In the survivorship setting, adolescent and young adult (AYA) cancer survivors frequently demonstrate little knowledge of infertility risk, are unclear regarding their fertility status and may under- or over-estimate their treatment-related risk for infertility. In female AYA survivors, ovarian function usually parallels fertility, and can be assessed with serum hormone levels and ultrasonography. Post-treatment fertility preservation may be appropriate for survivors at risk for primary ovarian insufficiency. In male AYA survivors, fertility and gonadal function are not always equally affected, and can be assessed with a semen analysis and serum hormones, respectively. As reproductive health issues are commonly cited as an important concern by survivors of AYA cancer, multidisciplinary care teams including oncology, endocrinology, psychology, and reproductive medicine are advocated, with the aim of optimal provision of fertility advice and care for AYA cancer survivors.
Background Metabolic syndrome and obesity occur commonly in long-term pediatric cancer survivors and exacerbate other chronic conditions. The intestinal microbiome is associated with metabolic syndrome and obesity in the general population, and is perturbed during cancer therapy. We aimed to determine if long-term survivors of pediatric cancer would have reduced bacterial microbiome diversity, and if these findings would be associated with components of the metabolic syndrome, obesity, and chronic inflammation. Methods We performed a cross-sectional study examining the intestinal microbiome, clinical factors, and biomarkers between 35 long-term survivors and 32 age, sex, and race matched controls. All subjects were ages 10-40, and survivors were at least five years from the time of diagnosis. Results Survivors had decreased alpha diversity compared to controls (Shannon index p=0.001, Simpson index p=0.032) and differently abundant bacterial taxa. Further, among survivors, those who received radiation to the central nervous system or abdomen/pelvis had decreased alpha diversity compared to those that did not receive radiation (Shannon and Simpson p<0.05 for both). Although, no specific component of metabolic syndrome or cytokine was associated with measures of alpha diversity, survivors with low adiponectin-lectin ratio, elevated body mass index, and elevated C-Reactive protein had differently abundant taxa compared to those with normal measures. Conclusions The microbiome of cancer survivors remains less diverse than controls even many years after diagnosis, and exposure to radiation may lead to further loss of diversity in survivors. The microbiome may be associated with metabolic syndrome and chronic inflammation in survivors.
Palifermin as Primary Prophylaxis for Mucositis Prevention in Patients with B-Cell Non-Hodgkin LymphomaAnthony S. Zembillas, PharmD, BCPS, BCOP1,3, Stefanie M. Thomas, MD, MS2, Seth J. Rotz MD2, Ilia N. Buhtoiarov, MD2, Rabi Hanna, MD2(1) Pharmacy, Cleveland Clinic, Cleveland, OH;(2) Department of Pediatric Hematology Oncology and Bone Marrow Transplantation, Cleveland Clinic Children’s, Cleveland, OH;(3) Address correspondence to:Funding Source: Supported in part by a grant from the NIH NCATS (2KL2TR002547 PI Dweik, to S.J.R.)To the Editor:Progress continues to be made regarding the treatment of children and adolescents with aggressive B-cell Non-Hodgkin Lymphoma (NHL). Recent data demonstrated patients with mature B-cell NHL have an improved overall survival with the addition of rituximab to lymphomes malins B (LMB) chemotherapy.1 However, these patients experienced significant therapy-related adverse events including febrile neutropenia, stomatitis, and infection. Oral mucositis, the second most common adverse event, occurred in up to 80% of patients with grade 3 oral mucositis occurring in 71% of patients. 