bluuebunny/crossref_metadata_2025 huggingface dataset:
Resource utilization and total cost of care among Medicare advantage patients with metastatic pancreatic cancer receiving NCCN category 1 preferred regimens.
Authors: Dieguez Gabriela , Tomicki Samantha , DeStephano David , Hsu Benjamin , Cockrum Paul
Published: January 2022

531

Background: Medicare Advantage accounts for almost 40% of Medicare beneficiaries in 2021. There is limited research evaluating utilization and cost for Medicare Advantage patients with metastatic pancreatic cancer (m-PANC) receiving various NCCN Category 1 preferred regimens. Methods: We used ICD-10 diagnosis codes to identify patients with m-PANC without end-stage renal disease in the 2016-2019 Milliman Consolidated Health Cost Guidelines Sources Database (CHSD) claims files. Study patients had 2+ claims with a pancreatic cancer diagnosis and Medicare Advantage coverage for 3 months pre- and 1 month post-metastasis diagnosis. Patients with stand-alone Part D plan coverage or aged<65 years were excluded. Total cost of care (TCOC) was the sum of the average paid by the insurer and patient. Study patients were treated with NCCN Category 1 preferred regimens: 1L gemcitabine/nab-paclitaxel (gem/nab), 1L gemcitabine monotherapy (gem mono), 1L FOLFIRINOX (FFX), and 2L+ liposomal irinotecan (5FU was not included in this analysis; see Limitations for further details). Results: Of the approximately 2.5 million patients covered by Medicare Advantage in CHSD, there were 946 patients that received an NCCN Category 1 chemotherapy regimen between 2016 and 2019. Among NCCN Category 1 preferred regimens, patients receiving 2L+ liposomal irinotecan had the lowest mean admissions per beneficiary and mean readmission rate (0.5 and 8%) compared to patients receiving gem/nab (0.8 and 12%), gem mono (0.6 and 8%), or FFX (0.6 and 9%). Patients receiving 2L+ liposomal irinotecan also had the shortest length of stay per inpatient admission in days (2.9) compared to patients receiving gem/nab (5.1), gem mono (3.6), or FFX (4.3). Mean claims per beneficiary for emergency department observations was lowest among patients receiving 2L+ liposomal irinotecan (0.7), compared to patients receiving gem/nab (0.9), gem mono (1.0), or FFX (0.89). Patients receiving 2L+ liposomal irinotecan had lower median TCOC ($31,885) than patients receiving gem/nab ($39,479) or FFX ($32,632). Conclusions: Patients with Medicare Advantage receiving 2L+ liposomal irinotecan-based regimens to treat m-PANC had lower healthcare resource utilization in key categories and lower median total costs than patients receiving other NCCN Category 1 preferred regimens. Limitations: Analysis of different populations or time periods may yield different results. Our study used claims data and not electronic health records (EHRs), so we could not control for clinical covariates. Patient characteristics and regimen performance might influence which regimens patients receive. We did not adjust TCOC or utilization for LOT durations. We did not study whether liposomal irinotecan-based therapy patients received concomitant 5FU or prior gemcitabine-based therapy.
Pancreatic cancer detection using 5-hydroxymethylation signatures in plasma-derived cell free DNA in high-risk patients with new onset diabetes.
Authors: Haan David , Guler Gulfem , Bergamaschi Anna , Volkmuth Wayne , Levy Samuel
Published: January 2022

539

Background: Pancreatic cancer (PaCa) is the third leading cause of cancer death in the United States despite a low incidence rate. It is often diagnosed when cancer has already metastasized to distant organs. Late diagnosis deprives patients of potentially curative treatments such as surgery and impacts survival rates. People with new onset diabetes (NOD) are at 6-8 fold increased risk for PaCa compared to the general population. Indeed, 0.85% of patients with NOD will be diagnosed with PaCa within 3 years. This population of PaCa patients with NOD constitute 25% of all new pancreatic cancer diagnoses. Surveillance of the NOD population for PaCa presents an opportunity to shift PaCa diagnosis to earlier stage. Methods: Whole blood was obtained from a cohort of 167 PaCa patients and 490 patients with cancers other than PaCa as well as 836 non-cancer controls with and without NOD. Plasma was processed to isolate cfDNA and 5hmC libraries were generated and sequenced. 5hmC data is used to generate models for PaCa detection using Bluestar Genomics’s technology platform. Results: To investigate whether PaCa can be detected in plasma, we interrogated plasma-derived cfDNA hydroxymethylation in PaCa patients and non-cancer controls. Models trained using 5hmC-based biomarkers from cfDNA consistently performed with a mean test sensitivity of 61.1% [95% confidence interval (CI): 35.7% to 82.7%] and a test specificity of 97.6% (CI: 93% to 99.5%) measured across 50 cross validation iterations within the training data set, which was composed of 48.3% early stage (Stages I & II) disease. The final model was trained using all of the training data, yielding 58.4% (CI: 47.5% to 68.8%) sensitivity at 98% (CI: 96.5% to 99.0%) specificity. This model was then tested on an independent test set with 22 PaCa patients (51.7% early stage, 15 of which was NOD) and 123 non-cancer control patients (53 of which were NOD) and yielded a classification performance of 59.1% (CI: 36.4% to 79.3%) sensitivity at 95.9% (CI: 90.8% to 98.7%) specificity. The model performance in the subset of patient cohort with NOD was 53.3% (CI: 26.6% to 78.7%) sensitivity at 94.3% (CI: 84.3% to 98.8%) specificity. Lastly, sensitivity observed on an independent validation set, composed of 56 PaCa and 117 ITTP samples, was 46.4% (CI: 33.0% to 60.2%) with 100% (CI: 96.8 to 100%) specificity. Conclusions: Our results demonstrate PaCa detection in plasma-derived cfDNA using 5hmC profiles. Overall, the model performed consistently between the training and independent validation datasets. A larger clinical study is under development to clinically validate the model described in this study with the goal of identifying occult PaCa within the NOD population in order to enable earlier detection and thus improve patient outcomes.
Efficacy of SBP-101, a polyamine metabolic inhibitor, administered in combination with gemcitabine and nab-paclitaxel, as a first-line treatment for patients with metastatic pancreatic ductal adenocarcinoma.
Authors: Singhal Nimit , Sigal Darren , Tebbutt Niall C. , Hezel Aram F , Nagrial Adnan , Lumba Sumit , George Thomas J. , Smith Sheri Lynn , Gagnon Suzanne , Cullen Michael T. , Walker Michael
Published: January 2022

