The impact of race, ethnicity, and obesity on CAR T-cell therapy outcomes.

Cancer outcomes with chemotherapy are inferior in patients of minority racial/ethnic groups and those with obesity. Chimeric antigen receptor (CAR) T-cell therapy has transformed outcomes for relapsed/refractory hematologic malignancies, but whether its benefits extend commensurately to racial/ethnic minorities and patients with obesity is poorly understood. With a primary focus on patients with B-cell acute lymphoblastic leukemia (B-ALL), we retrospectively evaluated the impact of demographics and obesity on CAR T-cell therapy outcomes in adult and pediatric patients with hematologic malignancies treated with CAR T-cell therapy across 5 phase 1 clinical trials at the National Cancer Institute from 2012 to 2021. Among 139 B-ALL CAR T-cell infusions, 28.8% of patients were Hispanic, 3.6% were Black, and 29.5% were overweight/obese. No significant associations were found between race, ethnicity, or body mass index (BMI) and complete remission rates, neurotoxicity, or overall survival. Hispanic patients were more likely to experience severe cytokine release syndrome compared with White non-Hispanic patients even after adjusting for leukemia disease burden and age (odds ratio, 4.5; P = .001). A descriptive analysis of patients with multiple myeloma (n = 24) and non-Hodgkin lymphoma (n = 23) displayed a similar pattern to the B-ALL cohort. Our findings suggest CAR T-cell therapy may provide substantial benefit across a range of demographics characteristics, including for those populations who are at higher risk for chemotherapy resistance and relapse. However, toxicity profiles may vary. Therefore, efforts to improve access to CAR therapy for underrepresented populations and elucidate mechanisms of differential toxicity among demographic groups should be prioritized.

COVID-19 Outcomes in Patients Undergoing B Cell Depletion Therapy and Those with Humoral Immunodeficiency States: A Scoping Review.

BACKGROUND: The role of humoral immunity has been well established in reducing infection risk and facilitating viral clearance in patients with COVID-19. However, the relationship between specific antibody responses and severity of COVID-19 is less well understood. METHODS: To address this question and identify gaps in knowledge, we utilized the methodology of a scoping review to interrogate risk of infection and clinical outcomes of COVID-19 in patients with iatrogenic and inborn humoral immunodeficiency states based on existing literature. RESULTS: Among patients with iatrogenic B-cell depletion, particularly with agents targeting CD20, our analysis found increased risk of severe COVID-19 and death across a range of underlying disease states. Among patients with humoral inborn errors of immunity with COVID-19, our synthesis found that patients with dysregulated humoral immunity, predominantly common variable immunodeficiency (CVID), may be more susceptible to severe COVID-19 than patients with humoral immunodeficiency states due to X-linked agammaglobulinemia and other miscellaneous forms of humoral immunodeficiency. There were insufficient data to appraise the risk of COVID-19 infection in both populations of patients. CONCLUSIONS: Our work identifies potentially significant predictors of COVID-19 severity in patients with humoral immunodeficiency states and highlights the need for larger studies to control for clinical and biologic confounders of disease severity.

HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease.

Immunodeficiency often coincides with hyperactive immune disorders such as autoimmunity, lymphoproliferation, or atopy, but this coincidence is rarely understood on a molecular level. We describe five patients from four families with immunodeficiency coupled with atopy, lymphoproliferation, and cytokine overproduction harboring mutations in NCKAP1L, which encodes the hematopoietic-specific HEM1 protein. These mutations cause the loss of the HEM1 protein and the WAVE regulatory complex (WRC) or disrupt binding to the WRC regulator, Arf1, thereby impairing actin polymerization, synapse formation, and immune cell migration. Diminished cortical actin networks caused by WRC loss led to uncontrolled cytokine release and immune hyperresponsiveness. HEM1 loss also blocked mechanistic target of rapamycin complex 2 (mTORC2)-dependent AKT phosphorylation, T cell proliferation, and selected effector functions, leading to immunodeficiency. Thus, the evolutionarily conserved HEM1 protein simultaneously regulates filamentous actin (F-actin) and mTORC2 signaling to achieve equipoise in immune responses.

Elevated follicular fluid angiotensin II and pregnancy outcome.

