bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of half-dose spiomet treatment in girls with early puberty and accelerated bone maturation: a multicenter, randomized, placebo-controlled study protocol
Authors: Bassols Judit , de Zegher Francis , Diaz Marta , Carreras-Badosa Gemma , Garcia-Beltran Cristina , Puerto-Carranza Elsa , Oliver-Vila Cora , Casano Paula , Franco Céline Alicia , Malpique Rita , López-Bermejo Abel , Ibáñez Lourdes
Published: January 2023

Background

A “mismatch” sequence of less prenatal weight gain and more postnatal weight gain may lead to ectopic lipid accumulation, and trigger the development of early adrenarche/pubarche and the activation of the gonadotropic axis resulting in early puberty and ending up in full-blown adolescent polycystic ovary syndrome (PCOS). In the present study, we assess whether a low-dose combination of generics that collectively reduce ectopic fat through different pathways can slow down the accelerated maturation in “mismatch” girls with early puberty.

Methods

Randomized, placebo-controlled, multicenter, phase 2a, study in 64 girls [age, 8.0–9.5 years; birthweight (BW) for gestational age: −2.5 < Z-score <0, body mass index (BMI): 0 < Z-score < +2.5 and early progressive puberty (Tanner B2 at 7.7–9.3 years)]. Pharmacological intervention will be with a half-dose version of SPIOMET (mini-spiomet), a combination that reverts the PCOS phenotype in “mismatch” adolescents; mini-spiomet will contain spironolactone (25 mg/day, to raise brown adipose tissue activity), pioglitazone (3.75 mg/day, to raise adiponectin and insulin sensitivity), and metformin (425 mg/day, to raise AMPK activity and GDF15). Recruitment: 1 year; double-blind treatment: 1 year; open follow-up: 1 year; analyses and reporting: 1 year. Interventions: randomization (1:1) for placebo vs mini-spiomet. Primary outcome: annualized bone age advancement (0–1 year) by BoneXpert; secondary outcomes: insulin, IGF-I, high-molecular-weight adiponectin (HMW-adip), sex hormone binding globulin (SHBG), ultra-sensitive C-reactive protein (usCRP), androgens, luteinizing hormone (LH), follicle-stimulating hormone (FSH), oestradiol, growth-and-differentiation factor 15 (GDF15), C-X-C motif chemokine ligand-14 (CXCL14), safety parameters, and quantification of hepato-visceral fat.

Discussion

The present study, if successful, may provide a first proof of the concept that the rapid maturation of girls with an upward mismatch between pre- and post-natal weight gain can be slowed down with a fixed low-dose combination of old and safe generics jointly targeting a reduction of ectopic fat without necessarily lowering body weight.

Trial registration

EudraCT 2021-006766-21. Registered on May 30, 2022.
Diversity of Hepatozoon species in wild mammals and ticks in Europe
Authors: Uiterwijk Mathilde , Vojta Lea , Šprem Nikica , Beck Ana , Jurković Daria , Kik Marja , Duscher Georg G. , Hodžić Adnan , Reljić Slaven , Sprong Hein , Beck Relja
Published: January 2023

Background

Hepatozoon spp. are tick-borne parasites causing subclinical to clinical disease in wild and domestic animals. Aim of this study was to determine Hepatozoon prevalence and species distribution among wild mammals and ticks in Europe.

Methods

Samples of wild mammals and ticks, originating from Austria, Bosnia and Herzegovina, Croatia, Belgium and the Netherlands, were tested with PCR to amplify a ~ 670-bp fragment of the small subunit ribosomal RNA gene.