575

Background: SBP-101, a polyamine metabolic inhibitor, inhibited growth in 6 human pancreatic ductal adenocarcinoma (PDA) cell lines and 3 murine xenograft tumor models of human PDA. SBP-101 monotherapy in heavily pre-treated PDA patients (> 2 prior regimens) showed a median survival of 5.9 months at the optimal dose level. Purpose: To assess the PK, safety and efficacy of SBP-101 in combination with gemcitabine (G) and nab-paclitaxel (A) in patients with previously untreated metastatic PDA. Methods: In a modified 3+3 dose escalation scheme, subcutaneous injections of SBP-101 were dosed at 0.2, 0.4 or 0.6 mg/kg days 1-5 of each 28-day cycle. G (1000 mg/m2) and A (125 mg/m2) were administered intravenously on Days 1, 8, and 15 of each cycle. PK was evaluated on day 1 of cycle 1 in cohorts 1-3. Safety was evaluated by clinical and laboratory assessments. Efficacy was assessed by CA19-9 levels, objective response using RECIST criteria, progression-free survival (PFS) and overall survival (OS). A 4th cohort using a modified dosing schedule of 0.4 mg/kg SBP-101 days 1-5 for cycles 1-2 and days 1, 8, and 15 every cycle thereafter was added to mitigate hepatic toxicity, and that dose and schedule were recommended for Phase 1b expansion. Results: Fifty patients were enrolled (N=25, Phase 1a and N=25, Phase 1b) and received up to 13 treatment cycles. SBP-101 plasma Cmax and AUC0-t increased in a slightly more than dose proportional manner and were unchanged by the addition of G and A. PK parameters of G and A were unaltered by increasing doses of SBP-101. The most common nonserious adverse events related to SBP-101 (>10%) are fatigue (N=14), LFT/transaminase abnormalities (N=15), vision abnormalities (N=10), injection site pain (N=13), dehydration (N=7), nausea (N=7). Serious adverse events related to SBP-101 observed in some subjects include hepatic toxicity (N=6) and retinal toxicity (N=8) both occurring after prolonged treatment and requiring dose reduction or discontinuation. At the recommended dose and schedule (N=30), CA19-9 levels decreased 60-99% in 19 of 29 evaluable patients, with 1/29 (3%) achieving a complete remission 13/29 achieving partial responses (45%) and 10/29 achieving stable disease at 8 weeks (35%). PFS was confounded by SBP-101 dosing holds implemented to investigate potential toxicity. Sixteen subjects are in survival follow-up. Median OS is 10.1 months and is not final. Conclusions: Interim results suggest SBP-101 may enhance first-line treatment with G and A in patients with metastatic PDA. Hepatic toxicity can be mitigated with dose reduction or discontinuation. A vision screening program will be used in future studies to mitigate retinal toxicity. Clinical trial information: NCT03412799.
Understanding extended duration of therapy (DOT) among patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with liposomal irinotecan-based regimens.
Authors: Mokrzecky Cheryl , Cockrum Paul , Surinach Andy , Becerra Carlos Roberto
Published: January 2022

579

Background: Few analyses have identified characteristics associated with extended DOT (eDOT) among a large group of patients (pts) treated with liposomal irinotecan. This study examines the characteristics associated with eDOT among pts with mPDAC treated with liposomal irinotecan in a real-world setting. Methods: This retrospective observational study utilized the Flatiron Health EHR database from over 280 cancer clinics in the US. Data were analyzed for adult pts with mPDAC treated with liposomal irinotecan-based regimens between January 2016 and October 2020. eDOT was defined as a DOT > 2 standard deviations (SD) above the mean. Demographic and clinical characteristics evaluated included age, sex, stage at diagnosis, ECOG performance score (PS), and the number of prior lines of therapy at the time of treatment initiation. Dose delays and dose reductions during treatment were assessed. Additionally, changes in lymphocyte counts during treatment were described. Chi-squared test and Fisher’s exact test were used to test for significance for categorical variables and the t-test was used for continuous variables. Results: 675 pts with mPDAC treated with a liposomal irinotecan-based regimen were included. The overall mean DOT was 14.6 weeks (SD: 22.1). There were 30 pts (4.4%) that met the definition for eDOT. Patient sex and median age at treatment initiation were similar between those with eDOT and non-eDOT: male, 46.7% vs. 51.9% (p = 0.582); age, median 70 years vs 69 years (p = 0.923), respectively. A higher proportion of pts with eDOT had ECOG PS of 0-1 compared to those with non-eDOT, 73.3% vs 57.7%, respectively (p = 0.397). At treatment initiation 80.0% of pts who had eDOT had a serum albumin level of ≥ 35g/L versus 55.2% of pts with non-eDOT (p = 0.013). On average, those with eDOT experienced a 55.1% reduction in lymphocyte count (baseline to nadir) during treatment compared to a 34.7% reduction among pts with non-eDOT (p < 0.0001). Pts who experienced eDOT were more likely to be treated in earlier lines of therapy than those with non-eDOT: 33.3% vs 14.1% received 0 prior lines and 46.7% vs 47.3% received 1 prior line, respectively (p = 0.008). 53.3% of pts with eDOT experienced a dose reduction (of at least 7mg/m2) compared to 24.7% pts with non-eDOT (p = 0.0005). All pts with eDOT experienced a dose delay of > 16 days during treatment versus 45.3% of pts with non-eDOT (p < 0.0001). Conclusions: This real-world study identified pts treated earlier in their disease course with a liposomal irinotecan-based regimen and normal baseline serum albumin were more likely experience extended DOT. Treatment modifications and delays appear to have enabled longer treatment duration with liposomal irinotecan-based regimens. Further prospective studies should be considered to characterize factors that may predict extended DOT.
Detection of circulating DNA methylated BCAT1 and IKZF1 in pancreatic adenocarcinoma.
Authors: Winter Jean M. , Sheehan-Hennessy Lorraine , Pedersen Susanne Kartin , Young Graeme P. , Symonds Erin L.
Published: January 2022

