Purpose: Our purpose was to examine outcomes of patients with locally advanced endometrial cancer who undergo neoadjuvant chemotherapy followed by surgery (PreCT) with/without postoperative adjuvant radiation therapy. A secondary analysis of down staging and margin clearance was made with reference to those receiving upfront surgery and then adjuvant chemotherapy (PostCT). Methods and Materials: The National Cancer Database was queried for FIGO (The International Federation of Gynecology and Obstetrics) stage III/IV locally advanced endometrial cancer cases who underwent definitive surgery from 2010 to 2016 and received chemotherapy as part of their treatment. Cases were classified into 2 cohorts: preoperative chemotherapy +/-postoperative chemotherapy cohort (PreCT) and postoperative chemotherapy cohort (PostCT) for reference for margin assessment. Cases who received preoperative radiation therapy were excluded while those who received postoperative radiation were included in the analysis. Primary endpoints were overall survival (OS), surgical margin status, rate of downstaging, and effect of adjuvant radiation therapy on OS among the PreCT cohort. Univariable (UVA) and multivariable (MVA) Cox regression analyses were performed.Results: A total of 13,369 cases were identified with 1059 in PreCT and 12,310 in PostCT cohorts. PreCT had lower OS than PostCT (UVA: hazard ratio [HR], 2.18; P < .001; MVA: HR, 1.873; P < .001). PreCT cases with negative margins, who presumably had unresectable tumors initially, also had worse OS compared with PostCT with negative margins (UVA: HR, 2.20; P < .001; MVA: HR, 1.84; P < .001); however, PreCT with negative margins had similar survival to PostCT with positive margins (UVA: HR, 0.825; P < .001; MVA: P = .885). The addition of radiation after surgery in the PreCT cohort was associated with improved survival (5-year OS 20.5% compared with 50%, respectively; UVA: HR, 0.450; P < .001; MVA: HR, 0.337; P < .001). Although fewer cases in PreCT had negative margins compared with PostCT (72% compared with 84%, P < .001), approximately 19% of cases in PreCT had lower pathologic T-stage compared with clinical T-stage and 11% had lower N-stage. Conclusions: Neoadjuvant chemotherapy was given in cases with worse oncologic prognostic factors, many of whom were likely unresectable at outset, compared with those who received postoperative chemotherapy. Although neoadjuvant chemotherapy is associated with tumor downstaging, survival is lower than with primary surgery probably because of these baseline differences. The addition of adjuvant radiation after surgery in cases who received preoperative chemotherapy is associated with improved survival.& COPY; 2022 The Authors. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PDF file - 246K, NVP-BEZ235 inhibits the DDR in U87-vIII cells.

PDF file - 650K, NVP-BEZ235 impairs growth of U87-vIII tumors when given in conjunction with IR.

Supplementary Methods from Prostate Cancer Radiosensitization through Poly(ADP-Ribose) Polymerase-1 Hyperactivation

Supplemental Figure Legends; Supplemental Table Legends

Supplementary Figures 1-5 from Prostate Cancer Radiosensitization through Poly(ADP-Ribose) Polymerase-1 Hyperactivation

BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) requires complex multidisciplinary care. European evidence suggests potential benefit from regionalization, however, data characterizing the ideal setting in the United States are sparse. Our study compares the significance of four hospital designations on guideline-concordant care (GCC) and overall survival (OS).PATIENTS AND METHODS:The Texas Cancer Registry was queried for 17,071 patients with PDAC treated between 2004 and 2015. Clinical data were correlated with hospital designations: NCI designated (NCI), high volume (HV), safety net (SNH), and American College of Surgeons Commission on Cancer accredited (ACS). Univariable (UVA) and multivariable (MVA) logistic regression were used to assess associations with GCC [on the basis of National Comprehensive Cancer Network (NCCN) recommendations]. Cox regression analysis assessed survival.RESULTS:Only 43% of patients received GCC. NCI had the largest associated risk reduction (HR 0.61, CI 0.58-0.65), followed by HV (HR 0.87, CI 0.83-0.90) and ACS (HR 0.91, CI 0.87-0.95). GCC was associated with a survival benefit in the full (HR 0.75, CI 0.69-0.81) and resected cohort (HR 0.74, CI 0.68-0.80). NCI (OR 1.52, CI 1.37-1.70), HV (OR 1.14, CI 1.05-1.23), and SNH (OR 0.78, CI 0.68-0.91) all correlated with receipt of GCC. For resected patients, ACS (OR 0.63, CI 0.50-0.79) and SNH (OR 0.50, CI 0.33-0.75) correlate with GCC.CONCLUSIONS:A total of 43% of patients received GCC. Treatment at NCI and HV correlated with improved GCC and survival. Including GCC as a metric in accreditation standards could impact survival for patients with PDAC.

<p>Top 10% (251 genes) identified by S2N analysis to be upregulated in HORMAD1 high LUAD tumors</p>

PDF file - 92K, NVP-BEZ235 does not interfere with the anti-tumor effects of TMZ in U87-vIII tumors.

PDF file - 23K, Radiosensitization of normal human astrocytes (NHA) with NVP-BEZ235.