Results

Of the 2801 mammal samples that were used for this study, 370 (13.2%) tested positive. Hepatozooncanis was detected in samples of 178 animals (3 Artiodactyla, 173 Carnivora, 1 Eulipotyphia, 1 Lagomorpha), H.martis in 125 (3 Artiodactyla, 122 Carnivora), H.sciuri in 13 (all Rodentia), Hepatozoon sp. in 47 (among which Hepatozoon sp. Vole isolate, all Rodentia) and H.ayorgbor in 4 (all Rodentia). Regarding origin, 2.9% (6/208) tested positive from Austria, 2.8% (1/36) from Bosnia and Herzegovina, 14.6% (173/1186) from Croatia and 13.9% (190/1371) from Belgium/the Netherlands. Of the 754 ticks collected, 0.0% (0/35) Hyalomma sp., 16.0% (4/25) Dermacentor spp., 0.0% (0/23) Haemaphysalis spp., 5.3% (24/50) Ixodes and 1.4% (3/221) Rhipicephalus spp. tested positive for Hepatozoon (4.2%; 32/754), most often H.canis (n = 22).

Conclusions

Hepatozooncanis is most present in mammals (especially in Carnivora such as gray wolves and golden jackals) and ticks, followed by H.martis, which was found merely in stone martens and pine martens. None of the rodent-associated Hepatozoon spp. were detected in the ticks, suggesting the possible implication of other arthropod species or non-vectorial routes in the transmission cycle of the hemoprotozoans in rodents. Our findings of H.canis in ticks other than R.sanguineus add to the observation that other ticks are also involved in the life cycle of Hepatozoon. Now that presence of Hepatozoon has been demonstrated in red foxes, gray wolves, mustelids and rodents from the Netherlands and/or Belgium, veterinary clinicians should be aware of the possibility of spill-over to domestic animals, such as dogs.

Graphical Abstract
Lung ultrasound to evaluate aeration changes in response to recruitment maneuver and prone positioning in intubated patients with COVID-19 pneumonia: preliminary study
Authors: Cammarota Gianmaria , Bruni Andrea , Morettini Giulio , Vitali Leonardo , Brunelli Francesco , Tinarelli Filippo , Simonte Rachele , Rossi Elisa , Bellucci Matteo , De Girolamo Giacomo , Galzerano Antonio , Vetrugno Luigi , Maggiore Salvatore M. , Bignami Elena , Azzolina Danila , Dow Olivia , Navalesi Paolo , De Robertis Edoardo
Published: January 2023

Background

This single-center preliminary prospective observational study used bedside ultrasound to assess the lung aeration modifications induced by recruitment maneuver and pronation in intubated patients with acute respiratory disease syndrome (ARDS) related to coronavirus 2019 disease (COVID-19).

All adult intubated COVID-19 patients suitable for pronation were screened. After enrollment, patients underwent 1 h in a volume-controlled mode in supine position (baseline) followed by a 35-cmH2O-recruitment maneuver of 2 min (recruitment). Final step involved volume-controlled mode in prone position set as at baseline (pronation). At the end of the first two steps and 1 h after pronation, a lung ultrasound was performed, and global and regional lung ultrasound score (LUS) were analyzed. Data sets are presented as a median and 25th–75th percentile.

Results

From January to May 2022, 20 patients were included and analyzed. Global LUS reduced from 26.5 (23.5–30.0) at baseline to 21.5 (18.0–23.3) and 23.0 (21.0–26.3) at recruitment (p < 0.001) and pronation (p = 0.004). In the anterior lung regions, the regional LUS were 1.8 (1.1–2.0) following recruitment and 2.0 (1.6–2.2) in the supine (p = 0.008) and 2.0 (1.8–2.3) in prone position (p = 0.023). Regional LUS diminished from 2.3 (2.0–2.5) in supine to 2.0 (1.8–2.0) with recruitment in the lateral lung zones (p = 0.036). Finally, in the posterior lung units, regional LUS improved from 2.5 (2.3–2.8) in supine to 2.3 (1.8–2.5) through recruitment (p = 0.003) and 1.8 (1.3–2.2) with pronation (p < 0.0001).

Conclusions

In our investigation, recruitment maneuver and prone positioning demonstrated an enhancement in lung aeration when compared to supine position, as assessed by bedside lung ultrasound.

