bluuebunny/crossref_metadata_2025 huggingface dataset:
A single-arm phase II study of cabozantinib and atezolizumab in patients with recurrent or metastatic esophageal squamous cell carcinoma (R/M ESCC) who failed platinum-based chemotherapy.
Authors: Kuo Hung-Yang , Guo Jhe-Cyuan , Huang Ta-Chen , Lin Chia-Chi , Lee Jang-Ming , Yeh Kun-Huei , Hsu Chih-Hung
Published: January 2022

TPS364

Background: Patients with R/M ESCC failing platinum-based chemotherapy have grave prognosis. Anti PD-1 immune-checkpoint inhibitors (ICIs), by demonstrating survival benefits over 2nd-line chemotherapy in multiple phase III trials, have emerged as a new standard-of-care for patients with platinum-refractory R/M ESCC. However, the efficacy of anti-PD-1 ICIs remains modest with an objective response rate (ORR) of 17-20%; and the median overall survivals (OS) for these patients range from 8.2 to 10 months. Cabozantinib, a multikinase inhibitor, in combination with atezolizumab has been investigated in the phase Ib COSMIC-021 trial, which includes multiple cohorts of various cancer types including gastroesophageal cancer and head-and-neck cancer. Promising preliminary results were reported in lung cancer and genitourinary cancer cohorts. To investigate the combination of cabozantinib plus atezolizumab in patients with ESCC, a subtype of esophageal cancer that may be under-represented in the gastroesophageal cancer cohort of COSMIC-021 trial, we thus proposed this phase II trial to verify the hypothesis whether adding cabozantinib to atezolizumab would improve the outcomes of R/M ESCC patients who have failed platinum-based chemotherapy. Methods: This single institution single-arm phase II study includes patients with histologically confirmed R/M ESCC who failed at least one platinum-based chemotherapy. Patients with prior exposure of any ICI or kinase inhibitor are excluded. Patients enrolled will receive cabozantinib 40mg once per day and atezolizumab 1200mg once every three weeks until disease progression or intolerable toxicities. The primary endpoint of this study is the ORR evaluated by RECIST 1.1; and the key secondary endpoints include progression-free survival, OS, and toxicity profile. We hypothesize that combination of cabozantinib plus atezolizumab will improve the ORR from 15% to 30%. With one-sided, 0.1 type I error (α), 0.2 type II error (β, corresponding power: 0.8), the sample size will be 37. The study, registered with clinical trial ID of NCT05007613, started patient enrollment in Jun 2021. As of Sep of 2021, 5 patients have been enrolled. Clinical trial information: NCT05007613.
An open-label phase 2 study of lenvatinib plus pembrolizumab in the neoadjuvant and adjuvant treatment for patients with gastric and gastroesophageal junction adenocarcinoma (EPOC2001).
Authors: Kawazoe Akihito , Wakabayashi Masashi , Furuya Hideki , Sato Akihiro , Sakamoto Naoya , Kuwata Takeshi , Kinoshita Takahiro , Shitara Kohei
Published: January 2022

TPS372

Background: Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, substantially decreased the tumor-associated macrophages and increased infiltration of CD8-positive T cells and enhanced anti-tumor activity of PD-1 inhibitors in vivo model. A phase 2 study demonstrated remarkable clinical activity of lenvatinib plus pembrolizumab for advanced gastric cancer with objective response rate of 69% (Kawazoe A, et al. Lancet Oncol. 2020), leading to the global phase 3 LEAP-015 trial at first-line (NCT04662710). The objective of this study is to evaluate anti-tumor activity of lenvatinib with pembrolizumab as neoadjuvant and adjuvant treatment for patients with gastric and gastroesophageal junction adenocarcinoma. Methods: The study is an open-label, single-arm, single-center, phase 2 clinical trial. Eligible patients are with previously untreated gastric and gastroesophageal junction adenocarcinoma as defined by cT2-4 and/or cN+ without evidence of metastatic disease. Patients will receive 3 cycles of 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks as the neoadjuvant treatment followed by surgery, and then 3 cycles of lenvatinib plus pembrolizumab followed by 11 cycles of pembrolizumab monotherapy as the adjuvant treatment. The primary endpoint is major pathological response rate, and the secondary endpoints are pathological complete response rate, tumor shrinkage effect on primary lesions, radical resection rate, treatment completion rate until surgery or adjuvant treatment, event-free survival, overall survival, and incidence of adverse events. We also investigate several biomarkers using pre- and post-treatment tumor and blood samples. First patient will be enrolled in November 2021. Clinical trial information: NCT04745988.
SKYSCRAPER-07: A phase III, randomized, double-blind, placebo-controlled study of atezolizumab with or without tiragolumab in patients with unresectable ESCC who have not progressed following definitive concurrent chemoradiotherapy.
Authors: Goodman Karyn A. , Xu Rui-hua , Chau Ian , Chen Ming Huang , Cho Byoung Chul , Shah Manish A. , Muro Kei , Wang Yifan , Ichimaru Mari , Liu Qingyuan , Wang Luhua
Published: January 2022