597

Background: Pancreatic adenocarcinoma patients have poor survival outcomes and there are no non-invasive tests to aid diagnosis or therapy. Detection of circulating tumour DNA (ctDNA) methylated for BCAT1 and/or IKZF1 is over 60% sensitive for colorectal adenocarcinoma. Both pancreatic and colorectal adenocarcinomas are of endodermal origin, therefore, these methylated biomarkers might also have utility in detecting pancreatic cancer. The aim of this study was to investigate whether individuals with pancreatic adenocarcinoma have detectable methylated BCAT1 and IKZF1 DNA in circulation. Methods: In this pilot study, pre-treatment blood and clinicopathological findings were collected from 21 patients diagnosed with pancreatic adenocarcinoma. DNA isolated from plasma was bisulfite-converted and assayed for methylated BCAT1, IKZF1 and a non-methylated region in ACTB (for yield estimates). Samples with methylation in either gene was deemed positive. Chi -squared test was used to compare positivity between Stage I/II and Stage III/IV cases. The sum of percent (%) methylation ([average BCAT1]+[average IKZF1])/average ACTB) ± standard error was compared between stages using Kruskal-Wallis rank test. Results: 10/21 (47.6%) patients were positive for methylated BCAT1 and/or IKZF1. There was a trend of increasing positivity with advancing stage (Stage I/II 2/8 (25.0%) vs Stage III/IV 8/13 (61.5%, p=0.104)), and for higher % methylation with more advanced disease (Stage II 0.01%±0.004 vs Stage IV 5.0%±3.7, p=0.06). No other comorbidities or demographics were associated with positivity. Conclusions: Assay for methylated BCAT1 and IKZF1 ctDNA detects approximately two-thirds of late-stage pancreatic adenocarcinoma. Future studies are warranted to assess the clinical utility of these biomarkers for detection and monitoring of pancreatic cancer. Clinical trial information: 12616001138471.
Real-world use of PARP inhibitors in BRCA1/2-mutated pancreatic cancer: A retrospective analysis.
Authors: Amin Suvina , Li Weiyan , Joo Seongjung , Adeboyeje Gboyega , DeArbeloa Patricia , Petricoin Emanuel , Blais Edik Matthew , Pishvaian Michael J.
Published: January 2022

599

Background: BRCA1 or BRCA2 mutations can be found in approximately 6 to 8 percent of patients patients with metastatic pancreatic adenocarcinoma (mPaC). Olaparib is the only PARP inhibitor (PARPi) approved in the EU and the US as maintenance treatment for biomarker-selected patients with mPaC in the 1st line platinum-sensitive setting. However, treatment sequencing can be heterogeneous, and there is a lack of real-world data on patterns of PARPi use in relation to platinum use in BRCA1/2-mutated mPaC. Methods: Longitudinal records collected between 1/2012-12/2020 were analyzed for a cohort of 55 mPaC patients with BRCA1 or BRCA2 mutations identified by commercial NGS testing who enrolled in Perthera’s US real-world observational registry study. Treatment patterns including PARPi utilization and platinum-sensitivity (16 weeks without progression at any point within known history) were abstracted via physician notes across all lines of therapy. Results: PARPi use was documented in 60% (N=33) of 55 patients with BRCA1/2-mutated mPaC in any treatment setting. Within this cohort, 21 patients received a single agent PARPi outside of clinical trials. Among these patients, only 38% (8 of 21) transitioned to a PARPi in a platinum-sensitive context, and only 14% (3 of 21) of these transitions occurred before 2nd line. Notably, 6 patients received a PARPi in the platinum-resistant setting. Within the broader cohort, platinum-sensitive criteria was fully met for 73% (40 of 55); however, only 49% (27 of 55) reached this milestone of platinum-sensitivity prior to initiating a 2nd line therapy. Conclusions: The majority of these BRCA1/2-mutated patients received a PARPi-based therapy in a variety of contexts with respect to line of therapy and prior platinum history. These findings highlight the value of upfront genetic and molecular testing and the need for further exploration to identify factors associated with treatment response as well as optimized treatment sequencing.
Genomic classification of clinically advanced pancreatic ductal adenocarcinoma (PDAC) based on methylthioadenosine phosphorylase (MTAP) genomic loss (MTAP loss).
Authors: Ngoi Natalie , Scholefield Emma L. , Parini Vamsi , Huang Richard S.P. , Janovitz Tyler , Danziger Natalie , Levy Mia Alyce , Pant Shubham , Javle Milind M. , Ross Jeffrey S. , Rodon Ahnert Jordi
Published: January 2022