Trial registration: www.clinicaltrials.gov, Number NCT05209477, prospectively registered and released on 01/26/2022.
Fractional version of Ostrowski-type inequalities for strongly p-convex stochastic processes via a k-fractional Hilfer–Katugampola derivative
Authors: Qi Hengxiao , Saleem Muhammad Shoaib , Ahmed Imran , Sajid Sana , Nazeer Waqas
Published: January 2023

In the present research, we introduce the notion of convex stochastic processes namely; strongly p-convex stochastic processes. We establish a generalized version of Ostrowski-type integral inequalities for strongly p-convex stochastic processes in the setting of a generalized k-fractional Hilfer–Katugampola derivative by using the Hölder and power-mean inequalities. By using our main results, we derived some known results as special cases and many well-known existing results are also recaptured. It is assumed that this research will offer new guidelines in fractional calculus.
Existence of solutions for Caputo fractional delay differential equations with nonlocal and integral boundary conditions
Authors: Cui Ziyue , Zhou Zongfu
Published: January 2023

In this paper, the existence and uniqueness of the solutions of Caputo fractional delay differential equations under nonlocal and integral boundary value conditions are studied. By using the Banach contraction principle and the Burton and Kirk fixed-point theorem, some new conclusions about the existence and uniqueness of solutions are obtained. An example is given to illustrate the main results.
Preoperative hemoglobin and perioperative blood transfusion in major head and neck surgery: A systematic review and meta-analysis
Authors: Ali Munib , Dort Joseph C. , Sauro Khara M.
Published: January 2023

Background

There is a growing concern with inappropriate, excessive perioperative blood transfusions. Understanding the influence of low preoperative hemoglobin (Hgb) on perioperative blood transfusion (PBT) in head and neck cancer (HNC) surgery with free flap reconstruction may help guide clinical practice to reduce inappropriate treatment among these patients. The objective is to synthesize evidence regarding the association between preoperative Hgb and PBT among major HNC free flap surgeries.

Methods

Terms and synonyms for HNC surgical procedures, Hgb and PBT were used to search MEDLINE, Embase, CINAHL, Cochrane Central Register of Controlled Trials and Cochrane Database of Reviews from inception to February 2020. Reference lists of included full texts and studies reporting the preoperative Hgb, anemia or hematocrit (exposure) and the PBT (outcome) in major HNC surgery with free flap reconstruction were eligible. Studies examining esophageal, thyroid and parathyroid neoplasms were excluded; as were case reports, case series (n < 20), editorials, reviews, perspectives, viewpoints and responses. Two independent, blinded reviewers screened titles, abstracts and full texts in duplicate. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses was followed. A random-effects model was used to pool reported data. The primary outcome was the proportion of patients who had a PBT. Subgroup analysis examined sources of heterogeneity for perioperative predictors of PBT (age, sex, flap type, flap site and preoperative Hgb). We also examined mean preoperative Hgb in the PBT and no PBT groups.

Results

Patients with low preoperative Hgb were transfused more than those with normal Hgb (47.62%, 95% CI = 41.19–54.06, I2 = 0.00% and 13.92%, 95% CI = 10.19–17.65, I2 = 20.69%, respectively). None of the predictor variables explained PBT. The overall pooled mean preoperative Hgb was 12.96 g/dL (95% CI = 11.33–14.59, I2 = 0.00%) and was 13.58 g/dL (95% CI = 11.95–15.21, I2 = 0.00%) in the no PBT group and 12.05 g/dL (95% CI = 10.01 to 14.09, I2 = 0.00%) in the PBT group.

Conclusions

The heterogeneity between studies, especially around the trigger for PBT, highlights the need for additional research to guide clinical practice of preoperative Hgb related to PBT to enhance patient outcomes and improve healthcare stewardship.

Graphical Abstract
Prevalence of Internet gaming disorder and its association with psychiatric comorbidities among a sample of adults in three Arab countries
Authors: Almutairi Tourki Abdulmhsen , Almutairi Khaled Sultan , Ragab Khaled Mohamed , Nourelden Anas Zakarya , Assar Ahmed , Matar Sajeda , Rashid Hivan Haji , Elsayed Mohamed , Fathallah Ahmed Hashem , Spitzer Manfred , Schönfeldt-Lecuona Carlos ,   Collaboration Team, Albazee Ebraheem , Klib Mohamad , Hassan Zeina Mohammed
Published: January 2023

Background

As Internet gaming became publicly available over the past 25 years, Internet gaming disorder emerged as a new diagnostic entity and became established in psychiatric diagnostic systems as a form of addiction. Given the recency of its advent, reliable data on the epidemiology and psychiatric comorbidity of this disorder in specific geographic regions are scarce and dearly needed for appropriate treatment.