OBJECTIVE: To assess whether a relationship exists between follicular fluid (FF) angiotensin II (AII) concentration and pregnancy outcome or earlier fecundity parameters and whether correlations exist among FF AII concentrations and P, E2, T, androstenedione (A), or various ratios of these. DESIGN: Retrospective study in which hormone concentrations in FF samples were measured. SETTING: In vitro fertilization clinic-Assisted Reproductive Technology Program, Rush Medical Center. PATIENTS: Twenty-six female patients underwent ovarian stimulation for IVF. INTERVENTION: Leuprolide acetate was combined with hMG and FSH for ovarian stimulation. MAIN OUTCOME MEASURE: Follicular fluid aspirates were collected and oocytes were recovered 34 to 36 hours after hCG injection. The patients proceeded to undergo IVF and ET. Follicular fluid hormones were measured using standard RIA. Angiotensin II and steroid hormone concentrations in FF were compared for pregnant versus nonpregnant women using the Student's t-test and rank-sum test. Pearson multiple-correlation analysis was performed to calculate correlation coefficients among AII concentrations and steroid concentrations in FF aspirates. RESULTS: Mean FF concentration of AII was significantly lower in samples from women showing clinical pregnancies (112.2 +/- 13.9 pg/mL [107.3 +/- 13.3 pmol/L]) compared with samples from women who did not achieve pregnancy (217.1 +/- 23.8 pg/mL [207.5 +/- 22.7 pmol/L]) (mean +/- SE). A negative correlation was observed between FF concentrations of AII and P. Correlations of AII with E2, T, A, or with ratios of these did not show significance. CONCLUSION: These data suggest that high AII concentration at time of oocyte recovery may indicate poor pregnancy outcome in women undergoing ovarian stimulation for IVF. These data corroborate previous results in animal models showing that AII predisposes follicles to undergo atresia-like conditions.

Pituitary sarcoidosis causing secondary amenorrhea. A case report.

A 32-year-old woman with hypogonadotropic amenorrhea and sarcoidosis had an enlarged pituitary stalk and gland on computed tomography. Concentrations of luteinizing and growth hormone did not increase after the administration of gonadotropin releasing hormone and insulin-induced hypoglycemia, respectively. The absence of response possibly was the consequence of the patient's estrogen deficiency. The response of thyroid stimulating hormone, prolactin and cortisol was normal after provocative pituitary stimulation. Central nervous system sarcoidosis occurs in 3.5-5.0% of patients with systemic sarcoidosis. Hypothalamic or pituitary sarcoidosis occurs in approximately 0.5% of patients. Diabetes insipidus and hyperprolactinemia are the most frequent manifestations of hypothalamic-pituitary sarcoidosis, occurring in one-half and one-third, respectively, of such patients. Menstrual disturbances, including amenorrhea, are reported infrequently. Computed tomography and provocative pituitary-hypothalamic testing are useful in detecting central nervous system sarcoidosis and in delineating the site of involvement.

Level of reading difficulty in the American College of Obstetricians and Gynecologists patient education pamphlets.

Written educational and informational materials are an important and potentially useful means to complement verbal instructions, assure that consent for tests and procedures is informed, and enhance compliance with treatment. In specialties other than obstetrics and gynecology, many of these materials have been found to be written at a level of difficulty above the reading ability of the intended audience. The SMOG formula was used to assess the level of reading difficulty of all 74 English-language patient education pamphlets developed by The American College of Obstetricians and Gynecologists (ACOG) Committee on Patient Education. Sixty-one of these pamphlets are written at a reading difficulty level of 11th grade or higher. Although the mean reading education level in the United States is at grade 12.6, the mean literacy level is at or below eighth grade. With the exception of one ACOG pamphlet written specifically for low-readability audiences (p-063, Birth Control Pills), all the pamphlets are written at a level higher than the literacy level of many women. The information is unlikely to be understood if it is written above the reading ability of the intended audience. This disparity is accentuated for health-education materials because scientific and technical terms further reduce the level of comprehension. The SMOG formula is a simple means to ensure that educational materials are written at a level appropriate for the intended audience.

Inability of sonography to detect imminent ovulation.

Sonographic visualization of the cumulus oophorus or of morphologic alterations in the wall of the dominant follicle have been reported to be reliable signs of imminent ovulation when conventional transabdominal sonography is used. To determine if transvaginal sonography could allow a more frequent and confident prediction of imminent ovulation, we prospectively monitored 22 ovulatory menstrual cycles in four women undergoing artificial insemination and in 13 normally menstruating volunteers. Scanning was done on alternate days in the periovulatory period; a 7.5-MHz transvaginal transducer was used. Despite the improved resolution obtained with transvaginal sonography, confident identification of the cumulus oophorus or of mural changes in the follicle was not possible in any of the cycles followed. No other consistent follicular characteristic predicted imminent ovulation. We conclude that confident prediction of imminent ovulation is not possible with sonographic analysis.

