Nutlin-3a efficacy in sarcoma predicted by transcriptomic and epigenetic profiling

Nutlin-3a is a small-molecule antagonist of p53/MDM2 that is being explored as a treatment for sarcoma. In this study, we examined the molecular mechanisms underlying the sensitivity of sarcomas to Nutlin-3a. In an ex vivo tissue explant system, we found that TP53 pathway alterations (TP53 status, MDM2/MDM4 genomic amplification/mRNA overexpression, MDM2 SNP309, and TP53 SNP72) did not confer apoptotic or cytostatic responses in sarcoma tissue biopsies (n = 24). Unexpectedly, MDM2 status did not predict Nutlin-3a sensitivity. RNA sequencing revealed that the global transcriptomic profiles of these sarcomas provided a more robust prediction of apoptotic responses to Nutlin-3a. Expression profiling revealed a subset of TP53 target genes that were transactivated specifically in sarcomas that were highly sensitive to Nutlin-3a. Of these target genes, the GADD45A promoter region was shown to be hypermethylated in 82% of wild-type TP53 sarcomas that did not respond to Nutlin-3a, thereby providing mechanistic insight into the innate ability of sarcomas to resist apoptotic death following Nutlin-3a treatment. Collectively, our findings argue that the existing benchmark biomarker for MDM2 antagonist efficacy (MDM2 amplification) should not be used to predict outcome but rather global gene expression profiles and epigenetic status of sarcomas dictate their sensitivity to p53/MDM2 antagonists.Kathleen I. Pishas, Susan J. Neuhaus, Mark T. Clayer, Andreas W. Schreiber, David M. Lawrence, Michelle Perugini, Robert J. Whitfield, Gelareh Farshid, Jim Manavis, Steve Chryssidis, Bronwen J. Mayo, Rebecca C. Haycox, Kristen Ho, Michael P. Brown, Richard J. D'Andrea, Andreas Evdokiou, David M. Thomas, Jayesh Desai, David F. Callen and Paul M. Neilse

Development of a rat model of oral small molecule receptor tyrosine kinase inhibitor-induced diarrhea

Orally administered small molecule receptor tyrosine kinase inhibitors (RTKIs) are increasingly common treatments for cancer, both alone and in combination with chemotherapy. However, their side effect profiles and the underlying mechanisms of such are not yet fully elucidated. Management of their most common dose limiting side effect, diarrhea, has been hampered by a lack of suitable animal models. We aimed to develop a clinically relevant rat model of RTKI-induced diarrhea that could be utilized for investigating supportive care interventions and pharmacokinetics. Albino Wistar rats were treated daily for 4 weeks with various concentrations of lapatinib to determine the optimal dose for development of diarrhea. This was then followed by an experiment with addition of paclitaxel once weekly for 4 weeks to observe effects of combination drug treatment on diarrhea. Data regarding animal tolerance to the treatment, organ weights, circulating lapatinib concentration and histopathology were collected weekly. Lapatinib caused diarrhea in rats that was dose-dependent. Diarrhea occurred without causing significant intestinal histopathology. Follow up experiments are currently underway to determine the exact pathogenesis and mechanisms of lapatinib-induced diarrhea and potential protective strategies.Joanne M. Bowen, Bronwen J. Mayo, Erin Plews, Emma Bateman, Andrea M. Stringer, Frances M. Boyle, John W. Finnie and Dorothy M.K. Keef

Systematic review of agents for the management of cancer treatment-related gastrointestinal mucositis and clinical practice guidelines