Results

A total sample of number = 1332 participants completed the questionnaire. Four-hundred twenty-three of them were gamers; in this cohort, the prevalence of Internet gaming disorder was 6.1%. A strong association between Internet gaming and several psychiatric disorders (attention deficit, hyperactivity, depression, and anxiety) was found.

Conclusions

Internet gaming disorder is frequent in adults from Arab countries. It is associated with psychiatric comorbidities in this current sample; the nature of this association needs to be properly investigated.
In vivo serotonin 1A receptor hippocampal binding potential in depression and reported childhood adversity
Authors: Bartlett Elizabeth A. , Yttredahl Ashley A. , Boldrini Maura , Tyrer Andrea E. , Hill Kathryn R. , Ananth Mala R. , Milak Matthew S. , Oquendo Maria A. , Mann J. John , DeLorenzo Christine , Parsey Ramin V.
Published: January 2023

Background

Reported childhood adversity (CA) is associated with development of depression in adulthood and predicts a more severe course of illness. Although elevated serotonin 1A receptor (5-HT1AR) binding potential, especially in the raphe nuclei, has been shown to be a trait associated with major depression, we did not replicate this finding in an independent sample using the partial agonist positron emission tomography tracer [11C]CUMI-101. Evidence suggests that CA can induce long-lasting changes in expression of 5-HT1AR, and thus, a history of CA may explain the disparate findings.

Methods

Following up on our initial report, 28 unmedicated participants in a current depressive episode (bipolar n = 16, unipolar n = 12) and 19 non-depressed healthy volunteers (HVs) underwent [11C]CUMI-101 imaging to quantify 5-HT1AR binding potential. Participants in a depressive episode were stratified into mild/moderate and severe CA groups via the Childhood Trauma Questionnaire. We hypothesized higher hippocampal and raphe nuclei 5-HT1AR with severe CA compared with mild/moderate CA and HVs.

Results

There was a group-by-region effect (p = 0.011) when considering HV, depressive episode mild/moderate CA, and depressive episode severe CA groups, driven by significantly higher hippocampal 5-HT1AR binding potential in participants in a depressive episode with severe CA relative to HVs (p = 0.019). Contrary to our hypothesis, no significant binding potential differences were detected in the raphe nuclei (p-values > 0.05).

Conclusions

With replication in larger samples, elevated hippocampal 5-HT1AR binding potential may serve as a promising biomarker through which to investigate the neurobiological link between CA and depression.
Cesarean section and parenting stress: Results from the Japan Environment and Children’s Study
Authors: Matsumura Kenta , Hatakeyama Takehiro , Yoshida Taketoshi , Tsuchida Akiko , Inadera Hidekuni ,   The Japan Environment and Children’s Study (JECS) Group
Published: January 2023

Background

Accumulating evidence suggests a long-term health risk of cesarean section for the mother and child, but few studies have examined the link between cesarean section and parenting stress. Here, we examined this association by exploiting a large dataset.

Methods

Participants were 65,235 mothers participating in the Japan Environment and Children’s Study, an ongoing nationwide birth cohort. Outcome variables were parenting stress assessed as total score and subscale scores (representing the difficult child, parental distress, and spouse factors) on the Japanese 19-item version of the Parenting Stress Index Short Form (J-PSI-SF). Exposures were the mode of delivery, the timing of the J-PSI-SF assessment (1.5, 2.5, and 3.5 years postpartum), and the interaction between them. Multivariate regression analysis was used to calculate adjusted β coefficients and standard error of the means (SEMs).

Results

The J-PSI-SF total score was higher in the cesarean section group than in the vaginal delivery group (adjusted β = 0.24, SEM = 0.09). This increase was primarily due to higher scores for the difficult child factor (adjusted β = 0.18, SEM = 0.05) and not to higher scores for the parental distress or spouse factor.