604

Background: MTAP loss is represented across a wide variety of cancer types including PDAC and is an emerging target for synthetic lethality-based cancer therapies. Preclinically, MTAP loss leads to the accumulation of 2-methylthioadenosine, reduced protein arginine N-methyltransferase 5 (PRMT5) methylation activity and increased vulnerability to targeting of the methionine adenosyltransferase IIα (MAT2A)/ PRMT5 axis. In addition, 9p21 loss, homozygous co-deletion of MTAP/CDKN2A or homozygous deletion of either gene have been associated with an immunologically “cold” tumor microenvironment, primary resistance to anti PD(L)1 immunotherapy (IO) and poor prognosis phenotype (Han G, Nat Commun 2021). We investigated concurrent mutations and immune biomarkers in clinical PDAC samples with MTAP-loss versus -intact status. Methods: From a series of 177705 consecutive cases, we performed comprehensive genomic profiling on 9423 cases of PDAC using an FDA-approved assay (F1CDx) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by immunohistochemistry (Dako 22C3). Furthermore, we correlated pertinent findings within a database of 16558 cases of clinically advanced cancer with MTAP loss. Results: 2003 (21.3%) of 9423 PDAC demonstrated MTAP-loss. Similar gender, age and number of GA per tumor were observed between MTAP-loss and -intact groups. Frequencies of TP53, CDKN2A/B, SMAD4, PTEN and ARID1A were significantly higher in MTAP-loss PDAC. However, previously-described biomarkers of IO efficacy (MSI, TMB, CD274 amplification and PD-L1 expression) and resistance ( STK11, KEAP1 and MDM2) were infrequent and similar in both groups. The frequencies of other potentially targetable GA including BRCA1/2, ATM, KRAS G12C, ERBB2, BRAF, FGFR1, NF1 and PIK3CA were also infrequent and similar in both groups of PDAC patients. Amongst a database of 16558 cases of clinically advanced cancer with MTAP loss, 1538 (9.3%) featured co-alterations in MTAP and SMAD4. 52% of the MTAP/SMAD4 co-altered cases were PDAC. Conclusions: MTAP loss is associated with a distinctive concurrent genomic profile in PDAC and represents a potential new synthetic lethality-based opportunity for treatment with PRMT5 and MAT2A inhibitors. Furthermore, MTAP loss may represent an independent negative predictive biomarker for immune checkpoint inhibition in PDAC.[Table: see text]
A multi-modular phase I/II study of UCB6114, a first-in-class, fully human IgG4P anti-Gremlin-1 monoclonal antibody, as monotherapy and in combination with mFOLFOX6 or trifluridine/tipiracil, for patients with advanced gastrointestinal (GI) tumors.
Authors: Sarker Debashis , Banerji Udai , Blagden Sarah Patricia , Cook Natalie , Evans T.R. Jeffry , Plummer Elizabeth Ruth , Braun Marina , Cleverly Ann , Diaz Nieves , Jones Paul , Matthews Ivan , Glatt Sophie
Published: January 2022

TPS221

Background: Despite recent advances, effective treatment for GI cancers remains a significant unmet medical need. Gremlin-1 is secreted by the peri-tumoral stroma and down-regulates bone morphogenetic proteins (BMP) -2, -4, and -7 (members of the transforming growth factor-β superfamily), thereby allowing malignant cell expansion, renewal, and a more treatment-resistant mesenchymal phenotype. Gremlin-1 mRNA is highly expressed in multiple solid tumors including >60% of colorectal, pancreatic and esophageal cancers. UCB6114 is a first-in-class, fully human IgG4P monoclonal antibody optimized for neutralizing the activity of human Gremlin-1 thereby restoring BMP signaling. Preclinical studies have demonstrated that UCB6114 binds to Gremlin-1, inhibits its pharmacological activity, and has antitumor activity in several in vivo mouse models (including several GI cancers). Methods: ONC001 (clinicaltrials.gov: NCT04393298) is an ongoing multi-part, multicenter, nonrandomized, open-label, Phase I/II study evaluating the safety, pharmacokinetics (PK) and antitumor activity of UCB6114 administered intravenously as monotherapy or in combination with selected standard of care (SOC) regimens. Eligible patients (pts) are: aged ≥18 years; resistant or refractory to standard therapy; ECOG performance status 0/1; and have adequate renal, hepatic and bone marrow function. In the Phase I monotherapy dose escalation and adaption part (part A and A1; modified rolling 6 design), up to 66 pts with advanced solid tumors associated with high levels of Gremlin-1 mRNA expression will be recruited. In parts B and C (modified toxicity probability interval design), up to 54 pts with locally advanced or metastatic colorectal, gastric or gastroesophageal junction adenocarcinomas will receive UCB6114 in escalating doses in combination with either mFOLFOX6 (5-fluorouracil, leucovorin and oxaliplatin) or trifluridine/tipiracil, given at SOC dosing and schedules. The overarching objective of the phase I parts of the study (Parts A‒C) is to identify the recommended phase II dose of UCB6114 either as monotherapy or in combination. The primary objective is to characterize the safety profile of UCB6114; secondary and exploratory objectives include PK, antitumor activity (RECIST v1.1), and pharmacodynamics (including circulating Gremlin-1). Enrollment in ONC001 began in July 2020; as of Sept 2021, four dose escalation levels in the monotherapy dose-escalation module (Part A) have been completed without DLT. Recruitment to parts B and C is due to commence in Q4 2021. Clinical trial information: NCT04393298.
Zolbetuximab + CAPOX versus CAPOX in first-line treatment of claudin18.2+/HER2– advanced/metastatic gastric or gastroesophageal junction adenocarcinoma: GLOW phase 3 study.
Authors: Shah Manish A. , Ajani Jaffer A. , Al-Batran Salah-Eddin , Bang Yung-Jue , Catenacci Daniel V.T. , Enzinger Peter C. , Ilson David H. , Kim Sunnie S. , Lordick Florian , Shitara Kohei , Van Cutsem Eric , Arozullah Ahsan , Raizer Jeffrey J. , Park Jung Wook , Xu Rui-hua
Published: January 2022