A semiquantitative human chorionic gonadotropin assay for the detection of ectopic pregnancy.

Human chorionic gonadotropin (hCG) was measured in 117 serum samples with known quantities of hCG after a dilutional modification of a reliable, simple, and inexpensive qualitative assay for hCG. The modification yielded a semiquantitative assay for hCG with a sensitivity of 5000 mIU/mL. At hCG concentrations below 4000 mIU/mL, the assay had no false-negative or false-positive results; above 6500 mIU/mL, there were also no false-negative or false-positive results. In the range of 4000-6500 mIU/mL, the clinical false-positive rate was 28%. Using the described dilutional modification of this qualitative hCG assay, the test is semiquantitative, and is useful in selecting the appropriate time to perform ultrasound and laparoscopy in women suspected of having an ectopic pregnancy.

Serum and seminal plasma prolactin concentrations in men with normospermia, oligospermia, or azoospermia.

Semen analyses were performed and serum and seminal plasma prolactin (PRL) concentrations were determined in 165 samples from 120 men seen with their wives because of infertility. The mean (+/- standard deviation) serum and seminal plasma PRL concentrations were 6.5 +/- 3.3 and 7.5 +/- 3.1 ng/ml, respectively. The mean concentrations of PRL in serum and seminal plasma were similar in groups of men divided by sperm concentration. Seven men had an increased serum PRL concentration. Three of these 7 men had sperm concentrations less than 20 million/ml and none of these 7 men had an increased seminal plasma PRL concentration. Four men had an increased seminal plasma PRL concentration; the serum PRL concentration, sperm concentrations, and motilities were normal in all 4. No man had a decreased serum or seminal plasma PRL concentration. Increased serum PRL concentrations were found infrequently and the increase was slight (23.2 ng/ml or less). Seminal plasma PRL concentrations were related directly to sperm concentrations and motilities, relationships that were statistically significant.

The effect of epidural analgesia on the frequency of instrumental obstetric delivery.

In a retrospective study, 155 women who had epidural analgesia only for pain relief during labor and delivery were matched by age, parity, and race with 155 women who had either pudendal or local analgesia for delivery. Infant birth weights were similar in the two groups. The frequency of low forceps, vacuum extraction, and midforceps delivery in the epidural group was significantly higher than in the control group (P less than .05). Women having epidural analgesia who delivered their infants in an occiput anterior position also had a significantly higher frequency of instrumental delivery. Thus, epidural analgesia increased the frequency of instrumental delivery, an increase that was not a consequence of larger infants or fetal malposition.

Androgen and estrogen secretion by normal and neoplastic ovaries in premenopausal women.

Peripheral and ovarian venous concentrations of estradiol-17 beta, estrone, testosterone, and androstenedione were measured in 47 premenopausal women at the time of laparotomy. Ovarian histology was normal in 32 women, and 15 women had a unilateral (N = 13) or bilateral (N = 2) ovarian neoplasm. That the concentrations of these steroids in women with normal ovaries were comparable to values reported by others suggests that surgical stress did not affect the results. The concentration of both estrogens in the vein draining a nonfunctional neoplasm were significantly less than estrogen concentrations in the vein draining the ovary with the dominant follicle or corpus luteum. Peripheral venous estrogen, as well as androgen concentrations were normal in women with a nonfunctional neoplasm. Peripheral concentrations and concentrations of both androgens in the vein draining the ovary with a functional neoplasm were increased significantly. In 21 to 33% of all women with a neoplasm, the ovarian venous concentration of one or both androgens was increased significantly. No woman with an ovarian neoplasm had a significant increase in ovarian venous estrogen concentration. Although we did not define the mechanism for a selective increase in ovarian androgen secretion in a fraction of women, we conclude that any ovarian neoplasm may be associated with abnormal ovarian secretion of sex steroids.

Secretion of androgens and estrogens by normal and neoplastic ovaries in postmenopausal women.

Peripheral and ovarian venous concentrations of testosterone, androstenedione, estradiol-17 beta, and estrone were measured in 30 postmenopausal women. Ovarian venous concentrations of testosterone and estradiol-17 beta were 5.6 and 4.3 times the peripheral concentrations of women with normal ovaries. This suggests that the ovaries of postmenopausal women continue to secrete these two steroids. Mean peripheral testosterone concentrations in 14 postmenopausal women with a nonfunctional or functional ovarian tumor were increased significantly. Ovarian venous concentrations of these four steroids from the side draining the tumor-bearing ovary were increased in 40 to 80% of the women. The venous concentrations from the normal ovary were also increased in 22% or more of the women with an ovarian tumor. Any ovarian neoplasm in postmenopausal women may be associated with increased ovarian sex-steroid secretion.

