Marianne Phillips

Breast Cancer Before Age 40 Years

Approximately 7% of women with breast cancer are diagnosed before the age of 40 years, and this disease accounts for more than 40% of all cancer in women in this age group. Survival rates are worse when compared to those in older women, and multivariate analysis has shown younger age to be an independent predictor of adverse outcome. Inherited syndromes, specifically BRCA1 and BRCA2, must be considered when developing treatment algorithms for younger women. Chemotherapy, endocrine, and local therapies have the potential to significantly impact both the physiologic health-including future fertility, premature menopause, and bone health-and the psychological health of young women as they face a diagnosis of breast cancer.

Novel BRD4-NUT fusion isoforms increase the pathogenic complexity in NUT midline carcinoma.

Nuclear protein in testis (NUT)-midline carcinoma (NMC) is a rare, aggressive disease typically presenting with a single t(15;19) translocation that results in the generation of a bromodomain-containing protein 4 (BRD4)–NUT fusion. PER-624 is a cell line generated from an NMC patient with an unusually complex karyotype that gave no initial indication of the involvement of the NUT locus. Analysis of PER-624 next-generation transcriptome sequencing (RNA-Seq) using the algorithm FusionFinder identified a novel transcript in which Exon 15 of BRD4 was fused to Exon 2 of NUT, therefore differing from all published NMC fusion transcripts. The three additional exons contained in the PER-624 fusion encode a series of polyproline repeats, with one predicted to form a helix. In the NMC cell line PER-403, we identified the ‘standard’ NMC fusion and two novel isoforms. Knockdown by small interfering RNA in either cell line resulted in decreased proliferation, increased cell size and expression of cytokeratins consistent with epithelial differentiation. These data demonstrate that the novel BRD4–NUT fusion in PER-624 encodes a functional protein that is central to the oncogenic mechanism in these cells. Genomic PCR indicated that in both PER-624 and PER-403, the translocation fuses an intron of BRD4 to a region upstream of the NUT coding sequence. Thus, the generation of BRD4–NUT fusion transcripts through post-translocation RNA-splicing appears to be a common feature of these carcinomas that has not previously been appreciated, with the mechanism facilitating the expression of alternative isoforms of the fusion. Finally, ectopic expression of wild-type NUT, a protein normally restricted to the testis, could be demonstrated in PER-403, indicating additional pathways for aberrant cell signaling in NMC. This study contributes to our understanding of the genetic diversity of NMC, an important step towards finding therapeutic targets for a disease that is refractory to current treatments.

Bacillus cereus bacteremia and multiple brain abscesses during acute lymphoblastic leukemia induction therapy.

Bacillus cereus can cause serious infections in immunosuppressed patients. This population may be susceptible to B. cereus pneumonia, bacteremia, cellulitis, and rarely cerebral abscess. Here we report an 8-year-old boy undergoing induction therapy for acute lymphoblastic leukemia who developed multifocal B. cereus cerebral abscesses, highlighting the propensity for B. cereus to develop cerebral abscesses. A review of the literature over the past 25 years identified another 11 cases (3 children and 8 adults) of B. cereus cerebral abscess in patients undergoing cancer therapy. B. cereus cerebral abscesses were associated with a high mortality rate (42%) and significant morbidity. Notably, B. cereus bacteremia with concomitant cerebral abscess was associated with induction chemotherapy for acute leukemia in both children and adults (10 of 12 case reports). Our case report and review of the literature highlights the propensity for B. cereus to develop cerebral abscess(es). Therefore, early consideration for neuroimaging should be given for any neutropenic cancer patient identified with B. cereus bacteremia, in particular those with acute leukemia during induction therapy.

Chemotherapy increases amenability of surgical resection in congenital glioblastoma.

Brain tumors presenting in infancy, especially during the first 6 months of life, are often very large and highly vascular. It is generally accepted that gross total resection of the tumor affords the best outcome to the patient. However, tumor resection is frequently very challenging due to the risk of significant bleeding. We report two cases of congenital glioblastoma whose initial surgery was hampered by tumor hypervascularity and excessive blood loss, resulting in subtotal resection. Subsequent carboplatin-based chemotherapy led to a significant reduction in tumor size and vascularity, enabling safe gross total resection at second-look surgery. Based on these findings and a review of the literature, we recommend cytoreductive chemotherapy following diagnostic biopsy for infants presenting with large, highly vascular tumors, such as congenital glioblastoma, in lieu of aggressive upfront surgery, to increase the feasibility and facilitate safe gross total excision at second-look surgery.

Hepatic sinusoidal obstruction syndrome during chemotherapy for childhood medulloblastoma: report of a case and review of the literature.

