Induction therapy with 177Lu-DOTATATE procures long-term survival in locally advanced or oligometastatic pancreatic neuroendocrine neoplasm patients

Purpose: Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE induces objective response in up to 57% of pancreatic neuroendocrine neoplasms (panNENs). Therefore, PRRT may comprise a downstaging option for panNEN patients who are not eligible for upfront curative surgery or are at high risk for recurrence. The aim of this study was to assess the potency of induction PRRT for locally advanced panNENs and to evaluate the effect of surgery after PRRT on overall survival (OS). Methods: Retrospective cohort study of panNEN patients treated with induction 177Lu-DOTATATE. Results: After PRRT, 26 out of 49 patients underwent pancreatic surgery with curative intent (PRRT + surgery). Partial objective response was obtained in 62% of the PRRT + surgery group versus 26% of the patients not undergoing panNEN surgery (PRRT-only group, p = 0.02). Downstaging in tumour-vessel interface was observed in 38% of all patients with at least one involved vessel. Median OS was 14.7 years (95% CI 5.9–23.6) for the PRRT + surgery group compared to 5.5 years (95% CI 4.5–6.5) for the PRRT-only group (p = 0.003). In the Cox proportional hazards analysis, surgery was not significantly associated with OS after propensity score adjustment with cumulative activity, performance status, tumour size after PRRT, and tumour grade. Median progression-free survival was 5.3 years (95% CI 2.4–8.1) for the PRRT + surgery group and 3.0 years (95% CI 1.6–4.4) for the PRRT-only group (p = 0.02). Conclusion: Early administration of PRRT followed by surgery is associated with favourable long-term outcomes in patients with locally advanced or oligometastatic panNEN and can be considered for selected patients with vascular involvement and/or increased risk of recurrence

Sensitivity of CT, MRI, and EUS-FNA/B in the preoperative workup of histologically proven left-sided pancreatic lesions

Background and objectives: Left-sided pancreatic lesions are often treated surgically. Accurate diagnostic work-up is therefore essential to prevent futile major abdominal surgery. Large series focusing specifically on the preoperative work-up of left-sided pancreatic lesions are lacking. This surgical cohort analysis describes the sensitivity of CT, MRI, and EUS-FNA/B in the diagnostic work-up of left-sided pancreatic lesions. Methods: We performed a post-hoc analysis of patients who underwent surgery for a left-sided pancreatic lesion between April 2010 and August 2017 and participated in the randomized CPR trial. Primary outcome was the sensitivity of CT, MRI, and EUS-FNA/B. Sensitivity was determined as the most likely diagnosis of each modality compared with the postoperative histopathological diagnosis. Additionally, the change in sensitivity of EUS versus EUS-FNA/B (i.e., cyst fluid analysis, and/or tissue acquisition) was measured. Results: Overall, 181 patients were included (benign: 23%, premalignant: 27%, malignant: 50%). Most patients had solid lesions (65%). Preoperative imaging included CT (86%), MRI (41%), EUS (68%). Overall, CT and EUS-FNA/B reached a sensitivity of both 71%, compared with 66% for MRI. When EUS was combined with FNA/B, sensitivity rose from 64% to 71%. For solid lesions, CT reached the highest sensitivity (75%) when compared with MRI (70%) and EUS-FNA/B (69%). For cystic lesions, EUS-FNA/B reached the highest sensitivity (75%) when compared with CT and MRI (both 62%). Conclusions: CT is the most sensitive diagnostic modality for solid and EUS-FNA/B for cystic left-sided pancreatic lesions. EUS-FNA/B was associated with an increased sensitivity when compared to EUS alone

Targeting histone methylation to reprogram the transcriptional state that drives survival of drug-tolerant myeloid leukemia persisters

Although chemotherapy induces complete remission in the majority of acute myeloid leukemia (AML) patients, many face a relapse. This relapse is caused by survival of chemotherapy-resistant leukemia (stem) cells (measurable residual disease; MRD). Here, we demonstrate that the anthracycline doxorubicin epigenetically reprograms leukemia cells by inducing histone 3 lysine 27 (H3K27) and H3K4 tri-methylation. Within a doxorubicin-sensitive leukemia cell population, we identified a subpopulation of reversible anthracycline-tolerant cells (ATCs) with leukemic stem cell (LSC) features lacking doxorubicin-induced H3K27me3 or H3K4me3 upregulation. These ATCs have a distinct transcriptional landscape than the leukemia bulk and could be eradicated by KDM6 inhibition. In primary AML, reprogramming the transcriptional state by targeting KDM6 reduced MRD load and survival of LSCs residing within MRD, and enhanced chemotherapy response in vivo. Our results reveal plasticity of anthracycline resistance in AML cells and highlight the potential of transcriptional reprogramming by epigenetic-based therapeutics to target chemotherapy-resistant AML cells

IGFBP7 Induces Differentiation and Loss of Survival of Human Acute Myeloid Leukemia Stem Cells without Affecting Normal Hematopoiesis

Leukemic stem cells (LSCs) are thought to be the major cause of the recurrence of acute myeloid leukemia (AML) due to their potential for self-renewal. To identify therapeutic strategies targeting LSCs, while sparing healthy hematopoietic stem cells (HSCs), we performed gene expression profiling of LSCs, HSCs, and leukemic progenitors all residing within the same AML bone marrow and identified insulin-like growth factor-binding protein 7 (IGFBP7) as differentially expressed. Low IGFBP7 is a feature of LSCs and is associated with reduced chemotherapy sensitivity. Enhancing IGFBP7 by overexpression or addition of recombinant human IGFBP7 (rhIGFBP7) resulted in differentiation, inhibition of cell survival, and increased chemotherapy sensitivity of primary AML cells. Adding rhIGFBP7 reduced leukemic stem and/or progenitor survival and reversed a stem-like gene signature, but it had no influence on normal hematopoietic stem cell survival. Our data suggest a potential clinical utility of the addition of rhIGFBP7 to current chemotherapy regimens to decrease AML relapse rates