Pituitary carcinoma: Two case reports and review of literature

BACKGROUND: Pituitary carcinoma is a rare type of malignancy that can be very difficult to diagnose and treat. Many cases were diagnosed at autopsy. Delays in diagnosis often adversely impact patients\u27 outcomes. Even with prompt diagnosis, treatment decisions remain challenging in the absence of randomized controlled trials. CASE SUMMARY: We report two cases of pituitary carcinoma in men with a history of pituitary adenoma. In the first case, a 55-year-old man was initially diagnosed with pituitary macroadenoma. He underwent subtotal debulking of the tumor followed by adjuvant radiotherapy. Subsequently, he developed relapsed disease and multifocal intracranial metastases and a diagnosis of pituitary carcinoma was rendered. He passed away despite several lines of systemic therapies including temozolomide, lomustine and bevacizumab. Another 52-year-old man was diagnosed with atypical pituitary adenoma with presentation of sudden onset of vision loss in the right eye. He had recurrent pituitary carcinoma with spinal metastases, treated with surgery, radiation and temozolomide. CONCLUSION: Pituitary carcinoma is a rare neoplasm with poor prognosis that is difficult to diagnose and treat. The small number of cases restricts our ability to design randomized clinical trials. Management is largely driven by retrospective studies and case series. Establishing molecular biomarkers and comprehensive genomic profiling could help in decisions about diagnosis and management of pituitary carcinoma

http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-17151 Mitochondrial DNA Damage in Iron Overload

Chronic iron overload has slow and insidious effects on heart, liver, and other organs. Because iron-driven oxidation of most biologic materials (such as lipids and proteins) is readily repaired, this slow progression of organ damage implies some kind of biological "memory. " We hypothesized that cumulative iron-catalyzed oxidant damage to mtDNA might occur in iron overload, perhaps explaining the often lethal cardiac dysfunction. Real time PCR was used to examine the "intactness " of mttDNA in cultured H9c2 rat cardiac myocytes. After 3–5 days exposure to high iron, these cells exhibited damage to mtDNA reflected by diminished amounts of near full-length 15.9-kb PCR product with no change in the amounts of a 16.1-kb product from a nuclear gene. With the loss of intact mtDNA, cellular respiration declined and mRNAs for three electron transport chain subunits and 16 S rRNA encoded by mtDNA decreased, whereas no decrements were found in four subunits encoded by nuclear DNA. To examine the importance of the interactions of iron with metabolically generated reactive oxygen species, we compared the toxic effects of iron in wild-type and rho o cells. In wild-type cells, elevated iron caused increased production of reactive oxygen species

CTNI-08. DB102-01 ENGAGE STUDY: A BIOMARKER-GUIDED, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTI-CENTER PHASE 3 CLINICAL TRIAL OF DB102 IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)

Abstract Precision medicine is vital for treating many cancers. Lack of valid biomarkers might contribute to the failure of drug therapy for GBM. The Denovo Genomic Marker 1 (DGM1), a novel pharmacogenomic biomarker, has been discovered by a genome-wide screen of patients treated with DB102 (enzastaurin) in a trial for lymphoma. Similarly, retrospective analyses showed that DB102 significantly improved outcomes in the biomarker positive GBM patients treated with DB102, regardless of MGMT promoter methylation status. The ENGAGE Study (DB102-01, NCT03776071) is a global Phase 3 clinical trial to confirm clinical benefits in patients with newly diagnosed GBM who are DGM1 biomarker positive. This is a prospective, randomized, double-blind, placebo-controlled, multi-center study. A total of 318 patients with newly diagnosed GBM will be enrolled. After screening, patients will be randomized to receive radiation therapy (RT) and temozolomide (TMZ) plus either DB102 or a matched placebo for 6 weeks in the Concurrent Phase, followed by DB102 or placebo for approximately 5 weeks in the Single-Agent Phase and then TMZ plus DB102 or placebo in the Adjuvant Phase (up to 12 cycles). Thereafter DB102 or placebo may be continued as a single agent for up to 2 years. The primary endpoint is overall survival (OS). The secondary endpoints include progression free survival (PFS), objective response rate (ORR) and drug safety. By April 2021, the safety-run-in part was completed. The study is now open for enrollment in the US and soon in Canada and China

Alliance A071601: Phase II trial of BRAF/MEK inhibition in newly diagnosed papillary craniopharyngiomas.

2000 Background: Craniopharyngiomas, a rare brain tumor along the pituitary-hypothalamic axis, can cause significant clinical sequelae. Surgery and radiation, the only effective treatments, can cause significant morbidity. Genetic analysis of craniopharyngiomas revealed that 95% of papillary craniopharyngiomas (PCP) have BRAF V600E mutations (Brastianos et al. Nature Genetics 2014). We evaluated the efficacy of BRAF/MEK inhibition in patients (pts) with previously untreated PCP. Methods: Eligible pts without prior radiation whose PCP screened positively for BRAF mutations were treated with oral vemurafenib/cobimetinib in 28-day cycles. The primary endpoint of response rate (RR) based on centrally determined volumetric data was evaluated in 16 pts, where a partial response was defined as >20% decrease in volume. This single arm, Simon two-stage phase 2 trial had 89% power to detect a true RR of at least 30% (vs. the null RR 5%; alpha=0.04). In this design, 3 or more observed volumetric responses in 16 evaluable pts would be considered promising activity. Results: In the 16 pts evaluated, 56% were female, and the median age was 49.5 years. Median follow-up was 22 months (95% CI: 16-26.5) and median number of treatment cycles was 8. Three patients progressed after therapy was discontinued and none have died. Based on volumetric response criteria, 14 of 15 pts with volumetric data available for central review had response to therapy (93%; 95% CI: 68% to 99.8%). Of 16 patients evaluable based on local review, 15 had response to therapy (93.75%; 95% CI: 70% to 99.8%). The median tumor reduction was -83% (range: -52% to -99%). The one nonresponder received 2 days of treatment before coming off therapy due to toxicity. Median progression-free survival was not reached. Grade 3 toxicities at least possibly related to treatment occurred in 12 pts (rash in 6 pts). Grade 4 toxicities were observed in two pts: hyperglycemia (n=1) and increased CPK (n=1). Three pts discontinued treatment for adverse events. Conclusions: Vemurafenib/cobimetinib resulted in an objective response in all pts who received 1 or more cycles of therapy. Our study indicates that BRAF/MEK inhibitors could be a powerful tool in the treatment of previously untreated PCP and warrants further evaluation in larger studies. A second arm of this study is enrolling pts with progressive PCP after prior radiotherapy. Support: U10CA180821, U10CA180882; U24CA196171, U10CA180868 (NRG); Genentech; https://acknowledgments.alliancefound.org. Clinical trial information: NCT03224767