and 90% (9 of 10) of patients with and without GI GVHD, respectively. Breath analysis is a feasible and promising noninvasive method to detect acute GI GVHD. Further study of serial breath analysis and the gut microbiome in a larger cohort are ongoing to validate these findings.

Physiological, Genetic, and Transcriptomic Analysis of Alcohol-Induced Delay of Escherichia coli Death.

When Escherichia coli K-12 is inoculated into rich medium in batch culture, cells experience five phases. While the lag and logarithmic phases are mechanistically fairly well defined, the stationary phase, death phase, and long-term stationary phase are less well understood. Here, we characterize a mechanism of delaying death, a phenomenon we call the "alcohol effect," where the addition of small amounts of certain alcohols prolongs stationary phase for at least 10 days longer than in untreated conditions. We show that the stationary phase is extended when ethanol is added above a minimum threshold concentration. Once ethanol levels fall below a threshold concentration, cells enter the death phase. We also show that the effect is conferred by the addition of straight-chain alcohols 1-propanol, 1-butanol, 1-pentanol, and, to a lesser degree, 1-hexanol. However, methanol, isopropanol, 1-heptanol, and 1-octanol do not delay entry into death phase. Though modulated by RpoS, the alcohol effect does not require RpoS activity or the activities of the AdhE or AdhP alcohol dehydrogenases. Further, we show that ethanol is capable of extending the life span of stationary-phase cultures for non-K-12 E. coli strains and that this effect is caused in part by genes of the glycolate degradation pathway. These data suggest a model where ethanol and other shorter 1-alcohols can serve as signaling molecules, perhaps by modulating patterns of gene expression that normally regulate the transition from stationary phase to death phase.IMPORTANCE In one of the most well-studied organisms in the life sciences, Escherichia coli, we still do not fully understand what causes populations to die. This is largely due to the technological difficulties of studying bacterial cell death. This study provides an avenue to studying how and why E. coli populations, and perhaps other microbes, transition from stationary phase to death phase by exploring how ethanol and other alcohols delay the onset of death. Here, we demonstrate that alcohols are acting as signaling molecules to achieve the delay in death phase. This study not only offers a better understanding of a fundamental process but perhaps also provides a gateway to studying the dynamics between ethanol and microbes in the human gastrointestinal tract.

Nipple Discharge: Imaging Variability Among U.S. Radiologists.

OBJECTIVE: The purpose of this study was to assess radiologists' choice of imaging modality for the evaluation of clinical symptoms of physiologic nipple discharge (e.g., bilateral discharge, multiple-duct orifices, and yellow, green, or white color) and pathologic nipple discharge (e.g., unilateral discharge, single-duct orifices, spontaneous and serous discharge, and clear or bloodstained color). MATERIALS AND METHODS: An online survey was sent to lead interpreting physicians at mammography facilities accredited by the American College of Radiology (ACR). Statistical analysis was performed using chi-square tests for frequency data and multinomial logistic regression. RESULTS: A total of 849 responses to 8170 distributed surveys were received, for a response rate of 10.4%. For the workup of physiologic nipple discharge, 30% of respondents recommended screening mammography (SM); 24%, diagnostic mammography (DM) only; and 46%, both DM and targeted ultrasound (US) (DM plus US). For the workup of physiologic nipple discharge, practitioners in nonacademic settings and those who read breast images during less than 50% of their practice were significantly more likely to recommend DM (with or without US), compared with SM (the standard recommended by the ACR). Those reading breast images less than 50% of the time were also more likely to recommend MRI after conventional imaging revealed negative results. For the workup of pathologic nipple discharge, 91.0% of respondents recommended DM plus US; 8.5%, DM only; and fewer than 1.0%, SM. Nonacademic providers and those who read breast images less than 50% of the time were significantly less likely to recommend DM plus US (the standard recommended by the ACR), compared with DM only. CONCLUSION: The present study shows variability in imaging modality selection among U.S. radiologists handling the imaging workflow for benign and pathologic nipple discharge. Radiologists do not uniformly follow ACR practice guidelines, which potentially leads to unnecessary workups and extra health care costs.

Value Added of Preoperative Contrast-Enhanced Digital Mammography in Patients With Invasive Lobular Carcinoma of the Breast.