TPS374

Background: The current standard of care for patients (pts) diagnosed with unresectable, locally advanced esophageal squamous-cell carcinoma (ESCC) is definitive platinum-based concurrent chemoradiotherapy (dCRT). However, ESCC has poor prognosis, with more than half of tumors reoccurring after dCRT (Smyth et al. Nat Rev Dis Primers 2017), highlighting the need for additional therapy options in this setting. Cancer immunotherapies have demonstrated activity in ESCC, and targeted inhibition of the PD-L1/PD-1 pathway may be further amplified using novel anti-TIGIT agents such as tiragolumab. In preclinical mouse models, concomitant blockade of PD-L1/PD-1 and TIGIT pathways demonstrated prolonged survival over the respective single-agents. In the phase II CITYSCAPE study (NCT03563716), tiragolumab plus atezolizumab (anti-PD-L1) resulted in a clinically meaningful improvement in PFS and higher ORR vs atezolizumab alone (31.3 vs 16.2%) in first-line pts with PD-L1+ (TPS ≥1%) metastatic NSCLC. SKYSCRAPER-07 (NCT04543617) will determine if tiragolumab plus atezolizumab combination therapy provides superior clinical benefit to atezolizumab monotherapy or placebo in pts with unresectable ESCC whose cancers have not progressed following dCRT. We hypothesize that combination therapy will prolong PFS and OS compared with placebo in this setting. Methods: Eligible pts (≥18 years) must have unresectable ESCC, without progressive disease (PD) after platinum-based dCRT (according to regional oncology guidelines for ESCC); ECOG PS 0–1; no prior treatment with any immune checkpoint inhibitor. Approximately 750 pts will be randomized 1:1:1 to either Arm A (tiragolumab 600mg + atezolizumab 1200mg IV Q3W), Arm B (atezolizumab 1200mg + placebo IV Q3W) or Arm C (double placebo IV Q3W). Treatment will continue for up to 17 cycles of 21 days, or until unacceptable toxicity or investigator-assessed radiographic PD (per RECIST v1.1). Stratification factors include geographic region (Asia vs rest of world), PD-L1 expression and staging prior to dCRT (II vs III vs IV). Co-primary efficacy endpoints are investigator-assessed PFS and OS; key secondary endpoints include independent review facility-assessed PFS and DoR. Safety, pharmacokinetic, biomarker and immunogenicity analyses will be performed. Recruitment is ongoing. Clinical trial information: NCT04543617.
CA209-8YD: A phase I/II trial of rucaparib in combination with ramucirumab with or without nivolumab in previously treated advanced gastroesophageal adenocarcinoma (GEA) (RiME).
Authors: Saeed Anwaar , Park Robin , Al-Rajabi Raed Moh'd Taiseer , Kasi Anup , Saeed Azhar , Ng Elizabeth , Thompson Kayra , Moya Stephanie , Barbosa Lori , Phadnis Milind , Williamson Stephen K. , Baranda Joaquina Celebre , Sun Weijing , Catenacci Daniel V.T.
Published: January 2022

TPS377

Background: GEA is one of the leading causes of cancer-related deaths worldwide and in the US. In chemo refractory GEA, therapeutic options are limited with modest efficacy. About 35% of GC have DNA damage response (DDR) gene alterations and PARP inhibitors have shown to induce synthetic lethality and reduce tumor burden in in vitro and in vivo models of GEA. DDR deficient tumors have increased tumor mutational load, tumor infiltrating lymphocytes, and increased chemokines and PD-L1 expression in the tumor microenvironment. PARP inhibitors like rucaparib enhance antigen presentation, induce pro-inflammatory cytokines, influence PD-1/PD-L1 expression, and modulate T- and B- cell activity. Furthermore, results from multiple GEA early phase trials have supported the immune modulatory impact of VEGF targeted agents like ramucirumab. We hypothesize that modulation of the tumor microenvironment via PARP and VEGF inhibition will enhance anti-tumor immunity and lead to clinical synergy when combined with immune checkpoint inhibitors like nivolumab in this population. Methods: A safety lead in phase of 6-9 patients will be followed by an open label, two parallel cohorts phase II study. A total of 52 patients (26 in each cohort) will be enrolled. A starting rucaparib dose of 600 mg BID in combination with the standard doses of ramucirumab and flat doses of nivolumab will be used for the safety lead in. Rucaparib dose will be lowered for phase II if > 1/6 patients experienced DLTs. Participants enrolled to cohort A will receive rucaparib at the recommended phase II dose (RP2D) PO twice daily + ramucirumab 8mg/kg IV q2w + nivolumab 480mg IV q4w (28-day cycles). Participants in cohort B will receive rucaparib at RP2D PO twice daily + ramucirumab 8mg/kg IV q2w (28-day cycles). Assessment of tumor response using modified RECIST v1.1 will be done every 2 cycles. 50% of Pts who will be enrolled in each of the 2 cohorts must have a deleterious tumor gene alteration in at least 1 gene in a screening 17-gene homologous recombination deficient (HRD) panel. Eligible Pts received ≥1 line of therapy, ECOG PS 0-1, adequate organ function, no prior PARP inhibitors, and have mismatch repair (MMR) proficient tumors with measurable disease. Primary objectives are to determine the RP2D and overall response rate (ORR) in phase I and II respectively. Secondary objectives include safety, overall benefit rate (OBR), median PFS, OS, and ORR in HRD positive and negative cohorts. Enrollment to the RiME trial is currently ongoing. The study is funded by research grants from Bristol Myers Squibb and Clovis. Clinical trial information: NCT03995017.
A multicenter, observational, phase 4 study (STELLAR) to evaluate the safety and tolerability of lenvatinib (LEN) in patients with advanced or unresectable hepatocellular carcinoma (uHCC).
Authors: Peck-Radosavljevic Markus , Goyal Lipika , Strasser Simone , Matilla Peña Ana Maria , Marinho Rui , Granito Alessandro , Roderburg Christoph , Marsico Mark , Christou Vanessa C , Xie Ran , Saraf Pankhoori , Meyer Tim
Published: January 2022