TPS365

Background: Despite standard treatment options (eg, CAPOX, capecitabine + oxaliplatin), 5-year survival with advanced/metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ) is poor and limited biomarkers exist to inform treatment selection. Claudin 18.2 (CLDN18.2), a targetable biomarker, is a tight junction protein that is normally confined to gastric mucosa of healthy tissue and is often retained in G/GEJ. Zolbetuximab, a chimeric IgG1 monoclonal antibody, binds to CLDN18.2 and mediates cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Phase 2 (FAST; Sahin, Ann Oncol. 2021) results showed prolonged survival with zolbetuximab + EOX (epirubicin, oxaliplatin, capecitabine) vs EOX in CLDN18.2+ advanced G/GEJ. Preliminary phase 2 (NCT03505320, ILUSTRO Cohort 2; Klempner, J Clin Oncol. 2021) results showed promising antitumor activity with combination zolbetuximab + mFOLFOX6 (5-fluorouracil, folinic acid, oxaliplatin) in CLDN18.2+ advanced G/GEJ. Methods: GLOW (NCT03653507) is enrolling ̃500 adults from global sites. Patients are required to have radiologically evaluable (RECIST v1.1) CLDN18.2+/HER2– locally advanced unresectable or metastatic G/GEJ. Prior chemotherapy for advanced/metastatic G/GEJ is not permitted. Patients will be randomized 1:1 to zolbetuximab + CAPOX or placebo + CAPOX. Randomization will be stratified by region (Asia vs non-Asia), number of metastatic sites (0 to 2 vs ≥3), and prior gastrectomy (yes vs no). Zolbetuximab will be administered at 800 mg/m2 IV on Cycle 1 Day 1 (loading dose), then at 600 mg/m2 IV every 3 weeks; 8 cycles of CAPOX will be administered. Central testing of tumor tissue will determine CLDN18.2 status; tumors will be considered CLDN18.2+ if ≥75% of tumor cells show moderate to strong membranous immunohistochemical staining. Primary endpoint: progression-free survival per independent review. Secondary endpoints: overall survival; objective response rate; duration of response; safety/tolerability, pharmacokinetics, and immunogenicity of zolbetuximab. As of September 22, 2021, 135 sites were open for screening and enrollment. Clinical trial information: NCT03653507.
LEAP-014: An open-label, randomized, phase 3 study of first-line lenvatinib plus pembrolizumab plus chemotherapy in esophageal squamous cell carcinoma.
Authors: Sun Jong-Mu , Enzinger Peter C. , Adenis Antoine , Shah Manish A. , Kato Ken , Bennouna Jaafar , Doi Toshihiko , Hawk Natalyn Nicole , Yu Li , Shah Sukrut , Bhagia Pooja , Shen Lin
Published: January 2022

TPS367

Background: Recent data from the KEYNOTE-590 study demonstrated the superiority of pembrolizumab plus chemotherapy compared with chemotherapy as first-line treatment for unresectable locally advanced recurrent or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus, or advanced/metastatic Siewert type 1 adenocarcinoma of the gastroesophageal junction. Prior data also suggest promising antitumor activity of lenvatinib plus pembrolizumab in advanced solid tumors. LEAP-014 (NCT04949256) is a randomized, 2-part, open-label, phase 3 study that will evaluate the efficacy and safety of first-line lenvatinib plus pembrolizumab plus chemotherapy versus pembrolizumab plus chemotherapy in patients with metastatic esophageal squamous cell carcinoma (ESCC). Methods: Key eligibility criteria include metastatic ESCC, measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and Eastern Cooperative Oncology Group performance status ≤1. In part 1 (safety run-in), ̃6 patients will be treated for induction with intravenous (IV) pembrolizumab 400 mg every 6 weeks (Q6W) for 2 cycles plus oral lenvatinib 8 mg daily (QD) plus IV 5-fluorouracil (FU; 4000 mg/m2 on days 1-5) plus IV cisplatin (80 mg/m2) (FP) for 4 cycles and treated for consolidation with pembrolizumab 400 mg Q6W for ≤16 doses plus lenvatinib 20 mg QD; patients will be closely monitored for 21 days after the first dose of study intervention for dose-limiting toxicities. Approximately 850 patients will be randomly assigned 1:1 to induction with pembrolizumab plus lenvatinib plus chemotherapy (FP or mFOLFOX6 [Q2W for 6 cycles {IV oxaliplatin 85 mg/m2 plus bolus IV 5-FU 400 mg/m2 plus continuous IV 5-FU 2400 mg/m2 plus IV leucovorin 400 mg/m2 or IV levoleucovorin 200 mg/m2}]) followed by consolidation with pembrolizumab plus lenvatinib (arm 1) or pembrolizumab plus chemotherapy (FP or mFOLFOX6; arm 2). Randomization will be stratified by PD-L1 combined positive score (CPS; ≥10 vs < 10), region (East Asia vs North America and Western Europe vs rest of world), and chemotherapy backbone (FP vs mFOLFOX6). Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. Tumor imaging assessment will be performed Q6W for ≤1 year and Q9W thereafter. In part 1, the primary end point is safety and tolerability. In part 2, the dual primary end points are overall survival and progression-free survival (per RECIST v1.1 assessed by blinded independent central review [BICR]); secondary end points include objective response rate and duration of response (per RECIST v1.1 assessed by BICR) and safety and tolerability. Clinical trial information: NCT04949256.
TALENTACE: A phase III, open-label, randomized study of on-demand transarterial chemoembolization combined with atezolizumab + bevacizumab or on-demand transarterial chemoembolization alone in patients with untreated hepatocellular carcinoma.
Authors: Kudo Masatoshi , Guo Yabing , Hua Yongqiang , Zhao Ming , Xing Wenge , Zhang Yonghong , Liu Ruibao , Ren Zhenggang , Gu Shanzhi , Lin Zhengyu , Lv Weifu , Wang Yumeng , Dong Jiahong
Published: January 2022