Premature ovarian failure.

The diagnosis of premature ovarian failure was made in 35 women (ages 17 to 40) with increased concentrations of follicle-stimulating hormone and luteinizing hormone. Three had primary amenorrhea, 29 had secondary amenorrhea (less than one to 15 years), and three had irregular menstrual intervals of less than six months. Symptoms and signs of estrogen deficiency were present in fewer than 50% of these women and were not helpful in distinguishing the different causes of ovarian failure. Six of these women had an autoimmune disorder associated with ovarian failure. Thirteen of 16 women had a normal 46,XX karyotype, and five of 14 women who had an ovarian biopsy had a specimen that contained follicles with oocytes. Two women conceived after they developed ovarian failure and while taking cyclic estrogen and progestin.

Atypical ovarian hyperthecosis in a virilized postmenopausal woman.

Ovarian venous concentrations of testosterone (18.7 ng/mL and 8.2 ng/mL) were three to six times higher than the peripheral concentrations (2.8 ng/mL) in a hirsute postmenopausal woman. She had cystic hyperplasia of the endometrium and atypical hyperthecosis of the ovary. Postoperatively, the testosterone levels returned to normal. From the results of the immunoperoxidase reaction, the luteinized stromal cells of the ovaries were the site of increased production of the testosterone and estradiol. By the same technic, these cells were negative for LH but strongly positive for FSH. From these data, the authors conclude that the luteinized cells were the primary source of the excessive testosterone, that the same cells were the direct and indirect (by peripheral testosterone conversion) source of estradiol, that LH was very likely not involved in the process of steroid hormone production, and that FSH may be the trophic stimulus responsible for the functional activity of the luteinized stromal cells in this virilized postmenopausal woman.

The frequency of androgen receptor deficiency in infertile men.

To ascertain the frequency of androgen resistance as the cause of male infertility and to determine whether endocrine abnormalities are a universal feature of the disorder, we measured the androgen receptor in fibroblasts cultured from the genital skin of 28 unrelated phenotypically normal men with idiopathic azoospermia or oligospermia. The amounts of androgen receptor were compared with those in genital skin fibroblasts from a variety of other subjects, including 10 men with azoospermia of known cause, 5 normal men, 28 subjects with disorders of androgen formation of metabolism of known cause, and 28 persons with documented disorders of the androgen receptor (testicular feminization and Reifenstein syndrome). The mean androgen receptor Bmax (amount of high affinity binding) was 12 fmol/mg protein or greater in 10 infertile men with azoospermia of known cause and in 6 infertile men with mild oligospermia. In fibroblasts from 1 to 4 individuals with severe oligospermia of unknown cause (less than 1 million/ml) and 8 of 18 subjects with idiopathic azoospermia, the androgen receptor Bmax was less than 12 fmol/mg protein. The mean value in these 9 men was not significantly different from that in subjects with testicular feminization or Reifenstein syndrome. Serum concentrations of testosterone and LH were normal in 6 of these 9 infertile men, and plasma production rates of testosterone were elevated in only 2 of the 6 men studied in whom the Bmax values in genital skin fibroblasts were less than 12 fmol/mg protein. We conclude that androgen resistance may be the cause of a significant fraction (40% or more) or idiopathic male infertility due to azoospermia or severe oligospermia, and that this disorder may not be manifested by a functional defect in the pituitary-testicular axis.

The 24-hour secretory pattern of LH and the response to LHRH in transsexual men.

Ten separate aspects of hypothalamic and pituitary function were studied in 13 male-to-female transsexuals and compared to the results of 7 heterosexual adult men. In 4 of 5 transsexuals, the 24-hour mean serum concentration of LH, the LH pulse frequency or amplitude, or the apparent half-life of disappearance of serum LH were greater than the 95% confidence limit of normal men. The maximum concentration of LH or FSH following the administration of 100 micrograms LHRH, the area under the response curve of LH or FSH following LHRH, or both were significantly greater than normal in 5 of 13 male-to-female transsexuals. The response of LH following the administration of LHRH was repeated in 3 subjects during estrogen therapy, and in one there was a paradoxical increase in the response of LH. Transsexualism may be associated with a neuroendocrine defect in the hypothalamus or pituitary that is characterized by high-frequency, high-amplitude pulsatile secretion of pituitary LH.