DC Cancer Consortium

Purpose:Therapy resistance and fatal disease progression in glioblastoma are thought to result from the dynamics of intra-tumor heterogeneity. This study aimed at identifying and molecularly targeting tumor cells that can survive, adapt, and subclonally expand under primary therapy.Experimental Design:To identify candidate markers and to experimentally access dynamics of subclonal progression in glioblastoma, we established a discovery cohort of paired vital cell samples obtained before and after primary therapy. We further used two independent validation cohorts of paired clinical tissues to test our findings. Follow-up preclinical treatment strategies were evaluated in patient-derived xenografts.Results:We describe, in clinical samples, an archetype of rare ALDH1A1+ tumor cells that enrich and acquire AKT-mediated drug resistance in response to standard-of-care temozolomide (TMZ). Importantly, we observe that drug resistance of ALDH1A1+ cells is not intrinsic, but rather an adaptive mechanism emerging exclusively after TMZ treatment. In patient cells and xenograft models of disease, we recapitulate the enrichment of ALDH1A1+ cells under the influence of TMZ. We demonstrate that their subclonal progression is AKT-driven and can be interfered with by well-timed sequential rather than simultaneous antitumor combination strategy.Conclusions:Drug-resistant ALDH1A1+/pAKT+ subclones accumulate in patient tissues upon adaptation to TMZ therapy. These subclones may therefore represent a dynamic target in glioblastoma. Our study proposes the combination of TMZ and AKT inhibitors in a sequential treatment schedule as a rationale for future clinical investigation.

This work identifies a novel promoter that drives aberrant FOXR2 expression and delineates FOXR2 as a pan-cancer oncogene that specifically activates ETS transcriptional circuits across human cancers. See related commentary by Liu and Northcott, p. 2977.

BackgroundTo compare cholesteatoma care internationally and to evaluate outcomes, ear surgeons must use the same terminology. However, a clear universal definition on how to describe the extension, destruction and accompanying morbidity caused by the cholesteatoma is lacking. The practical applicability by means of interrater agreement is assessed for the STAMCO and the ChOLE classification.MethodsA total of 134 adult patients derived from the nationwide multicentre study in the Netherlands, entitled Dutch Cholesteatoma Data (DCD) were included. Retrospective analysis of 134 surgical reports according to the STAMCO and ChOLE classification for localisation/extension of the cholesteatoma, complication status and ossicular chain status. Both the percentage agreement and the interrater agreement were determined for each item of the classifications and interrater agreement was compared between the classifications as a whole.ResultsDifferences in interrater agreement were found for both the localisation/extension of the cholesteatoma and ossicular chain status. STAMCO classification derived from the surgical report scored better on the localisation/extension of the cholesteatoma, whereas the ChOLE classification derived from the surgical report scored better on the status of the ossicular chain. In both classifications, complication status had a low agreement level but was also poorly registered in the surgical reports.ConclusionBoth STAMCO and ChOLE will be beneficial in uniform registration of cholesteatoma pathology in practice. Modifications proposed for both classifications may make them even more practical applicable in the future. A common denominator obtained from these two classifications may be incorporated in a standardised surgical report to facilitate evaluation which make outcomes transferable towards both classifications.

Extraction methods are critical in the production and success of an extra virgin olive oil ready for consumption. The first step of olive oil extraction procedure produces an olive paste, which is subsequently processed by separation of the liquid phases (oil and vegetable water) from the pomace. Profiles of Apulian extra virgin olive oils and the deuterated chloroform extracts of its paste and pomace were studied by 1D and 2D NMR (NMR) spectroscopy without separation and pre‐treatment of samples. In order to study the metabolic profiles variation in the paste and pomace extracts with respect to the corresponding EVOOs, multivariate statistical analyses (PCA and OPLS DA) of the1H NMR data were performed. As expected, a different minor components profile, in particular for the presence of higher content of secoiridoids, lignans and phenolic compounds in olive paste and pomace extracts with respect to the EVOOs, was observed.Practical applications:Amount of extractable oil from olive paste and pomace after the production processes of EVOO was measured by1H NMR spectroscopy. Identification of metabolites in olive paste and pomace was performed by 1D and 2D NMR spectroscopy without separation and pre‐treatment of samples. The chemical composition of major and minor components (in particular secoiridoids, lignans, and phenolic compounds) present in olive paste and pomace chloroform extracts could be used for extraction process trimming purposes as well as in fingerprint analyses for cultivar and/or geographical origin certification of olive oil production. Moreover, determination of the entire metabolic content of different materials of the olive oil production process could be exploited in other applications such as recycling on agricultural land, studies of the health benefits on human nutrition and alternative dietary lipid source in animals. In fact, it is worth noting that the olive paste and pomace extracts could be even healthier than other vegetable oils.The extraction processes are critical in the extra virgin olive oil production. The chemical composition of EVOOs and its paste and pomace extracts have been investigated by Nuclear Magnetic Resonance Spectroscopy (NMR).

Purpose: Achieving safe and effective ablation of rectal tissue is a problem encountered when treating radiation proctopathy. We present a unique clinical scenario in which rectal tissue ablation reduced discharge from a rectal stump in a patient with a blast injury to his gluteal region. A 24 yearold active duty male with history of a blast injury to the buttocks from a rocket-propelled grenade suffered while serving in Iraq was referred to the gastroenterology service for bothersome rectal discharge. His initial injuries led to multiple surgeries including a right biceps femoris flap, urethra repair, colonic repair with placement of a colostomy, and other reconstructive surgeries. He was left disconnected with a rectal stump due to the absence of anal sphincter function and a difficult-to-reach rectal stump. Ten months after the injury, a flexible sigmoidoscopy was performed to evaluate rectal discharge and revealed a 10cm rectal stump with erythematous mucosa and copious, foul-smelling exudate. Biopsies were consistent with diversion proctitis. The patient was ineffectively treated with topical hydrocortisone foam and mesalamine enemas. A second endoscopy was performed with the intent of ablating rectal tissue using a radiofrequency ablation (RFA) electrode (HALO 90 system by BARRX Medical). Several weeks later, the patient noted a significant reduction in the amount of rectal discharge. Repeat endoscopy was performed 5 weeks later using argon plasma coagulation (APC), but he noted negligible improvement over the first ablative procedure. Another endoscopy was performed 8 weeks later using a combination of RFA and cryoablation, which resulted in a modest decrease in the amount of rectal discharge. One month later, he reported a decrease in the amount of discharge. The patient did not follow up in our clinic further due to discharge from the Army; however, he reported via phone continued improvement one year later. This is a unique case of a patient with diversion colitis and rectal stump drainage in the setting of an absent anal sphincter. Many of the topical therapies considered may have limited effect with absence of sphincter function. Using ablative procedures such as RFA and cryoablation had surprising effect. Although APC is considered the most helpful therapy for radiation proctopathy, it was difficult to use in this case due to the large surface area involved and the technical difficulty of the procedure. RFA and cryoablation seemed to be most effective and had a durable effect.