BACKGROUND: Invasive lobular carcinoma (ILC) is the second most frequently diagnosed breast cancer, accounting for 5% to 15% of all invasive breast cancers, yet it remains radiologically elusive in many cases. The goal of this study was to compare the ability to accurately assess disease extent with contrast-enhanced digital mammography (CEDM) and full-field digital mammography (FFDM) in patients with biopsy-proven ILC. PATIENTS AND METHODS: A single-institution retrospective review of patients diagnosed with ILC with preoperative CEDM was performed. One of 3 blinded radiologist readers rereviewed cases within 1 month of another. Final size diameter was based on the largest dimension on recombined CEDM or FFDM and compared to the reference standard histopathology. Bland-Altman plots were used to visualize the differences between tumor size on imaging and pathology. RESULTS: Thirty women were included. Mean tumor diameter was 27.0 mm (range, 7.0-118 mm) on postoperative histology, 26.0 mm on CEDM, and 16.4 mm on standard mammogram. For CEDM versus FFDM, 5 (16.7%) of 30 versus 9 (30.0%) of 30 cases underestimated pathology by > 10 mm and 5 (16.7%) of 30 versus 3 (10.0%) of 30 overestimated histopathology by > 10 mm, respectively. Two (6.7%) of 30 cases required surgical reexcision. Both Lin (0.87 vs. 0.55) and Pearson (0.87 vs. 0.70) correlation coefficient measures were higher for CEDM versus FFDM. CONCLUSION: CEDM outperforms standard digital mammography in ability to accurately assess disease extent in patients with biopsy-proven ILC, resulting in improved surgical outcomes. Future studies should compare surgical outcomes in patients with preoperative magnetic resonance imaging and CEDM in patients with ILC.

Hematopoietic Stem Cell Transplantation for Multiple Myeloma.

OBJECTIVE: To provide an overview of the hematopoietic stem cell transplantation (HSCT) process specific to patients with multiple myeloma (MM) and their caregivers. DATA SOURCES: Research studies, book chapters, websites, expert knowledge, and journal articles. CONCLUSION: Although not curative, autologous HSCT is an important, manageable treatment modality, and continues to be a standard of care in MM for those patients who are eligible. IMPLICATIONS FOR NURSING PRACTICE: Although an area of specialty practice, an understanding of the HSCT process is important to broaden the knowledge of all nurses who care for patients with MM.

Comparative Effectiveness of Busulfan and Fludarabine versus Fludarabine and 400 cGy Total Body Irradiation Conditioning Regimens for Acute Myeloid Leukemia/Myelodysplastic Syndrome.

Allogeneic hematopoietic cell transplantation conditioning regimen intensity has varied for patients with acute myeloid leukemia and myelodysplastic syndrome. A comparative effectiveness analysis was performed to assess outcomes of busulfan and fludarabine (BuFlu) versus those of fludarabine and 400 cGy total body irradiation (FluTBI) conditioning. Thirty-three subjects received BuFlu and 38 received FluTBI. The BuFlu group received more red blood cell transfusions (P = .02) and had a longer time to platelet recovery (P = .004). There were no differences between the regimens regarding incidence of acute or chronic graft-versus-host disease (GVHD), quality of life, or 2-year outcome estimates for relapse (48; 95% confidence interval [CI], 30 to 64 and 50; 95% CI, 33 to 65), nonrelapse mortality (29; 95% CI, 14 to 45 and 29; 95% CI, 15 to 44), relapse-free survival (27; 95% CI, 13 to 43 and 29; 95% CI, 16 to 44), and overall survival (35; 95% CI, 19 to 51; and 37; 95% CI, 22 to 52), respectively. These comparable outcomes have implications for health care resource utilization. Future prospective investigation comparing these regimens with larger patient cohorts and additional strategies to prevent relapse and limit toxicities as well as cost-effectiveness analyses are warranted.

Malignant single-origin coronary arteries arising from a left coronary sinus.

A 2-month-old boy with a heart murmur and suspected coronary artery anomalies presented for cardiac computed tomography to delineate the origin and course of these anomalies. A single-origin coronary artery was discovered, which arose from the left coronary sinus and coursed between the two outflow vessels, giving this single origin a potentially malignant course. This vessel then went on to split into right and left coronary arteries with normal anatomic distribution. Without the ability for collateral flow, this vessel was located in an extremely precarious position prone to compression during times of stress or exercise. Very rarely has a single-origin coronary artery supplied both ventricles, and even more astonishing was the presence of its interarterial course. This patient will need long-term follow-up care and undoubtedly will be a candidate for surgery to correct this rare potentially malignant anomaly to lessen the boy's chances of sudden cardiac death.