20Purpose: The aim of this study was to update the clinical practice guidelines for the use of agents for the prevention and/or treatment of gastrointestinal mucositis (GIM). Methods: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: Recommendation, Suggestion, and No Guideline Possible. Results: A total of 78 papers across 13 interventions were examined of which 25 were included in the final review. No new guidelines were possible for any agent due to inadequate and/or conflicting evidence. Existing guidelines for probiotics and hyperbaric oxygen were unchanged. Conclusions: Of the agents studied for the prevention and treatment of GIM, the evidence continues to support use of probiotics containing Lactobacillus spp. for prevention of chemoradiotherapy and radiotherapy-induced diarrhea in patients with pelvic malignancy, and hyperbaric oxygen therapy to treat radiation-induced proctitis. Additional well-designed research is encouraged to enable a decision regarding palifermin, glutamine, sodium butyrate, and dietary interventions, for the prevention or treatment of GIM.nonenoneBowen J.M.; Gibson R.J.; Coller J.K.; Blijlevens N.; Bossi P.; Al-Dasooqi N.; Bateman E.H.; Chiang K.; de Mooij C.; Mayo B.; Stringer A.M.; Tissing W.; Wardill H.R.; van Sebille Y.Z.A.; Ranna V.; Vaddi A.; Keefe D.M.; Lalla R.V.; Cheng K.K.F.; Elad S.Bowen, J. M.; Gibson, R. J.; Coller, J. K.; Blijlevens, N.; Bossi, P.; Al-Dasooqi, N.; Bateman, E. H.; Chiang, K.; de Mooij, C.; Mayo, B.; Stringer, A. M.; Tissing, W.; Wardill, H. R.; van Sebille, Y. Z. A.; Ranna, V.; Vaddi, A.; Keefe, D. M.; Lalla, R. V.; Cheng, K. K. F.; Elad, S

Return to Work Among Young Adult Survivors of Allogeneic Hematopoietic Cell Transplantation in the United States

Young adult (YA) survivors of allogeneic hematopoietic cell transplantation (HCT) are at risk for late psychosocial challenges, including the inability to return to work post-HCT. Work-related outcomes in this population remain understudied, however. We conducted this study to assess the post-HCT work status of survivors of allogeneic HCT who underwent HCT as YAs and to analyze the patient-, disease-, and HCT-related factors associated with their work status at 1 year post-HCT. Using Center for International Blood and Marrow Transplant Research data, we evaluated the post-HCT work status (full-time, part-time work, unemployed, or medical disability) of 1365 YA HCT survivors who underwent HCT between 2008 and 2015. Percentages of work status categories were reported at 4 time points: 6 months, 1 year, 2 years, and 3 years post-HCT. Percentages of post-HCT work status categories at the 1-year time point were also described in relation to survivors' pre-HCT work status categories. Factors associated with 1-year post-HCT work status (full-time or part-time work) were examined using logistic regression. From 6 months to 3 years post-HCT, the percentage of survivors working full-time increased from 18.3% to 50.7% and the percentage working part-time increased from 6.9% to 10.5%. Of patients in full-time work pre-HCT, 50% were unemployed or on medical disability at 1 year post-HCT. Female sex (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.40 to 0.77), HCT Comorbidity Index score ≥3 (OR, 0.57; 95% CI, 0.39 to 0.82), pre-HCT unemployment (OR, 0.37; 95% CI, 0.24 to 0.56), medical disability (OR, 0.44; 95% CI, 0.28 to 0.70), development of grade III-IV acute graft-versus-host disease (OR, 0.52; 95% CI, 0.34 to 0.80), and relapse within 1 year post-HCT (OR, 0.34; 95% CI, 0.21 to 0.56) were associated with a lower likelihood of employment at 1 year post-HCT. Compared with myeloablative conditioning (MAC) with total body irradiation (TBI), MAC without TBI (OR, 1.71; 95% CI, 1.16 to 2.53) was associated with a greater likelihood of employment at 1 year post-HCT. Graduate school-level education (OR, 2.47; 95% CI, 1.49 to 4.10) was also associated with a greater likelihood of employment at 1 year post-HCT. Although the work status among YA HCT survivors continued to improve over time, a substantial subset became or remained unemployed or on medical disability. These findings underscore the need for effective interventions to support return to work in this population

Return to Work Among Young Adult Survivors of Allogeneic Hematopoietic Cell Transplantation in the United States