Conclusions

Cesarean section was associated with higher parenting stress, especially in relation to the difficult child factor. Our results highlight the importance of paying particular attention to the mental health of both mother and child in the case of cesarean section.
Phase 2 multi-institutional prospective feasibility study of uracil-tegafur and leucovorin as adjuvant chemotherapy for patients aged 80 years or more after curative resection of colorectal cancer: The HiSCO-03 study.
Authors: Miguchi Masashi , Ikeda Satoshi , Shimomura Manabu , Nakahara Masahiro , Adachi Tomohiro , Ishizaki Yasuyo , Saitoh Yasufumi , Toyota Kazuhiro , Sumitani Daisuke , Shimizu Yosuke , Takakura Yuji , Shimizu Wataru , Yoshimitsu Masanori , Kodama Shinya , Fujimori Masahiko , Oeda Mamoru , Kobayashi Hironori , Ohdan Hideki
Published: January 2023

101

Background: There is no consensus on the safety and effectiveness of adjuvant chemotherapy for patients with stage III colorectal cancer (CRC) aged ≥80 years who underwent curative resection. We conducted a prospective phase II feasibility study of uracil-tegafur and leucovorin (UFT/LV) as adjuvant chemotherapy in this population. Methods: This study involved 15 institutions of the Hiroshima Surgical Oncology Study Group (HiSCO). Patients with stage III CRC aged ≥80 years who underwent curative resection with an Eastern Cooperative Oncology Group performance status of 0–1 were enrolled. Eligible patients received UFT/LV therapy (UFT, 300 mg/m2 per day as tegafur; LV, 75 mg/day on days 1–28, every 35 days for five courses). Primary endpoint was feasibility, and secondary endpoints were safety and relative dose intensity. Results: Sixty-nine patients were enrolled in the study between December 2013 and June 2021. Of the 69 patients, 65 were included in the analysis, excluding two ineligible patients and two who discontinued before treatment commenced. There were 32 males and 33 females with a median age of 82 years (range, 80–88 years). There were four patients with stage IIIA CRC, 49 with stage IIIB, and 12 with stage IIIC. In the primary endpoint, administration completion rate was 67.3% (95% confidence interval: 54.9The median relative dose intensities were 84% (range, 4–100%) for UFT, and 100% (range, 4–100%) for LV. Incidence of grade three or higher adverse events were neutropenia (1.5%), aspartate transaminase elevation (3%), alanine transaminase elevation (1.5%), oral mucositis (3%), anemia (1.5%), and diarrhea (4.6%). No treatment-related deaths occurred. An independent risk factor was not identified in the background risk factor analysis for treatment discontinuation. Conclusions: Uracil-tegafur and leucovorin are not recommended as standard adjuvant therapy for patients with stage III CRC ≥80 years of age because of the possibility of lower completion rates. The frequency of serious adverse events was acceptable, and safety was confirmed in the treated patients. It is necessary to clarify the background of patients in which administration is discontinued and to investigate the impact on long-term prognosis. Clinical trial information: R000013902 .
A meta-analysis of bevacizumab’s cardiovascular risks in patients treated for colorectal cancer.
Authors: Chitkara Akshit , Desai Aditya , Mehta Devanshi , Kaur Nirmaljot , Anamika Fnu , Desai Darshi , Thawani Rajat
Published: January 2023