TPS485

Background: HCC is a leading cause of cancer-related deaths worldwide. LEN is now a first-line treatment option for patients with uHCC, based on the REFLECT study in which LEN was established as noninferior to sorafenib (SOR) for overall survival (OS); LEN also demonstrated statistically significant and clinically meaningful improvements in progression-free survival, time-to-progression, and objective response rate vs SOR. The safety profile of LEN was consistent with its known side-effect profile. This postauthorization safety study aims to better characterize the safety of LEN, including hepatotoxicity, in real-life conditions in a Western population. Methods: This prospective, open-label, observational study (NCT04763408) will enroll patients with advanced or uHCC in routine clinical practice whom the treating physician has decided to treat with LEN (n = 500) or SOR (n = 500) according to the product labels. Enrollment is planned for 60 sites across Europe, Australia, USA, and Russia. The primary endpoint is the safety of LEN (hepatic-related toxicity and overall safety profile with regard to serious adverse events, grade ≥3 adverse events, and dose modifications and discontinuations due to adverse events). Secondary endpoints include treatment patterns (duration of treatment, incidence of dose interruptions and dose reductions, relative dose intensity, and subsequent treatments) and OS with LEN. Similar efficacy and safety data will be collected with SOR as an internal control for the population. Additionally, associations will be explored between patients’ baseline characteristics and treatment decisions as well as clinical and safety outcomes. Visits will be scheduled according to routine practice. Patients will be followed from initiation of treatment until the end of observation (whichever occurs first: withdrawal of consent, loss to follow-up, death, or end of the study [ie, 6 months after the last patient is enrolled]). Safety will be collected from initiation of LEN or SOR until the earlier of: 28 days after LEN/SOR discontinuation or the end of observation for patients who did not discontinue. Patients will be followed for survival and subsequent anticancer treatments until the end of observation, irrespective of length of treatment. Clinical trial information: NCT04763408.
Randomized phase II trial of postoperative adjuvant capecitabine and temozolomide versus observation in high-risk pancreatic neuroendocrine tumors: SWOG S2104.
Authors: Soares Heloisa P. , Guthrie Katherine A , Ahmad Syed A. , Washington Mary Kay , Ramnaraign Brian Hemendra , Raj Nitya Prabhakar , Seigel Carole , Bellasea Shay , Chiorean E. Gabriela , Dasari Arvind , Strosberg Jonathan R. , Eng Cathy , Philip Philip Agop
Published: January 2022

TPS515

Background: Pancreatic neuroendocrine tumors (pNETS) account for about 1-2% of all the pancreas tumors for which resection is the only curative intent modality, however, despite surgery, many patients will experience recurrence. Tumor size, positive lymph nodes and higher grade are prognostic factors for recurrence. The U.S. Neuroendocrine Tumor Study Group published a predictive score (Zaidi score, see table) demonstrating that tumors with a score≥6 had a 33% likelihood of recurrence by 24 months. Furthermore, it is known that that patients with metastatic disease who undergo curative intent resection also have a great risk of recurrence. Despite these known risk factors for recurrence, to date, no prospective study exploring the role of adjuvant cytotoxic chemotherapy has ever been performed in this population. Supported by the E2211 results using capecitabine and temozolomide (CAPTEM) in the metastatic setting, S2104 investigates the role of CAPTEM in the adjuvant setting. Methods: S2104 is a randomized phase II trial designed to evaluate recurrence-free survival (RFS) in participants with resected pNETs randomized on a 2:1 fashion to CAPTEM or observation. Patient are eligible if they had resected well-differentiated grade 2 or 3 (ki-67 up to 55%) pNETS with a Zaidi score of ≥ 3. Patients may have received resection/ablation of liver oligo-metastatic disease (up to 5 liver metastases) at the time of well-differentiated pNET resection. Key eligibility criteria: age ≥18 years, Zubrod performance status of 0-2, adequate organ and marrow function. Stratification factors include 1) Disease status prior to resection (metastatic vs. non-metastatic disease) and 2) Zaidi score (≥ 6 vs. < 6). Participants will be followed with imaging for 5 years. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180821, U10CA180868. Clinical trial information: NCT05040360. [Table: see text]
Phase 1b study of vactosertib in combination with nal-IRI plus 5FU/LV in patients with metastatic pancreatic ductal adenocarcinoma who have failed first-line gemcitabine/nab-paclitaxel.
Authors: Park Joon Oh , Kim Seung Tae , Hong Jung Yong , Kim Seong-Jin , Park Young Suk
Published: January 2022