TPS487

Background: In 2020, there were ̃905,000 new cases and ̃830,000 deaths from liver cancer globally, and a respective 410,038 and 391,152 in China (5-year overall survival [OS]: 14.1%).1,2,3 Hepatocellular carcinoma (HCC) accounts for 75%–85% of liver cancers.1 Transarterial chemoembolization (TACE) is the preferred treatment for patients with intermediate-stage unresectable HCC (uHCC); however, there are issues with the need for repeated dosing and the heterogenous target population (median OS: 13–43 mo). Treatment with TACE + systemic therapy may improve this. Although several trials reported negative results for TACE + sorafenib (sor) vs TACE alone in patients with uHCC, the TACTICS trial showed improved untreatable (unTACEable) progression-free survival (PFS) (25.2 vs 13.5 mo; P= 0.006).4 While promising, the unmet need for combination therapies remains. The recent IMbrave150 trial showed significantly improved OS with atezolizumab (atezo) + bevacizumab (bev) vs sor (19.2 vs 13.4 mo; P= 0.0009) in patients with uHCC5, making it an attractive option for combination with TACE. Methods: TALENTACE (NCT047126430) is a phase III, open-label, randomized study to evaluate the efficacy and safety of TACE + atezo + bev or TACE alone in patients with uHCC. Key inclusion criteria are ≥18 years old, HCC diagnosis, no prior systemic treatment, no prior locoregional treatment of target lesions, eligible for TACE treatment, tumor max diameter + tumor number ≥6, and not a candidate for curative therapy. Patients with tumors that have macrovascular invasion (MVI) or extrahepatic spread (EHS) are excluded. Patients will be randomized (1:1) to receive TACE + atezo + bev or TACE alone. TACE will be performed by clinical demand; atezo (1200 mg) and bev (15 mg/kg) will be administered by intravenous infusion on Day 1 of each 21-day cycle. Co-primary endpoints are independent review committee-determined TACE-PFS (randomization to unTACEable progression, TACE failure/refractoriness, or death) and OS. Secondary endpoints include investigator-determined TACE-PFS; time to unTACEable progression, progression, MVI, EHS, and MVI/EHS; objective response rate, duration of response, patient reported outcomes, and incidence of adverse events. References: Sung, H., et al. CA Cancer J Clin. 2021;71(3):209–249. World Health Organisation: Globocan 2020 – China Factsheet. Available at: https://gco.iarc.fr/today/data/factsheets/populations/160-china-fact-sheets.pdf [accessed 1 June 2021] Allemani, C., et al. Lancet. 2018, 391(10125): 1023–1075. Kudo, M., et al. Gut. 2020;69(8):1492–1501. Finn, RS., et al. J Clin Oncol. 2021;39(no. 3_suppl):267–267. Clinical trial information: NCT04712643.
Phase 1b expansion study of CX-5461 in patients with solid tumors and BRCA2 and/or PALB2 mutation.
Authors: Knox Jennifer J. , Oza Amit M. , Provencher Diane M. , Soong John , McCormick Daniel , Chen Jimmy , Chen Jenny , Chang Ariel
Published: January 2022

TPS622

Background: BRCA and PALB2 proteins play important roles in the maintenance of genomic stability as they are essential for error-free repair of double-stranded DNA breaks, while deficiency of these proteins promotes error-prone DNA repair, chromosomal instability and carcinogenesis. Inherited mutations in BRCA genes predispose to various early onset cancers. Poly(ADP-ribose) polymerase inhibitors (PARPi) inducing synthetic lethality in tumors with homologous recombination (HR)-mediated DNA repair deficiencies have been approved for treatment in patients with germline BRCA-mutated metastatic pancreatic adenocarcinoma. Unfortunately, resistance to PARPi associated with multiple mechanisms can be observed over time, suggesting a prominent unmet need for the development of new treatment options. CX-5461, a G-quadruplex stabilizer, employs an alternative mechanism in destabilizing the DNA replication fork to promote DNA damage resulting in cancer cell lethality in HR-deficient (HRD) tumors, thus represent a promising therapeutic strategy for patients with defects in HR-repair. Methods: A prior phase I dose escalation study has been completed for CX-5461 (CCTG IND.231, NCT02719977) but additional safety data are required to define the chronic tolerable dose for phase 2 trials. Therefore, a phase Ib expansion trial was designed for two doses preselected from our previous phase I trial to determine the final recommended phase II dose (RP2D) by evaluating safety, tolerability and objective response rate in a more selected population. This trial will enroll patients in two cohorts; the main cohort recruiting patients with pancreatic, breast, ovarian or prostate cancer with germline BRCA2 and/or PALB2 mutation, and an exploratory cohort recruiting ovarian cancer patients with BRCA1 and/or other HRD-associated mutations. Major eligibility criteria include documented evidence of pathogenic or likely pathogenic germline mutation in BRCA2 and/or PALB2 for main cohort patients, documented evidence of pathogenic or likely pathogenic germline mutation or a clinically actionable somatic mutation in BRCA1 and/or other HRD-associated mutation for exploratory cohort. Patients with non-adenocarcinoma histology of pancreatic cancer, known photosensitivity disorders of the skin, or patients with ophthalmological conditions will not be enrolled. An initial 16 eligible patients for the main cohort and 10 eligible patients for the exploratory cohort will be enrolled in parallel to receive CX-5461 at 250mg/m2, delivered via IV infusion on Day 1 and Day 8 of a 28-day cycle. Upon completion of the initial arms with no safety concerns, another two arms will open to enroll an additional 16 patients for the main cohort and 10 patients for the exploratory cohort to receive CX-5461 at 325mg/m2 of the same dosing schedule. Clinical trial information: NCT04890613.
A phase 2, multicenter, open-label study evaluating trastuzumab deruxtecan (T-DXd) for the treatment of select human epidermal growth factor receptor 2 (HER2)-expressing solid tumors (DESTINY-PanTumor02).
Authors: Meric-Bernstam Funda , Anoka Chiedozie , Dobrowolska Anna , Chaudhry Anubhavini , Rowbottom Jacqui , Gustavson Mark , Puvvada Soham D.
Published: January 2022