113

Background: Bevacizumab (BVZ), a recombinant humanized monoclonal IgG antibody, is commonly used as first- and second-line adjuvant therapy in metastatic colorectal cancer. Recent guidelines have shown that a combination of three cytotoxic drug regimens FOLFOX (fluorouracil, leucovorin and oxaliplatin) along with BVZ is regarded as one of the first-line options. As we see an upward trend in using BVZ; it is crucial to analyze the side effects and potential toxicities. A frequent adverse effect with BVZ is hypertension. The prevailing hypothesis for the mechanism of BVZ induced hypertension is an increase in vascular tone due to the inhibition of VEGF-mediated vasodilation. A persistent elevation of arterial blood pressure is generally asymptomatic, but unmanaged hypertension can lead to cardiovascular complications, encephalopathy, and subarachnoid hemorrhage. Therefore, this meta-analysis aims to evaluate and assess the risk of BVZ induced hypertension. Methods: Our search included articles from PubMed, EMBASE, Web of Science, and Cochrane Library from 1980 to March 2022. Randomized controlled trials and clinical trials with BVZ as an add-on therapy mentioning cardiovascular side effects were included. Full analysis control group included various guideline directed chemotherapies and the subgroup analysis control group focused on FOLFOX therapy. A random-effects model was used with Review Manager, and a P value < 0.05 was considered significant. Results: We included a total of 17,807 patients in our study with an average age of 65 years. Analysis pooled from 19 RCTs showed that the odds of hypertension (Grade 3 or more) in patients treated with BVZ were about four times higher than the control group (OR 3.82, 95% CI 3.35-4.36, p-value < 0.00001, I2 = 78%). In a subgroup analysis, BVZ was compared with FOLFOX group, with odds of hypertension (Grade 3 or more) in BVZ group being about five times higher than in FOLFOX group (OR 5.24, 95% CI 4.06-6.77, p-value < 0.00001, I2 = 58%). Conclusions: Our meta-analysis demonstrates a significant cardiovascular risk of Bevacizumab when added to the standard regime for advanced colorectal cancer treatment. When BVZ was used as an add-on therapy to FOLFOX regimens for colorectal cancer, it was associated with about five times higher odds of developing hypertension (Grade 3 or more) in the treatment group with BVZ. Previous RCTs have demonstrated that BVZ add-on therapy to the standard regime is safe and without significant risk of toxicity. Our findings are important as they give vital information in assessing the risk-benefit ratio of adding BVZ, especially in a population with vascular comorbidities. Now that we have established the statistical significance of hypertensive risk with BVZ, it will be interesting to see how these events can be prevented in patients treated for metastatic colorectal cancer. Dedicated RCTs are needed to confirm these findings.
Multicenter retrospective study of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) for vulnerable patients with pretreated metastatic colorectal cancer (mCRC): WJOG14520G (TWILIGHT).
Authors: Mitani Seiichiro , Kito Yosuke , Kawakami Hisato , Nishina Shinichi , Matsumoto Toshihiko , Tsuzuki Takao , Shinohara Yudai , Shimokawa Hozumi , Kumanishi Ryosuke , Ohta Takashi , Kimura Shinya , Kawakami Takeshi , Nishina Tomohiro , Hasegawa Hiroko , Akiyoshi Kohei , Chiba Yasutaka , Yamazaki Kentaro , Hironaka Shuichi , Muro Kei
Published: January 2023

121

Background: In the phase III SOLSTICE study, FTD/TPI plus BEV showed similar efficacy to capecitabine plus BEV as first-line treatment for patients with mCRC ineligible for full-dose combination chemotherapy with oxaliplatin [OX] or irinotecan [IRI] (intensive therapy). We evaluated clinical outcomes of FTD/TPI plus BEV as second- or later lines treatment for vulnerable patients, who were defined to be intolerant to intensive therapy. Methods: This was a multicenter retrospective study of vulnerable patients with unresectable mCRC who received FTD/TPI plus BEV as second- or later lines treatment between May 2014 and October 2020. Main eligibility criteria were histologically proven adenocarcinoma, ECOG PS 0-2, prior chemotherapy for unresectable disease, considered intolerant to intensive therapy, and underwent FTD/TPI plus BEV without prior exposure to at least one key cytotoxic agent (fluoropyrimidines [FP], OX, or IRI). Results: Of 96 patients enrolled from 26 Japanese hospitals, 93 patients were evaluable. Patient characteristics were as follows: median age, 79 years (range 21-90); male, 53%; ECOG PS 0-1, 89%; right-sided primary tumor, 30%; primary tumor resection, 86%; RAS mutant, 63%; BRAF mutant, 1%; second-line treatment, 80%; prior exposure to FP 100%, OX 50%, and IRI 15%. Main reasons for intolerance to intensive therapy were older age (65%), poor PS (20%), and renal failure (5%). Initial dose of FTD/TPI was reduced in 30 (32%) patients. The response rate was 5% and disease control rate was 68%. With median follow-up of 21.6 months, the median progression-free survival, time to treatment failure, and overall survival were 6.3, 4.5, and 18.6 months, respectively. Major grade >3 adverse events were neutropenia (54%), anemia (20%), thrombocytopenia (9%), hypertension (7%), and febrile neutropenia (2%). No treatment-related deaths were observed. The treatment was discontinued in 89 patients due to disease progression (n = 72), patient’s refusal (n = 10), and adverse events (n = 6). After FTD/TPI plus BEV, chemotherapies such as regimens including IRI or OX (n = 20), regorafenib (n = 16), and anti-EGFR antibody monotherapy (n = 7) were performed in 42 patients. Conclusions: FTD/TPI plus BEV as second- or later lines treatment for vulnerable patients with mCRC showed promising clinical activity and acceptable safety profile. This study suggested that FTD/TPI plus BEV could be a treatment option for vulnerable patients with pretreated mCRC. Clinical trial information: UMIN000044136 .
Colorectal endoscopic submucosal dissection using a concealable robotic add-on device: A comparative in vivo feasibility study.
Authors: Kim Sang Hyun , Keum Bora , Choi Hyuk Soon , Jeen Yoon Tae , Chun Hoon Jai , Hong Daehie
Published: January 2023