TPS632

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies and the leading cause of cancer-related death in the world, although recent advances in chemotherapies for metastatic PDAC provide better clinical outcomes. TGF-β is strongly involved in the tumor microenvironment of PDAC, and dysregulation of TGF-β signaling is a frequent molecular disturbance in PDAC progression and metastasis. Vactosertib is an orally bioavailable TGF-β signaling inhibitor that targets the TGF-β type I receptor kinase. In in vivo studies, vactosertib reduces cancer cell migration, invasion, and metastasis of various cancers, and combination of vactosertib with nal-IRI/5-FU/LV improves pancreatic cancer survival by suppressing cell migration, invasion, and epithelial-mesenchymal transition (EMT), highlighting a potential clinical application of this approach for PDAC patients (Hong et al, 2020). Based on this preclinical study, we develop a phase 1b study to determine the recommended phase 2 dose (RP2D) and to evaluate the safety of vactosertib in combination with nal-IRI/5FU/LV in patients with metastatic PDAC who have failed first-line gemcitabine/ nab-paclitaxel. Methods: Eligible patients have histologically confirmed PDAC who have failed first-line gemcitabine/ nab-paclitaxel with adequate organ function and performance status. This study is composed of two parts; dose escalation and dose expansion. In the dose escalation part (phase 1b), different dose levels of vactosertib (100 mg bid, 200 mg bid, and 300 mg bid) for escalation will be tested, starting with dose level 0 (DL 0, 200 mg bid) with 3 to 6 subjects recruited in each cohort. DL -1 is only tested when DL 0 is unacceptable. In the dose expansion part, one or two additional backfill cohorts among DL -1 through DL 2 will be opened for determination of the final RP2D. For each cohort, a maximum of 12 patients can be enrolled including the dose escalation and dose expansion phase. Patients in each cohort will receive vactosertib 100-300 mg orally twice per day 1-5 & day 8-12 with nal-IRI 70mg/m2 intravenously day 1, LV 400mg/m2 IV day 1, and continuous 5-FU 2400mg/m2 infusion over 48 hours every 2 weeks. The primary endpoint is to determine RP2D and to evaluate safety of this combination. The key secondary endpoints are progression free survival, overall response rate, disease control rate based on RECIST 1.1 and overall survival. As of September 2021, 5 patients have been enrolled in DL 0 and 1 DLT has been reported in DL 0. This study is prospectively registered on ClinicalTrials.gov, NCT04258072. Clinical trial information: NCT04258072.
Phase I study of hydroxychloroquine plus binimetinib in patients with metastatic pancreatic cancer (the HOPE trial).
Authors: Surana Rishi , Lee J. Jack , Smaglo Brandon George , Zhao Dan , Lee Michael Sangmin , Wolff Robert A. , Overman Michael J. , Willis Jason , Der Channing J. , Pant Shubham
Published: January 2022

TPS634

Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a dearth of effective therapeutic options. Over 90% of PDAC harbor activating mutations in the KRAS oncoprotein, which in turn leads to activation of downstream effector proteins in the the RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signaling cascade serving to promote tumor cell survival, growth and metastasis. Unfortunately, single agent treatment with MAPK-inhibitors have had limited therapeutic efficacy in patients with PDAC owing to development of various tumor-cell intrinsic resistance mechanisms, including upregulation of autophagy. Hydroxychloroquine is an antimalarial drug that functions to inhibit autophagy by inhibiting acidification of lysosomes. Previously published preclinical data suggest combination therapy with binimetinib, a MEK 1/2 inhibitor, and hydroxychloroquine leads to enhanced killing of PDAC cells in vitro and in vivo. Methods: This is a single arm, single center phase I trial of binimetinib plus hydroxychloroquine in patients with metastatic pancreatic cancer harboring a KRAS mutation. All patients will receive binimetinib at a fixed dose of 45mg PO twice daily (14-day cycles) while hydroxychloroquine will be dosed at 400mg PO twice daily (14-day cycles) and dose escalated using a Bayesian optimal interval design with a target toxicity rate of 0.3. Key eligibility criteria include histologically confirmed metastatic pancreatic adenocarcinoma, prior treatment with at least one line of systemic therapy and a documented KRAS mutation. An estimated 24 patients will be enrolled in the first phase of this study and up to 15 patients in the dose expansion cohort. The primary endpoint of this study is to determine the maximum tolerated dose (MTD) of hydroxychloroquine when combined with a fixed dose of binimetinib. Key secondary endpoints include safety and toxicity profile, response rate, progression free survival (PFS) and overall survival (OS). This study is ongoing and has enrolled 10 patients at the time of submission. Clinical trial information: NCT04132505.
A phase I study of first-line L-glutamine (Gln) with gemcitabine (gem) and nab-paclitaxel (nab-p) in advanced pancreatic cancer (GlutaPanc).
Authors: Davelaar John , Tighiouart Mourad , Hendifar Andrew Eugene , Osipov Arsen , Moshayedi Natalie , Placencio-Hickok Veronica , Bhowmick Neil , Gong Jun
Published: January 2022

TPS636

Background: Cytotoxic chemotherapy remains the preferred first-line treatment for advanced or unresectable pancreatic cancer with combination regimens including 5-fluoruracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), or gem and nab-p. The use and response of second- and third-line therapies remains dismal, thus the optimization of first-line treatment is critical. Our previous work investigating Gln metabolism in pancreatic ductal adenocarcinoma (PDAC) through glutaminase inhibition indicates that Gln deprivation in PDAC increases cancer cell survival and resistance to chemotherapy. However, when PDAC cell were treated with Gln supplementation, there was an increase in PDAC cell death with increasing concentrations of gem. In this present study we aim to test the feasibility and safety of combining L-Gln with gem and nab-p in treatment-naïve patients with unresectable or metastatic PDAC. Methods: This is a single arm, single center, phase I study. The primary objective is to assess the recommended phase II dose (RP2D) of L-Gln in combination with gem and nab-p. The RP2D will be assessed by escalation of overdose control (EWOC), an adaptive Bayesian design, through determination of the maximum tolerated dose (MTD) across 3 doses of gem, nab-p, and L-Gln. The MTD is defined as the dose such that the probability of dose-limiting toxicities (DLTs) at the MTD is θ = 0.33. The first patient will receive 1000 mg/m2 gem, 125 mg/m2 nab-p, and 0.1 g/kg L-Gln and the subsequent doses will be determined by the EWOC algorithm. We plan to enroll a maximum of 16 patients. L-Gln is administered orally BID throughout the 28-day cycle with a one-week lead-in prior to the beginning of the first cycle where gem and nab-p are administered on days 1, 8, and 15 of each cycle. Key inclusion criteria include: advanced or unresectable, histologically confirmed pancreatic cancer that is either new or recurrent (if recurrent, prior neoadjuvant or adjuvant chemotherapy or chemoradiation is allowed but must have been completed >12 months prior to recurrence), ECOG PS ≤ 2 or KP ≥ 60%, and normal organ and marrow function. Secondary objectives are to describe any preliminary evidence of antitumor activity by assessment of objective response rate, progression-free survival, and overall survival. Since October 2020, 3 patients have been screened and 3 enrolled. Clinical trial information: NCT04634539.
Randomized phase II trial of two different nutritional approaches for patients receiving treatment for their advanced pancreatic cancer.
Authors: Hanna Diana L. , Jameson Gayle S. , Rasco Drew W. , Alistar Angela Tatiana , Frank Richard C. , El-Khoueiry Anthony B. , Wiedmeier Julia , Roberts Caroline , Fell Brandon , Hallberg Sarah , Roe Denise , Cridebring Derek , Rabinowitz Joshua D , Gately Stephen , Von Hoff Daniel D.
Published: January 2022