Hepatic sinusoidal obstruction syndrome (HSOS), also known as veno-occlusive disease, is a well-recognized toxic complication after autologous and allogeneic hematopoietic stem cell transplant, during treatment of Wilms tumor and rhabdomyosarcoma associated with actinomycin-D, and during acute lymphoblastic leukemia therapy due to oral 6-thioguanine. However, its occurrence in the context of chemotherapy regimens for other childhood malignancies is rare. We report a 5-year-old girl with high-risk anaplastic medulloblastoma, who developed severe HSOS during her second cycle of maintenance chemotherapy, consisting of vincristine, cisplatin, and cyclophosphamide. She was treated with defibrotide with complete resolution of the HSOS. These findings and a review of the literature, highlight the occurrence of HSOS in children outside the established settings of hematopoietic stem cell transplantation, Wilms tumor, rhabdomyosarcoma, and acute lymphoblastic leukemia.

Inconsistencies and time delays in site-specific research approvals hinder collaborative clinical research in Australia

The aim of this study was to describe the time and documentation needed to gain ethics and governance approvals in Australian states with and without a centralised ethical review system.

Do Australian adolescents' and young adults' experiences of cancer care influence their quality of life?

To examine the relationship between the cancer care experiences of adolescents and young adults (AYAs) and their quality of life.

Allogeneic bone marrow transplantation in juvenile myelomonocytic leukemia without total body irradiation.

Allogeneic bone marrow transplantation (BMT) without a total body irradiation (TBI) conditioning regimen was investigated in children with juvenile myelomonocytic leukemia (JMML). Eight consecutive patients with JMML (n = 6) or monosomy 7 (n = 2) underwent BMT at a median age of 20 months. Donor source included fully matched related (n = 3), mismatched related (n = 2), or fully matched unrelated (n = 3). The conditioning regimen included busulfan, cyclophosphamide, and etoposide (VP16) (melphalan was substituted for VP16 in one patient). The first patient in the series underwent TBI. Graft-versus-host disease prophylaxis was with cyclosporin and methotrexate and in vivo T-cell depletion (Campath 1 g) for mismatched and unrelated transplants. Seven and two patients, respectively, received chemotherapy and splenectomy before BMT. At a median follow-up of 48 months after BMT, five patients remained in remission. The overall survival rate was 63% at 5 years. All deaths occurred in patients with refractory disease at the time of BMT. Allogeneic BMT without TBI appears to be effective therapy for JMML and avoids some of the potential late sequelae of TBI in preschool children.

Factors influencing the documentation of fertility-related discussions for adolescents and young adults with cancer

PURPOSE A cancer diagnosis and treatment may have significant implications for a young patients future fertility. Documentation of fertility-related discussions and actions is crucial to providing the best follow-up care, which may occur for many years post-treatment. This study examined the rate of medical record documentation of fertility-related discussions and fertility preservation (FP) procedures for adolescents and young adults (AYAs) with cancer in Australia. METHODS A retrospective review of medical records for 941 patients in all six Australian states. Patients were identified through population-based cancer registries (four states) and hospital admission lists (two states). Trained data collectors extracted information from medical records using a comprehensive data collection survey. Records were reviewed for AYA patients (aged 15-24 years at diagnosis), diagnosed with acute myeloid leukaemia, acute lymphoblastic leukaemia, central nervous system (CNS) tumours, soft tissue sarcomas (STS), primary bone cancer or Ewings family tumours between 2007 and 2012. RESULTS 47.2% of patients had a documented fertility discussion and 35.9% had a documented FP procedure. Fertility-related documentation was less likely for female patients, those with a CNS or STS diagnosis and those receiving high-risk treatments. In multivariable models, adult hospitals with an AYA focus were more likely to document fertility discussions (odds ratio[OR] = 1.60; 95%CI = 1.08-2.37) and FP procedures (OR = 1.74; 95%CI = 1.17-2.57) than adult hospitals with no AYA services. CONCLUSIONS These data provide the first national, population-based estimates of fertility documentation for AYA cancer patients in Australia. Documentation of fertility-related discussions was poor, with higher rates observed in hospitals with greater experience of treating AYA patients.

Clinical trial participation by adolescents and young adults with cancer: A continued cause for concern?

International data indicate that rates of clinical trial enrolment for Adolescents and Young Adults (AYAs) with cancer are markedly lower than for any other age group. This paper reviews the recent literature reporting international trends in clinical trial enrolment since 2010. Subsequently, we present the first population-based, national assessment of clinical trial enrolment for AYAs with cancer in Australia. Reported rates of trial enrolment from Australia, Canada, the United States, and the United Kingdom were variable, though consistently low, ranging between 2% and 29%. Trial enrolment was higher for younger AYAs (typically 15-19 years) and those attending pediatric hospitals, and this was replicated in the recent Australian data. The findings highlight a lack of substantial improvement in AYA clinical trial enrolment and in particular, a need for improved opportunities to access trials for patients treated at adult centers.