1Complications related to mucositis include significant morbidities such as severe pain requiring opioids, nutritional deficiencies necessitating parenteral nutrition, life-threatening bloodstream infections, and prolonged hospitalizations likely increasing the overall cost of care.2 Proper oral care is the standard first-line approach to mucositis prevention but its benefits may be limited with more intensive chemotherapy regimens.Palifermin, a human recombinant keratinocyte growth factor, is a preventative medication that has shown positive effects on reducing mucositis frequqncy and severity in children receiving cancer therapy.3 Studies of palifermin most frequently involve patient’s undergoing hematopoietic stem cell transplant (HSCT) with limited data in the non-HSCT setting.4-6 Data are encouraging regarding the use of palifermin as secondary prophylaxis, showing effectiveness in children and adolescents with NHL who previously developed mucositis.6 This data, combined with our experience of significant toxicity in our patient population led us to administer palifermin as primary prophylaxis for mucositis prevention in patients receiving Group B or Group C LMB therapy for B-cell NHL, as part of routine clinical practice.We first utilized this approach in a young adult male with Stage II A diffuse large B cell lymphoma (DLBCL) treated per Group B of ANHL1131. He received a single dose of palifermin 180 mcg/kg IV in the outpatient setting approximately three days prior to cycles 1 and 2. He did not receive palifermin prior to cycle 3 due to the perceived lower risk of mucositis. But after developing severe mucositis requiring opioid analgesics during cycle 3, palifermin was reinstituted prior to cycle 4. Of the three cycles where palifermin was used, there were no mucositis-related complications. The patient remains in complete remission one year post-therapy. The second patient was a young adult female with Burkitt lymphoma treated per Group C1 of ANHL1131. She received a single dose of palifermin 180 mcg/kg IV in the outpatient setting approximately 3 days prior to all 6 cycles of chemotherapy. She did not have mucositis-related complications or require opioids for mucositis-related pain throughout her entire treatment. She has no evidence of disease at end of therapy. No toxicities from palifermin were noted in either patient.Our experience suggests that palifermin is a potential therapeutic option as primary prophylaxis for NHL patients receiving high intensity chemotherapy commonly causing grade 3-4 mucositis. Prospective studies are warranted to confirm the benefit and safety of palifermin compared to other interventions such as oral saline rinses or a standardized oral mouth care protocol.ReferencesMinard-Colin V, Auperin A, Pillon M, Burke GAA, Barkauskas DA, Wheatley K. Rituximab for high-risk, mature B-cell non-Hodgkin’s lymphoma in children. N Engl J Med 2020;382:2207-2219.Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T. Palifermin for Oral Mucositis after Intensive Therapy for Hematologic Cancers. N Engl J Med2004;351:2590-2598.Mazhari, F, Shirazi AS, Shabzendehdar M. Management of oral mucositis in pediatric patients receiving cancer therapy: a systematic review and meta-analysis. Pediatr Blood Cancer 2019;66:e27403.Vadhan-Raj S, Trent J, Patel S, Zhou X, Johnson MM, Araujo D. Single-dose palifermin prevents severe oral mucositis during multicycle chemotherapy in patients with cancer. Ann Intern Med 2010;153:358-367.Saber W, Zhang MJ, Steinert P, Chen Min, Horowitz MM. The impact of palifermin use on hematopoietic cell transplant outcomes in children. Biol Blood Marrow Transplant 2016;22:1460-1466.Dazhi L, Seyboth B, Mathew S, Gilheeney SW, Chou AJ, Drill E. Retrospective evaluation of palifermin use in nonhematopoietic stem cell transplant pediatric patients. J Pediatr Hematol Oncol 2017;39:177-182.
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is an immune checkpoint, which downregulates T cell activation and T regulatory cell function. CTLA-4 haploinsufficiency (CTLA4 HI) leads to T cell hyperactivation, immune dysregulation, lymphoproliferation and cancer predisposition. Less well understood is the penetrance and expressivity of CTLA-4 mutations. We describe five members of a single family with heterozygous CTLA-4 splice site mutation c.458-1G>C, previously shown to result in CTLA-4 HI, who presented with variable degree of immune dysfunction, lymphocytic infiltration and autoimmunity. The host, environmental and the epigenetic factors affecting the penetrance and expressivity of CTLA-4 mutations merits further investigation.