TPS637

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by stromal fibrosis, hypoxia, and nutritional deprivation. PDAC tumors grow aggressively, diagnosis is typically made after metastasis and the disease remains associated with poor outcomes. The triplet chemotherapy regimen of gemcitabine, nab-paclitaxel with cisplatin was associated with a median overall survival of 16.4 months in patients with metastatic pancreatic cancer in the first-line setting (Jameson et al., 2020). Nutritional, metabolic interventions offer an opportunity to fundamentally change the tumor microenvironment and improve outcomes for patients. A ketogenic diet defined as lower carbohydrate, lower protein, and higher fat can significantly reduce glucose and insulin and increase metabolically active ketone bodies and has been evaluated in patients with a variety of solid tumors (Weber et al, 2020). Recently, a ketogenic diet combined with triplet chemotherapy was shown to inhibit murine pancreatic KPC tumor growth and significantly prolong animal survival over chemotherapy alone. Tumor growth inhibition was associated with glucose depletion, altered TCA substrate usage, and NADH elevation. Methods: In this Phase II randomized clinical trial (NCT04631445), we are evaluating a medically supervised ketogenic diet (MSKD) versus a standard diet when combined with the triplet therapy in patients with treatment-naive advanced pancreatic cancer. The primary endpoint is progression free survival for triplet therapy while on MSKD or non-MSKD. Secondary endpoints include disease control rate (PR+ CR+ SD for at least 9 weeks), change in CA 19-9 (or CA125, or CEA if not expressers of CA 19-9), average insulin levels, HbA1c, body weight, a comparison of gut microbial diversity, changes in serum metabolites and quality of life via the EORTC QLQ-C30 assessment. Unlike prior ketogenic intervention studies, the MSKD is being supported by a continuous care nutrition intervention through Virta Health Corp, that offers tracking of daily ketone and glucose levels, a web-based software application, education, and communication with a remote care team to ensure sustained nutritional ketosis. A total of 40 patients with untreated metastatic PDAC are planned for enrollment, 20 randomized to each arm. The trial opened for accrual November 2020. Clinical trial information: NCT04631445.
Randomized phase II selection study of ramucirumab and paclitaxel versus FOLFIRI in refractory small bowel adenocarcinoma: SWOG S1922.
Authors: Overman Michael J. , Guthrie Katherine A , Salem Mohamed E. , Pedersen Katrina Sophia , Kalyan Aparna , Bellasea Shay , Philip Philip Agop
Published: January 2022

TPS643

Background: Small bowel adenocarcinoma is a rare malignancy with limited data to support the choice of systemic chemotherapy beyond the frontline setting. Though second-line therapy has historically been extrapolated from colorectal cancers, recent molecular data has demonstrated small bowel adenocarcinoma to be genomically unique when compared to either colon or gastric cancer. Retrospective analyses of irinotecan- and taxane-based therapies and one prospective phase II clinical trial of nab-paclitaxel have demonstrated likely activity in this cancer. SWOG 1922 explores the clinical activity of FOLFIRI and ramucirumab with paclitaxel in the second- and later-line setting for small bowel adenocarcinoma. Methods: This is a randomized phase II selection design clinical trial of FOLFIRI (5-fluorouracil, leucovorin and irinotecan) every two weeks or ramucirumab D1,15 and paclitaxel D1,8,15 every 4 weeks with the primary endpoint of progression-free survival (PFS). Secondary endpoints include response rate, overall survival, and safety. Archived paraffin tumor tissue collection and serial blood collections are included for correlative analyses. Key eligibility include having mismatch repair proficient/microsatellite stable small bowel adenocarcinoma (ampullary location excluded); metastatic or locally advanced unresectable disease; prior fluoropyrimidine and/or oxaliplatin therapy; no prior treatment with irinotecan, ramucirumab, or taxanes; no recent bleeding, blood clots, or bowel perforation/fistula; and Zubrod performance status of 0/1. Measurable disease is not required. The null hypothesis is median PFS of 2.5 months. If a median PFS of at least 3.5 months is observed in one or both arms, the goal is to choose the better regimen with respect to this endpoint. The design provides a 90% probably of selecting the more active arm, assuming a hazard ratio of 1.4, if both arms meet this threshold. This trial is open and, as of September 1, 2021, 17 of 94 planned patients have been enrolled. NCT04205968. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868; and in part by Eli Lilly and Company. Clinical trial information: NCT04205968.
Association Between Radioactive Iodine Treatment for Pediatric and Young Adulthood Differentiated Thyroid Cancer and Risk of Second Primary Malignancies
Authors: Pasqual Elisa , Schonfeld Sara , Morton Lindsay M. , Villoing Daphnée , Lee Choonsik , Berrington de Gonzalez Amy , Kitahara Cari M.
Published: January 2022

PURPOSE

Since the 1980s, both the incidence of differentiated thyroid cancer (DTC) and use of radioactive iodine (RAI) treatment increased markedly. RAI has been associated with an increased risk of leukemia, but risks of second solid malignancies remain unclear. We aimed to quantify risks of second malignancies associated with RAI treatment for DTC in children and young adults, who are more susceptible than older adults to the late effects of radiation.