Supplemental Figure 1. Elevated NQO1 expression in patients with HNC correlates with poor overall survival to standard therapy; Supplemental Figure 2. Functional shRNA-NQO1 knockdown rescues β-lapinduced cell death; Supplemental Figure 3. β-Lap-induced NQO1 dependent DNA damage and NAD+ depletion; Supplemental Figure 4. Combination sublethal doses of β-lap and low dose IR induce NQO1 dependent anti-cancer lethality; Supplemental Figure 5. Cooperative antitumor efficacy using a combination of IR and β-lap to treat HNC xenograft models; Figure 6. Expression of Ki-67 after combination of β-lap and IR in HNC xenograft models; Supplemental Table 1. NQO1 enzyme activity and abrogation of activity in 41 HNC cell lines and primary human IMR90 fibroblasts; Supplemental Table 2. Equitoxic doses comparing single to combined treatment in HNC cells; Supplemental Table 3. Individual patient gender, age, subsite, stage, histology and IHC scoring for NQO1 and Catalase

PDF file - 523K, NVP-BEZ235 inhibits the DDR in GBM9 neurospheres.

More detailed methods for the Natural Product Library Generation, Natural Product Cytotoxicity Screens, Purification and Characterization of HORMAD1

Supplementary Figure Legends 1-7 from Prostate Cancer Radiosensitization through Poly(ADP-Ribose) Polymerase-1 Hyperactivation

Figure S1- Piericidin A and HORMAD1 association identified by NPF screen; Figure S2- Piericidin A induces DNA damage in NSCLC lines; Figure S3- S2N and geneset overlaps for HORMAD1 high LUAD tumors.

Supplementary Figure 6 from Prostate Cancer Radiosensitization through Poly(ADP-Ribose) Polymerase-1 Hyperactivation

PURPOSE: Advances in genomic techniques have led to increased use of next-generation sequencing (NGS). We evaluated the extent to which these tests guide treatment decisions. METHODS: We developed and distributed a survey assessing NGS use and outcomes to a survey pool of ASCO members. Comparisons between groups were performed with Wilcoxon two-sample, chi-square, and Fisher's exact tests. RESULTS: Among 178 respondents, 62% were male, 54% White, and 67% affiliated with academic centers. More than half (56%) indicated that NGS provided actionable information to a moderate or great extent. Use was highest (median ≥ 70% of cases) for lung and gastric cancer, and lowest (median < 25% of cases) in head and neck and genitourinary cancers. Approximately one third of respondents reported that, despite identification of an actionable molecular variant, patients were sometimes or often unable to access the relevant US Food and Drug Administration–approved therapy. When NGS did not provide actionable results, individuals reporting great or moderate guidance overall from NGS in treatment recommendations were more likely to request the compassionate use of an unapproved drug (P < .001), enroll on a clinical trial (P < .01), or treat off-label with a drug approved for another indication (P = .02). CONCLUSION: When NGS identifies an actionable result, a substantial proportion of clinicians reported encountering challenges obtaining approved therapies on the basis of these results. Perceived overall impact of NGS appears associated with clinical behavior unrelated to actionable NGS test results, including pursuing off-label or compassionate use of unapproved therapies or referring to a clinical trial.

In the relapsed/refractory setting for treatment of large B-cell lymphoma (LBCL), chimeric antigen receptor T-cell (CAR-T) therapy has emerged as an effective treatment modality. Patients often have aggressive disease that requires prompt treatment in the form of bridging therapy (BT) for disease stabilisation while CAR-T cells are manufactured. Patients (n = 75) undergoing CAR-T therapy infusion for LBCL at our institution were identified. A total of 52 (69·3%) received BT and 23 (30·7%) received no BT (NBT). BT modalities included systemic BT (SBT) in 28 patients, radiation BT (RBT) in 14, and high-dose steroid BT (HDS) in 10. There was no difference in incidence of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome between BT and NBT (P = 0·18 and P = 0·53 respectively). Prolonged cytopenias at Day 180 were more common in BT than NBT (50% vs. 13·3%, P = 0·04). The SBT and RBT subgroups had more cytopenias at Day 180 compared to the HDS and NBT subgroups (58·3% and 57·1% vs. 20% and 13·3% respectively, P = 0·04). Disease response at last follow-up, progression-free survival and overall survival were similar between BT, NBT, and BT subgroups. In summary, BT can be safely considered in patients undergoing CAR-T therapy. However, those undergoing BT with SBT or RBT are at higher risk of prolonged cytopenias after CAR-T therapy.

BACKGROUND:Previous studies have reported healthcare disparities in the Texas-Mexico border population. Our aim was to evaluate treatment utilization and oncologic outcomes of colon cancer patients in this vulnerable population.METHODS:Patients with localized and regional colon cancer (CC) were identified in the Texas Cancer Registry (1995-2016). Clinicopathological data, hospital factors, receipt of optimal treatment, and overall survival (OS) were compared between Texas-Mexico Border (TMB) and the Non-Texas-Mexico Border (NTMB) cohorts. Multivariable analysis was performed to identify risk factors associated with decreased survival.RESULTS:We identified 43,557 patients with localized/regional CC (9% TMB and 91% NTMB). TMB patients were more likely to be Hispanic (73% versus 13%), less likely to have private insurance (13% versus 21%), were more often treated at safety net hospitals (82% versus 22%) and less likely at ACS-CoC accredited hospitals (32% versus 57%). TMB patients were more likely to receive suboptimal treatment (21% versus 16%) and had a lower median OS for localized (8.58 versus 9.58 y) and regional colon cancer (5.75 versus 6.18 y, all P < 0.001). In multivariable analysis, TMB status was not associated with worse OS. Factors associated with worse survival included receipt of suboptimal treatment, Medicare/insured status, and treatment in safety net and non-accredited ACS-CoC hospitals (all P < 0.001) CONCLUSIONS: While TMB CC patients had worse OS, TMB status itself was not found to be a risk factor for decreased survival. This survival disparity is likely associated with higher rate of suboptimal treatment, Medicare/Uninsured status, and decreased access to ACS-CoC accredited hospitals.