128

Background: Appropriate tissue tension and clear visibility of the dissection area using traction are essential for effective and safe colonic endoscopic submucosal dissection (ESD). In this preclinical ex vivo and in vivo animal study, we developed a concealable robotic-assisted traction device and evaluated its performance in colorectal ESD. Methods: An experienced endoscopist performed ESD on an ex vivo porcine colon 18 times using our robot and 18 times using the conventional method. The outcome measures were procedure time, dissection speed, procedure-related adverse events, and blind dissection rate. We also conducted an in vivo feasibility study in live pigs. Robotic ESD was performed by experienced and novice endoscopist groups (n = 2, each). The outcomes included time to complete each ESD step, total procedure time, size of the dissected mucosa, rate of en bloc resection, and major adverse events. Results: Thirty-six colonic lesions were resected from ex vivo porcine colon samples. The total procedure time was significantly shorter in robotic ESD (RESD) than in conventional ESD (CESD) (20.1±4.1 vs. 34.3±8.3; P < 0.05). The submucosal dissection speed was significantly higher in the RESD group than in the CESD group (36.8±9.2 vs. 18.1±4.7; P < 0.05). The blind dissection rate was also significantly lower in the robotic group (12.8±3.4% vs. 35.1±3.9%; P < 0.05). In an in vivo feasibility study, the robot was attached to the colonoscope and successfully inserted into the proximal colon without damaging the colonic wall, and ESD was successfully performed. There was no significant difference in the submucosal dissection speed between the groups (P = 0.465). Conclusions: When the concealable robot assisted the colonic ESD procedure, the dissection speed and safety profile improved significantly. Thus, our robotic device can provide a simple, effective, and safe multidirectional traction during colonic ESD. When the robot was assisting in the ESD procedure, the dissection speed improved significantly, especially in the novice endoscopists.
Panitumumab plus trifluridine/tipiracil as third-line anti-EGFR rechallenge therapy in chemo-refractory RAS WT metastatic colorectal cancer: The VELO randomized phase II clinical trial.
Authors: Napolitano Stefania , De Falco Vincenzo , Martini Giulia , Esposito Lucia , Famiglietti Vincenzo , Martinelli Erika , Ciardiello Davide , Marrone Francesca , Avallone Antonio , Cardone Claudia , De Stefano Alfonso , Montesarchio Vincenzo , Zampino M. Giulia , Bordonaro Roberto , Scartozzi Mario , Santini Daniele , Di Maio Massimo , Ciardiello Fortunato , Troiani Teresa
Published: January 2023