METHODS

Using nine US SEER cancer registries (1975-2017), we estimated relative risks (RRs) for solid and hematologic malignancies associated with RAI (yes v no or unknown) using Poisson regression among ≥ 5- and ≥ 2-year survivors of nonmetastatic DTC diagnosed before age 45 years, respectively.

RESULTS

Among 27,050 ≥ 5-year survivors (median follow-up = 15 years), RAI treatment (45%) was associated with increased risk of solid malignancies (RR = 1.23; 95% CI, 1.11 to 1.37). Risks were increased for uterine cancer (RR = 1.55; 95% CI, 1.03 to 2.32) and nonsignificantly for cancers of the salivary gland (RR = 2.15; 95% CI, 0.91 to 5.08), stomach (RR = 1.61; 95% CI, 0.70 to 3.69), lung (RR = 1.42; 95% CI, 0.97 to 2.08), and female breast (RR = 1.18; 95% CI, 0.99 to 1.40). Risks of total solid and female breast cancer, the most common cancer type, were highest among ≥ 20-year DTC survivors (RRsolid = 1.47; 95% CI, 1.24 to 1.74; RRbreast = 1.46; 95% CI, 1.10 to 1.95). Among 32,171 ≥ 2-year survivors, RAI was associated with increased risk of hematologic malignancies (RR = 1.51; 95% CI, 1.08 to 2.01), including leukemia (RR = 1.92; 95% CI, 1.04 to 3.56). We estimated that 6% of solid and 14% of hematologic malignancies in pediatric and young adult DTC survivors may be attributable to RAI.

CONCLUSION

In addition to leukemia, RAI treatment for childhood and young-adulthood DTC was associated with increased risks of several solid cancers, particularly more than 20 years after exposure, supporting the need for long-term surveillance of these patients.
Phenotypic Heterogeneity and Fertility Potential of Patients With 17-Hydroxylase/17,20-lyase Deficiency
Authors: Xu Yue , Jiang Shutian , Yan Zheng , Niu Yao , Du Wenhua , Liu Bingli , Han Bing , Liu Xuemeng , Zhao Shuangxia , Song Huaidong , Kuang Yanping , Qiao Jie
Published: January 2022

Context

17α-Hydroxylase/17,20-lyase deficiency (17OHD) is caused by a human CYP17A1 gene mutation and has the classical phenotype of hypertension, hypokalemia, sexual infantilism, and primary amenorrhea in females (46,XX) and disorders of sexual development in males (46,XY). To date, few cases of 17OHD have been reported, and the likelihood of pregnancy has rarely been explored.

Objective

To study the clinical characteristics, phenotype heterogeneity, genotyping, and the likelihood of pregnancy of patients with 17OHD.

Design

Genotype analysis was performed by direct sequencing of the CYP17A1 gene and next-generation sequencing in nonclassical patients. In vitro enzyme activity assays and 3-dimensional structure observations were used to assess the function of 3 missense mutations of the CYP17A1 gene. Progestin-primed ovarian stimulation (PPOS) was chosen for ovulation induction in 2 patients.

Results

Eight mutations were identified from 13 patients, including the homozygous mutations p. N395D and p. R496C and compound heterozygous mutations p. Y329fs/p. A421A and p. I332T/p. D487_F489del in 4 nonclassical patients. For the 3 missense mutations, an in vitro functional study showed mild impairment of 17α-hydroxylase activities 15.3-25.0% but residual 17,20-lyase activities 6.6%-9.4%. Two 46,XX females succeeded in pregnancy and delivery by combined PPOS, in vitro fertilization embryo transfer (IVF-ET), and the use of low-dose glucocorticoids.

Conclusions

Partial 17OHD present nonclassical clinical features, without hypertension and hypokalemia. Successful pregnancy in such 46,XX patients could be attained by the appropriate choice of ovulation induction regimen, precise dose of glucocorticoid to reduce progesterone levels, and the use of IVF-ET.
MyD88-dependent TLR signaling oppositely regulates hematopoietic progenitor and stem cell formation in the embryo
Authors: Bennett Laura F. , Mumau Melanie D. , Li Yan , Speck Nancy A.
Published: January 2022

Hemogenic endothelial (HE) cells in the dorsal aorta undergo an endothelial-to-hematopoietic transition (EHT) to form multipotent progenitors, lympho-myeloid biased progenitors (LMPs), pre-hematopoietic stem cells (pre-HSCs) and adult-repopulating HSCs. These briefly accumulate in intra-arterial hematopoietic clusters (IAHCs) before being released into the circulation. It is generally assumed that the number of IAHC cells correlates with the number of HSCs. Here, we show that changes in the number of IAHC cells, LMPs and HSCs can be uncoupled. Mutations impairing MyD88-dependent toll-like receptor (TLR) signaling decreased the number of IAHC cells and LMPs, but increased the number of HSCs in the aorta-gonad-mesonephros region of mouse embryos. TLR4-deficient embryos generated normal numbers of HE cells, but IAHC cell proliferation decreased. Loss of MyD88-dependent TLR signaling in innate immune myeloid cells had no effect on IAHC cell numbers. Instead, TLR4 deletion in endothelial cells (ECs) recapitulated the phenotype observed with germline deletion, demonstrating that MyD88-dependent TLR signaling in ECs and/or in IAHCs regulates the numbers of LMPs and HSCs.
TAF4b transcription networks regulating early oocyte differentiation
Authors: Gura Megan A. , Relovská Soňa , Abt Kimberly M. , Seymour Kimberly A. , Wu Tong , Kaya Haskan , Turner James M. A. , Fazzio Thomas G. , Freiman Richard N.
Published: January 2022