BACKGROUND: Young adult (YA) survivors of allogeneic hematopoietic cell transplant (HCT) are at risk for late psychosocial challenges, including inability to return to work post-HCT. However, work-related outcomes in this population remain understudied. OBJECTIVES: To assess the post-HCT work status of survivors of allogeneic HCT who underwent HCT as YA and analyze the patient-, disease-, and HCT-related factors associated with their work status at 1-year post-HCT. STUDY DESIGN: Using the Center for International Blood and Marrow Transplant Research (CIBMTR) data, we described post-HCT work status (full-time, part-time work, unemployed, and medical disability) of YA HCT survivors (N=1365) who underwent HCT between 2008 and 2015. Percentages of work status categories were reported at four timepoints: 6-months, 1-, 2-, and 3-year post-HCT. Percentages of post-HCT work status categories at the 1-year timepoint were also described in relation to survivors’ pre-HCT work status categories. Factors associated with 1-year post-HCT work status (full-time or part-time work) were examined using logistic regression. RESULTS: From 6 months to 3 years post-HCT, the percentage of survivors working full-time and part-time increased from 18.3% to 50.7%, and from 6.9% to 10.5%, respectively. Of patients in full-time work pre-HCT, 50% were unemployed or on medical disability at 1-year post-HCT. Female sex (Odds ratio [OR] 0.55; 95% confidence interval [CI] 0.40–0.77), HCT-comorbidity index (HCT-CI) score ≥3 (OR 0.57; 95% CI 0.39–0.82), pre-HCT unemployment (OR 0.37; 95% CI 0.24–0.56), and medical disability (OR 0.44; 95% CI 0.28–0.70), development of grade 3–4 acute graft vs. host disease (OR 0.52; 95% CI 0.34–0.80), and relapse within one-year post-HCT (OR 0.34; 95% CI 0.21–0.56) were associated with lower likelihood of employment at 1-year post-HCT. Compared to myeloablative conditioning with total body irradiation (TBI), myeloablative conditioning without TBI (OR 1.71; 95% CI 1.16–2.53) was associated with higher likelihood of employment at 1-year post-HCT. Graduate school level education (OR 2.47; 95% CI 1.49–4.10) was also associated with higher likelihood of employment at 1-year post-HCT. CONCLUSIONS: While the work status among YA HCT survivors continued to improve over time, a substantial subset became or remained unemployed or on medical disability. These findings underscore the need for effective return to work supportive interventions in this population

Subsequent neoplasms and late mortality in children undergoing allogeneic transplantation for nonmalignant diseases

We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range, <1 to 20) from the Center for International Blood and Marrow Transplant Research (1995-2012) registry. Standardized mortality ratios (SMRs) in 2-year survivors and standardized incidence ratios (SIRs) were calculated to compare mortality and SN rates with expected rates in the general population. Median follow-up of survivors was 7.8 years. Diagnoses included severe aplastic anemia (SAA; 24%), Fanconi anemia (FA; 10%), other marrow failure (6%), hemoglobinopathy (15%), immunodeficiency (23%), and metabolic/leukodystrophy syndrome (22%). Ten-year survival was 93% (95% confidence interval [95% CI], 92% to 94%; SMR, 4.2; 95% CI, 3.7-4.8). Seventy-one patients developed SNs (1.2%). Incidence was highest in FA (5.5%), SAA (1.1%), and other marrow failure syndromes (1.7%); for other NMDs, incidence was <1%. Hematologic (27%), oropharyngeal (25%), and skin cancers (13%) were most common. Leukemia risk was highest in the first 5 years posttransplantation; oropharyngeal, skin, liver, and thyroid tumors primarily occurred after 5 years. Despite a low number of SNs, patients had an 11-fold increased SN risk (SIR, 11; 95% CI, 8.9-13.9) compared with the general population. We report excellent long-term survival and low SN incidence in an international cohort of children undergoing HCT for NMDs. The risk of SN development was highest in patients with FA and marrow failure syndromes, highlighting the need for long-term posttransplantation surveillance in this population

MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy

Background: Mucositis is a significant toxicity of cancer therapy with numerous systemic sequelae. The goal of this systematic review was to update the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for the management of mucositis. Methods: The literature was reviewed systematically to identify interventions for mucositis. Studies were rated according to the presence of major and minor flaws according to previously published criteria. The body of evidence for each intervention and in each treatment setting was assigned a level of evidence based on previously published criteria. Guidelines were developed based on the level of evidence, with 3 possible guideline determinations: recommendation, suggestion, or no guideline possible. Results: The guideline covers evidence from 1197 publications related to oral or gastrointestinal mucositis. Thirteen new guidelines were developed for or against the use of various interventions in specific treatment settings, and 11 previous guidelines were confirmed after aa review of new evidence. Thirteen previously established guidelines were carried over because there was no new evidence for these interventions. Conclusions: The updated MASCC/ISOO Clinical Practice Guidelines for mucositis provide professional health caregivers with a clinical setting-specific, evidence-based tool to help with the management of mucositis in patients who have cancer