Claire A. Carlson

An experimental protocol for fertility preservation in prepubertal boys recently diagnosed with cancer: a report of acceptability and safety

BACKGROUND Gonadal damage is a consequence of therapy for pediatric malignancies. Prepubertal males have no semen or mature spermatozoa, posing a challenge for fertility preservation. Testicular tissue cryopreservation is a potential option but is still experimental. We report on a pilot protocol that offered testicular biopsy cryopreservation to families of prepubertal boys with newly diagnosed malignancy. The aims were to determine the acceptability and safety of this procedure. METHODS Parents of prepubertal boys with diagnoses at highest risk for treatment-related gonadal damage were offered the option of testicular cryopreservation. Half of the biopsy was frozen for the subjects potential future use and the remainder used for research. Data on negative intraoperative and/or 7 day post-operative sequelae of testicular biopsies were assessed. Two to four weeks later, parents were asked to complete a questionnaire on factors influencing their decision to have the biopsy or not. RESULTS Since January 2008, 24 boys have met the eligibility criteria but three required immediate treatment and were excluded. Sixteen of 21 families (76%) consented to testicular biopsy, indicating the prospective acceptability of this option to parents of boys aged 3 months to 14 years; 14 underwent the procedure without any negative intra- or post-operative sequelae. Although the time at diagnosis is stressful, families can give thoughtful consideration to this option. Factors such as religion, finance, ethics and the experimental nature of cryopreservation did not play a major role in decision-making. CONCLUSIONS Parents of prepubertal boys with cancer are willing to pursue testicular tissue cryopreservation at diagnosis, and testicular biopsy caused no acute adverse effects.

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

In the human testis, beginning at ≈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 ≈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 α1, Gfrα1; 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 ≈75 million years ago.

Sperm Banking for Adolescent and Young Adult Cancer Patients: Sperm Quality, Patient, and Parent Perspectives

Infertility is often a complication for adolescent and young adult males who receive cancer therapy, a problem that might be averted through using cryopreserved sperm. We aim to evaluate feasibility of offering newly diagnosed patients the opportunity to bank sperm and, to determine the beliefs and decision‐making processes of patients and their parents who considered sperm banking.

Impact of cancer therapies on ovarian reserve

OBJECTIVE To determine whether measures of ovarian reserve differ between females exposed to cancer therapies in a dose-dependent manner as compared with healthy controls of similar age and late reproductive age. DESIGN Cross-sectional analysis of data from a prospective cohort study. SETTING University medical center. PATIENT(S) Seventy-one cancer survivors aged 15-39 years; 67 healthy, similarly aged unexposed subjects; and 69 regularly menstruating women of late reproductive age (40-52 years). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Early follicular-phase hormones (FSH, E(2), inhibin B, antimüllerian hormone [AMH]) and ovarian ultrasound measurements (ovarian volume and antral follicle counts [AFC]) were compared using multivariable linear regression. RESULT(S) In adjusted models, FSH, AMH, and AFC differed between exposed vs. unexposed subjects (FSH 11.12 mIU/mL vs. 7.25 mIU/mL; AMH 0.81 ng/mL vs. 2.85 ng/mL; AFC 14.55 vs. 27.20). In participants with an FSH <10 mIU/mL, survivors had lower levels of AMH and AFC compared with controls. Alkylating agent dose score was associated with increased levels of FSH and decreased levels of AMH. Exposure to pelvic radiation was associated with impairment in FSH, AMH, AFC, and ovarian volume. Antimüllerian hormone was similar in women previously exposed to high-dose cancer therapy and 40-42-year-old controls. CONCLUSION(S) Measures of ovarian reserve are impaired in a dose-dependent manner among cancer survivors compared with unexposed females of similar age. Reproductive hormone levels in menstruating survivors exposed to high-dose therapy are similar to those in late-reproductive-age women. The predictive value of measures for pregnancy and menopause must be studied. CLINICALTRIALS.GOV IDENTIFIER: NCT01143844.

Delivering long-term follow-up care to pediatric cancer survivors: transitional care issues.

One of the major challenges faced by young adult survivors of childhood cancer is the transition from a specialized pediatric care facility to adult‐based health care that provides appropriate follow‐up. This review summarizes the issues regarding the necessity of this transition, including a brief history of follow‐up care of childhood cancer survivors. The general principles of transition care, as well as the barriers and obstacles specific to this population are outlined with the advantages and limitations of several models of transition care that could be considered.

A comparative analysis of functional outcomes in adolescents and young adults with lower-extremity bone sarcoma

Comparison of functional mobility and quality of life is performed in patients with lower‐extremity bone sarcoma following either amputation, limb‐sparing surgery, or rotationplasty with four different types of outcome measures: (1) an objective functional mobility measure that requires patients to physically perform specific tasks, functional mobility assessment (FMA); (2) a clinician administered tool, Musculoskeletal Tumor Society Scale (MSTS); (3) a patient questionnaire, Toronto Extremity Salvage Scale (TESS); and (4) a health‐related quality of life (HRQL) measure, Short Form‐36 version 2 (SF‐36v.2).

Late effects in survivors of tandem peripheral blood stem cell transplant for high-risk neuroblastoma.

Increasing numbers of children with advanced neuroblastoma are achieving cure. We describe the clinical late effects specific to survivors of stage IV neuroblastoma all similarly treated using tandem autologous peripheral blood stem cell rescue with TBI.

Fertility in males treated for Hodgkins disease with COPP/ABV hybrid

More than 80% of those diagnosed with Hodgkins disease (HD) will survive long‐term. For the past decade, a modified hybrid consisting of cyclophosphamide (2.4–3.6g/m2), vincristine, procarbazine, and prednisone (COPP) together with adriamycin, bleomycin, and vinblastine (ABV) has been used to treat patients with HD. Little data exists on how this modified hybrid impacts male fertility. Eleven male patients treated with COPP‐ABV hybrid were studied. Nine out of 11 subjects were categorized as infertile by semen analysis; 7 of 9 were azoospermic. There was no association between fertility status and prepubertal status at diagnosis or gonadotropin status. Despite lower doses of cyclophosphamide, treatment with the current COPP/ABV hybrid leads to infertility in the majority of young men. It is likely that procarbazine, an effective yet potent gonadotoxic agent, is responsible for this outcome.

Pulmonary Function Abnormalities in Children Treated With Whole Lung Irradiation

We sought to determine the prevalence of abnormal pulmonary function tests (PFTs) in a cohort of children who had received whole lung irradiation (WLI) for treatment of metastatic disease.

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

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.