Establishment of a healthy ovarian reserve is contingent upon numerous regulatory pathways during embryogenesis. Previously, mice lacking TBP-associated factor 4b (Taf4b) were shown to exhibit a diminished ovarian reserve. However, potential oocyte-intrinsic functions of TAF4b have not been examined. Here, we use a combination of gene expression profiling and chromatin mapping to characterize TAF4b-dependent gene regulatory networks in mouse oocytes. We find that Taf4b-deficient oocytes display inappropriate expression of meiotic, chromatin modification/organization, and X-linked genes. Furthermore, dysregulated genes in Taf4b-deficient oocytes exhibit an unexpected amount of overlap with dysregulated genes in oocytes from XO female mice, a mouse model of Turner Syndrome. Using Cleavage Under Targets and Release Using Nuclease (CUT&RUN), we observed TAF4b enrichment at genes involved in chromatin remodeling and DNA repair, some of which are differentially expressed in Taf4b-deficient oocytes. Interestingly, TAF4b target genes were enriched for Sp/Klf family and NFY target motifs rather than TATA-box motifs, suggesting an alternative mode of promoter interaction. Together, our data connect several gene regulatory nodes that contribute to the precise development of the mammalian ovarian reserve.
Plasticity in fluctuating hydrodynamic conditions: tube foot regeneration in sea urchins
Authors: Narvaez Carla A. , Moura Andrew J. , Scutella Daniel F. , Cucchiara Jack P. , Stark Alyssa Y. , Russell Michael P.
Published: January 2022

Regenerating structures critical for survival provide excellent model systems for the study of phenotypic plasticity. These body components must regenerate their morphology and functionality quickly while subjected to different environmental stressors. Sea urchins live in high-energy environments where hydrodynamic conditions pose significant challenges. Adhesive tube feet provide secure attachment to the substratum but can be amputated by predation and hydrodynamic forces. Tube feet display functional and morphological plasticity in response to environmental conditions, but regeneration to their pre-amputation status has not been achieved under quiescent laboratory settings. In this study, we assessed the effect of turbulent water movement, periodic emersion and quiescent conditions on the regeneration process of tube foot morphology (length, disc area) and functionality (maximum disc tenacity, stem breaking force). Disc area showed significant plasticity in response to the treatments; when exposed to emersion and turbulent water movement, disc area was larger than that of tube feet regenerated in quiescent conditions. However, no treatment stimulated regeneration to pre-amputation sizes. Tube foot length was unaffected by treatments and remained shorter than non-amputated tube feet. Stem breaking force for amputated and non-amputated treatments increased in all cases when compared with pre-amputation values. Maximum tenacity (force per unit area) was similar among tube feet subjected to simulated field conditions and amputation treatments. Our results suggest a role of active plasticity of tube foot functional morphology in response to field-like conditions and demonstrate the plastic response of invertebrates to laboratory conditions.
Serum albumin levels monitoring in ICU in early days and mortality risk association in patients with moderate to severe COVID-19 pneumonia
Authors: Baig Mirza Ayub , Raza M. Mohsin , Baig Mougheesa , Baig M. Usman
Published: January 2022

Objective: To establish correlation between serum albumin during early days of ICU admission and risk of death in COVID-19 pneumonia.

Methods: In this retrospective study, we included 76 patients hospitalized in ICU, who stayed for at least four days with COVID-19 pneumonia, from May 1, 2020 to June 30, 2020 in Lahore Health Care Hospital and Al-Shafi Hospital. Patients were labelled as COVID-19 pneumonia on radiological basis as bilateral ‘ground-glass opacity’ in lower zones and RT-PCR positive result in nasopharyngeal swab. All patients were oxygen dependent, either on high flow oxygen via non rebreathing mask or invasive positive pressure ventilation support. Serum albumin levels were measured daily from first day to fourth day of ICU admission. The data was analyzed using SPSS version 26 and Microsoft excel 2016.

Results: Out of 76 patients of COVID-19 pneumonia admitted in ICU who stayed for more than four days, 38 patients expired. The mean age of all the patients was 58.9±12.56 years, 38(50%) of the patients were ≥60 years and 49 (62%) of them were male. On day four of ICU admission, mean serum albumin of discharged patients was 3.83±0.22 g/dl while mean serum albumin level of expired patients was 2.96±0.46 g/dl. Strong negative correlation (r = -767) was found between decrease in serum albumin level and increase number of deaths from COVID-19 pneumonia. Weak correlation was observed between increase in serum CRP and increase number of deaths in the same patients.

Conclusion: Daily monitoring of serum albumin level of COVID-19 pneumonia patients can be used as a biological marker for monitoring of cytokine storm and risk of death in COVID-19 pneumonia.

doi: https://doi.org/10.12669/pjms.38.3.4154

How to cite this:Baig MA, Raza MM, Baig M, Baig MU. Serum albumin levels monitoring in ICU in early days and mortality risk association in patients with moderate to severe COVID-19 pneumonia. Pak J Med Sci. 2022;38(3):---------.  doi: https://doi.org/10.12669/pjms.38.3.4154

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.
Investigation of Staphylococcus lugdunensis and Selected Coagulase Negative Staphylococci Isolated from Blood Culture bottles and Determination of their Sensitivities to Antibiotics
Authors: Veliev Aynur , Nakipoglu Yasar
Published: January 2022

Objectives: Coagulase-negative staphylococci (CNS) are commensal skin microbiota but may also cause septicemia, endocarditis, and systemic infections. Staphylococcus lugdunensis, is a member of CNS, ​​but their antibiotic susceptibility test should be evaluated as Staphylococcus aureus not as CNS. We aimed to investigate S.lugdunensis and selected CNS strains by simple biochemical method and determination of their susceptibilities to antibiotics.