TPS623

Background: Human epidermal growth factor receptor 2 (HER2) is an established therapeutic target in both breast and gastric cancer. However, HER2-targeting therapies are not approved beyond these malignancies despite a high prevalence of HER2 expression across cancers of epithelial origin. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In a cohort of pretreated patients with multiple HER2-expressing tumors, T-DXd demonstrated promising antitumor activity, with an investigator-assessed confirmed objective response rate of 40.9% (9 of 22 patients) and median progression-free survival of 11.1 months (95% CI, 5.4-20.5 months; Tsurutani J, et al. Cancer Discov. 2020;10:688-701). Here we describe the phase 2 DESTINY-PanTumor02 trial evaluating T-DXd in patients with select HER2-expressing solid tumors. Methods: DESTINY-PanTumor02 (NCT04482309) is an open-label, multicenter, multicohort, phase 2 study evaluating T-DXd for the treatment of patients with select HER2-expressing locally advanced, unresectable, or metastatic tumors. The study will consist of 7 cohorts of patients (n≈40 each) with urothelial bladder, biliary tract, cervical, endometrial, ovarian, pancreatic, or rare tumors (tumors excluding those in the other cohorts and breast, gastric, colorectal, and non-small cell lung cancer). Patients are required to have disease progression following ≥1 prior systemic treatment for advanced or metastatic disease or have no satisfactory alternative treatment options. Prior HER2-targeting therapy is allowed. The primary endpoint is investigator-assessed confirmed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints include duration of response, disease control rate, progression-free survival (all per investigator assessment according to RECIST 1.1), overall survival, safety, pharmacokinetics, and immunogenicity. Previously presented at the ESMO Congress 2021, FPN: 1869 TiP, Meric-Bernstam et al. Reused with permission. Clinical trial information: NCT04482309.
Strain-dependent doping behavior of WSe2 monolayer: A first-principle calculation
Authors: Chowdhury S. , Venkateswaran P. , Somvanshi D.
Published: January 2022

Control and enhancement of doping concentration in two-dimensional (2D) semiconductors is a critical issue. Here, we investigate the strain-dependent behavior of dopant formation energy (E

form
) for transition-metal–doped WSe2 monolayer using density functional theory (DFT) calculations. We found that E

form
tends to reduce under tensile and compressive strain for rhenium (Re) and vanadium (V) dopants, where the change in volume

due to substitution is negligible. However, E

form
is energetically more favorable under tensile strain for niobium (Nb) and tantalum (Ta) dopants, where

is significantly larger. This suggests strain engineering can be used to enhance the doping concentration in 2D semiconductors.
Comparison of efficacy of systemic antibiotics alone and combination of systemic antibiotics with gentamicin cream in diabetic foot infections
Authors: Memon Munawer Latif , Ikram Muhammad , Azhar Muhammad , Balouch Varda
Published: January 2022

Objective: To compare efficacy of systemic antibiotics alone and combination of systemic antibiotics with gentamicin cream in diabetic foot infections.

Methods: Prospective Observational Study was conducted at Department of Surgery, Pakistan Ordinance Factories (POF) Hospital, Wah Cantt for duration of two years (January 2018-December 2019). A sample size of 140 diabetic foot infection patients (70 patients in each group) was calculated using WHO calculator. DFI patients were selected through non probability (consecutive) sampling technique. All patients signed consent forms before participation into study. Patients were randomly divided into two group (computer generated random number table); Group-A patients were given systemic antibiotics alone while Group-B was given combination of gentamicin cream and systemic antibiotics. SPSS version 24 was utilized for analysis purpose. Chi-square test was applied in our study. Results with p-value ≤0.05 found significant.

Results: Total 140 patients were included in study. There were 87(62.1%) male and 53(37.9%) females in our data. Mean age of patients was 46 years±11.3SD. Group-B (combination of gentamicin and systemic antibiotics) showed significant reduction in inflammation (p=0.03), culture negativity(p=0.001), increase clinical cure (p=0.02) and pathological eradication (p=0.03) as compared to Group-A (systemic antibiotics alone). Gender, age and duration of diabetes mellitus had insignificant association with outcomes (p>0.05).

Conclusion: Diabetic foot infections are significant contributors of morbidity in our country. Combination of gentamicin cream with systemic antibiotics is highly effective in inflammation reduction, increasing clinical cure rate and pathological eradication as compared to systemic antibiotics alone in diabetic foot infections. Early identification of risk factors, proper patients care and multidisciplinary approach for diabetic foot infections prevention is required.

doi: https://doi.org/10.12669/pjms.38.3.3277

How to cite this:Memon ML, Ikram M, Azhar M, Balouch V. Comparison of efficacy of systemic antibiotics alone and combination of systemic antibiotics with gentamicin cream in diabetic foot infections. Pak J Med Sci. 2022;38(3):---------. doi: https://doi.org/10.12669/pjms.38.3.3277

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Cardiac cycle time-corrected electromechanical activation time greater than 15% is an independent risk factor for major adverse cardiovascular events in chronic heart failure outpatients
Authors: Zhang Jing , Liu Wenxian
Published: January 2022

Objectives: This study aimed to investigate the predictive value of cardiac cycle time-corrected electromechanical activation time (EMATc) for major adverse cardiovascular events (MACEs) in outpatients with chronic heart failure (CHF) in comparison with other clinic indexes.