Methods: A total of 251 CNS isolates were collected from blood culture bottles sent to Istanbul Faculty of Medicine Department of Medical Microbiology, between 2018 and 2019. PYR (pyrrolidonyl arylamidase) and ODC (ornithine decarboxylase) tests were performed on total of CNS isolates and API Staph was used for identification of the isolates giving positive result in both or either of these two tests. Disk diffusion method was used for the determination of antibiotic susceptibility of the isolates. S. aureus ATCC 25923 and S S.lugdunensis ATCC® 49576 strains were used as quality control strains in disc diffusion method, and biochemical tests, respectively.

Results: Twenty three out of 251 CNS isolates were positive in each or both of PYR and ODC tests. We detected the first S.lugdunensis isolate from eye vitreous fluid of patient developed a postoperative endophthalmitis in Turkey. This isolate gave dual positive with ODC, PYR, and API Staph. Other 22 CNS isolates were from blood cultures and distributed as follows; 14 Staphylococcus haemolyticus and three Staphylococcus chromogenes isolates were PYR positive and ODC negative and five Staphylococcus epidermidis isolates were ODC positive and PYR negative. All isolates except S.lugdunensis were resistant to penicillin (95.7%) and 20 (87.0%) isolates were found to be methicillin resistant.

Conclusions: ODC and PYR are cost effective tests and easily applicable for accurate identification of S.lugdunensis, and eliminating of opportinistic pathogens such as S. epidermidis, S. haemolyticus, and S. chromogenes from other CNS species in postoperative endophthalmitis and pateints with malignancies. Linezolid was very effective (100%) on four selected CNS species.

doi: https://doi.org/10.12669/pjms.38.3.4738

How to cite this:Veliev A, Nakipoglu Y. Investigation of Staphylococcus lugdunensis and Selected Coagulase Negative Staphylococci Isolated from Blood Culture bottles and Determination of their Sensitivities to Antibiotics. Pak J Med Sci. 2022;38(3):---------.  doi: https://doi.org/10.12669/pjms.38.3.4738

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.
Influenza Altmetric Attention Score and its association with the influenza season in the USA
Authors: AlRyalat Saif Aldeen , Al Oweidat Khaled , Al-Essa Mohammad , Ashouri Khaled , El Khatib Osama , Al-Rawashdeh Athar , Yaseen Abeer , Toumar Ahmad , Alrwashdeh Anas
Published: January 2022

Background: Altmetrics measure the impact of journal articles by tracking social media, Wikipedia, public policy documents, blogs, and mainstream news activity, after which an overall Altmetric attention score (AAS) is calculated for every journal article. In this study, we aim to assess the AAS for influenza related articles and its relation to the influenza season in the USA.

Methods: This study used the openly available Altmetric data from Altmetric.com. First, we retrieved all influenza-related articles using an advanced PubMed search query, then we inputted the resulted query into Altmetric explorer. We then calculated the average AAS for each month during the years 2012-2018.

Results: A total of 24,964 PubMed documents were extracted, among them, 12,395 documents had at least one attention. We found a significant difference in mean AAS between February and each of January and March (p< 0.001, mean difference of 117.4 and 460.7, respectively). We found a significant difference between June and each of May and July (p< 0.001, mean difference of 1221.4 and 162.7, respectively). We also found a significant difference between October and each of September and November (p< 0.001, mean difference of 88.8 and 154.8, respectively).

Conclusion: We observed a seasonal trend in the attention toward influenza-related research, with three annual peaks that correlated with the beginning, peak, and end of influenza seasons in the USA, according to Centers for Disease Control and Prevention (CDC) data.
Analysing the Sri Lankan civil war through the lens of conflict resolution theory
Authors: Sonia Dey
Published: January 2022

The Sri Lankan ethnic conflict can be identified as a landmark event in recent history, reflecting a visible social disunion between the majority and minority ethnic communities. Sri Lanka witnessed a major turnover of events, from circumscribed ethnic clashes to a full-scale civil war. The ripple effects of this Sri Lankan civil war crossed borders and it was neighbouring India that bore the brunt. Responding to the crisis, the Sri Lankan government deployed forces to contain the growing insurgency and involved external powers for added assistance. Neutral third parties were also involved for an unbiased resolution to Sri Lanka’s ethnic conflict. However, there were a multitude of shortcomings that restricted the scope for a successful conflict resolution. This paper highlights both conditions for success and failure of conflict resolution, and the use of third-party intervention as a crucial toolkit. It also throws light on the pre-conditions that were set for introducing third-party intervention in Sri Lankan, exposing the limitations that led to the fateful end of the Sri Lankan civil war. This research points out the equation between roles of third-party mediators and behavioural patterns of the disputed parties in conflict resolution processes. Theory teaches us how third-party intervention can be used as a preferred tool in attaining desirable outcomes. However, application of such tools become subjective on ground, depending upon the behaviour of the parties involved and their intentions towards solutions. Thus, exposing a variety of challenges that the mediators are often unprepared for. Such unpreparedness of third-party negotiators brings to the surface the drawbacks of this method of conflict resolution. Challenges faced in the Sri Lankan peace process uncovered the shortcomings of third-party mediation. This study holds potential to drive future researchers closer to exploring means to minimize the impacts of such limitations on forthcoming reconciliations.