Methods: This prospective observational study at Beijing Anzhen Hospital from January 01, 2015 to January 01 2018 enrolled 120 CHF patients who were admitted for acute onset of CHF and followed up after discharge for 616.5 days (range: 202.75–875.25 days). Based on the different endpoints, cardiogenic death, all-cause death, and HF-related readmission, patients were assigned to the following groups: cardiogenic death and non-cardiogenic death groups, all-cause death and survival groups, and HF readmission and non-readmission groups. EMATc and other clinic indexes were measured and compared between these groups. Cox regression analysis was used to identify independent risk factors for MACEs.

Results: The hazard ratio for EMATc>15% for cardiogenic death was 3.493 (P=0.046), suggesting that an EMATc>15% was an independent risk factor for cardiogenic death in CHF patients. The hazard ratios for B-type natriuretic peptide (BNP) >400 ng/L for all-cause death and CHF readmission were 3.810 (P=0.008) and 2.764 (P=0.031), respectively. Thus, BNP >400 ng/L was an independent risk factor for all-cause death and readmission for CHF. EF<40% was not found to be a significant risk factor for MACEs.

Conclusions: BNP level can predict the risk for poor prognosis in CHF patients. EMATc>15% is an independent risk factor for cardiogenic death and should be considered as a supplement to serum BNP level and other clinical indexes for predicting cardiogenic death in CHF outpatients.

doi: https://doi.org/10.12669/pjms.38.3.4500

How to cite this:Zhang J, Liu W. Cardiac cycle time-corrected electromechanical activation time greater than 15% is an independent risk factor for major adverse cardiovascular events in chronic heart failure outpatients. Pak J Med Sci. 2022;38(3):---------.  doi: https://doi.org/10.12669/pjms.38.3.4500

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Racial and socioeconomic inequalities in the financial stress of medical school
Authors: McMichael Brennan , Lee IV Anderson , Fallon Brian , Matusko Niki , Sandhu Gurjit
Published: January 2022

Background: The authors analyzed the distribution of medical student debt and identified demographic features that placed students at high risk for increased debt and financial stress.

Methods: From April to May 2019, a cross-sectional, anonymous, web-based survey was administered to first-year (M1) to fourth-year (M4) medical students at the University of Michigan to assess financial literacy, debt burden, financial stress, and demographic factors. A total of 216 of 680 (32%) students completed the survey. Respondents voluntarily answered 15 multiple-choice questions on personal finance and 30 questions on their demographics, current financial situation, and debt burden. To quantify debt burden, students estimated anticipated education-related debt in one of four categories: no debt, $1–99,999; $100,000–$199,999; and $200,000 or more. A chi-square test was used to identify associations between categorical variables and logistic regression was used to identify risk factors for debt and worry.

Results: Fifty-four respondents (25%) reported $0 in education related debt, while 44 (16%) had $200,000 or more. Race (p=0.006), first-generation college student status (p=0.004), first-generation medical student status (p<0.001), household income (p<0.001), and parental education (p=0.008) were associated with higher levels of debt. Students who were underrepresented in medicine (URiM) had higher odds of higher debt compared to Arab and Asian students (p=0.02). URiM students (p=0.02), first-generation college students (p=0.009), and parental education (p=0.01) were associated with increased financial stress. Additionally, female students had higher odds of increased financial stress (OR=1.85, p=0.045) on logistic regression.

Conclusions: URiM and socioeconomically disadvantaged students feel the burden of the high cost of medical school disproportionately more, suggesting that our current systems are not adequately supporting these students. Reducing this burden may serve to further promote diversity in medicine.
AUKUS and its significance for transatlantic relations
Authors: de Bruyn Martyn
Published: January 2022

The AUKUS agreement between Australia, the United Kingdom, and the United States is a major step in formalizing Washington’s commitment to the Indo-Pacific. The announcement surprised the Biden Administration’s European allies and led to an indignant reaction from France, which saw its submarine contract with Australia fall victim of the deal. The AUKUS agreement led to a renewed debate about the soft power nature of European Common Foreign and Security Policy (CFSP) in which the High Representative for Foreign Affairs and Security Policy called for a strategic compass. This paper analyzes the strategic policy papers of the European Union and the United States on the Indo-Pacific and concludes that their different approaches to peace and security complement each other in important ways.
The Development Students` Creative Thinking by Active Teaching Methods at Humanitarian University (on the Example of the Study of Bulgakov’s Feuilletons)
Authors: Smirnov S. , Kazorina A.
Published: January 2022

The article discussed the system of work on the M.A. Bulgakov`s feuilletons at literature lessons with students studying at the direction preparation of «philology» and «journalism». The study of writer`s journalistic speeches allows you to give an idea of his satirical prose of the 1920s and develop of students` creative thinking skills. The system of tasks for the student audience is based on ideas competence-based, systematic, active, personality-oriented and contextual approaches in the training of future specialists.
Przekonania magiczne w międzypokoleniowym przekazie dziedzictwa kulturowego. Refleksja etnopedagogiczna
Authors: Wesołek Ewelina
Published: January 2022

Celem artykułu jest przedstawienie znaczenia przekonań magicznych obecnych w międzypokoleniowym przekazie dziedzictwa kulturowego. Część teoretyczna pracy została oparta na definicji dziedzictwa kulturowego autorstwa Stanisława Ossowskiego. Badania prowadzone były na terenie wschodniej Wielkopolski z wykorzystaniem wywiadów pogłębionych częściowo strukturalizowanych. W badaniu uczestniczyło 6 rodzin, łącznie 21 osób z trzech pokoleń. Zebrany materiał pozwolił na przedstawienie znaczenia dziedzictwa kulturowego i magii w życiu współczesnych pokoleń. Następnie zaprezentowano podejście osób badanych do magii jako elementu dziedzictwa kulturowego, typologię magii i proces dziedziczenia przekonań magicznych.