129

Background: Rechallenge therapy with epidermal growth factor receptor (EGFR) inhibitors in chemo-refractory metastatic colorectal cancer (mCRC) is an emerging therapeutic approach. Trifluridine-tipiracil is approved for treatment of chemo-refractory mCRC patients. Methods: Chemo-refractory RAS WT mCRC patients, that had a major response (partial or complete response) to first-line chemotherapy plus an anti-EGFR monoclonal antibody and had an-anti-EGFR drug-free interval during second-line therapy of four or more months were randomized in a phase II trial to assess the addition of the anti-EGFR monoclonal antibody panitumumab to trifluridine-tipiracil as third-line rechallenge therapy. The primary endpoint was progression free survival (PFS). Baseline plasma was analyzed for circulating free tumor (ct) DNA by using Biocartis Idylla platform to detect mutations in KRAS, NRAS, BRAF ( V600E) and EGFRextracellular domain ( S492R). In 24 patients with baseline RAS/BRAF wild type (WT) ctDNA, Foundation One liquid CDx (324 gene profiling) was also performed before treatment and at disease progression. Results: 62 patients were treated with trifluridine-tipiracil (31 patients, arm A) or with trifluridine-tipiracil plus panitumumab (31 patients, arm B). As of September 16, 2022, 1 patient in arm A and 2 patients in arm B were on treatment. The primary endpoint was met. Median PFS (mPFS) was 4 months in arm B versus 2.5 months in arm A [hazard ratio (HR): 0.48; 95% CI 0.28-0.82; P = 0.007]. Baseline plasma RAS/BRAF WT ctDNA was found in 23/31 patients in Arm A and in 26/31 patients in Arm B. In this group, mPFS was 4.5 months in Arm B versus 2.6 months in Arm A (HR: 0.48; 95% CI 0.26-0.89; P = 0.019). Disease control (major responses plus stable disease) was higher for patients in Arm B compared to Arm A (81% versus 48%), whereas disease progression was the best response in 19% versus 52% patients, respectively. PFS rates at 6 and 12 months were 38.5% and 15.4% in arm B versus 13% and 0% in arm A. At disease progression, Foundation One liquid CDx detected several mutations within the EGFR pathway, which could correlate with cancer cell resistance to panitumumab. Conclusions: This is the first prospective randomized trial which evaluated anti-EGFR monoclonal antibody (panitumumab) in addition to standard of care (trifluridine-tipiracil) as third-line rechallenge therapy in chemo-refractory RASWT mCRC patients. Baseline liquid biopsy allows selection of RAS/BRAF WT ctDNA patients who could have a relevant clinical benefit. Clinical trial information: NCT05468892 .
Clinical outcomes and barriers to cancer care delivery for patients with rectal cancer in Nairobi, Kenya.
Authors: Wanda Dulcie , Merrell Kenneth , Ojuka Daniel , Okumu Joel Omundi , Ochieng Primus
Published: January 2023

17

Background: Rectal cancer is among the top ten cancers in Kenya with most patients presenting with locally advanced rectal cancer (LARC). Management requires multimodality treatment including neo-adjuvant therapy and surgery. There is limited data on the outcome for patients with LARC from Kenya and the broader region. The aim of our study was to evaluate outcomes of LARC from a tertiary hospital in Nairobi, Kenya, to identify barriers to care and methods to improve cancer outcomes. Methods: We conducted a retrospective study of patients with LARC treated at the Kenyatta National Hospital between January 2016 and January 2020. Patients with histologic confirmation of rectal cancer, received neo-adjuvant treatment, and had available survival data in the electronic medical record were included in the analysis. A data abstraction tool was used to collect patient demographics and cancer outcomes including age, gender, tumor stage, cancer and vital status. Overall and progression-free survival were estimated using the Kaplan-Meier method. Results: A total of 182 patients were identified that met inclusion on the study. The median age of 53 years (range, 21 - 82) years, 52.5% were female and 94.5% had cT3 (57.5%) or cT4 (37%) disease and 75% of patients had N+ disease. The time from symptoms onset to diagnosis and diagnosis date to treatment was 14 and 3.6 months, respectively. months76% of patients were from rural regions of Kenya. Most patients (95%) received long-course chemoradiation (50.4 Gy/28 fractions) with concurrent Capecitabine 825 mg/m2 chemotherapy. Only 5% (n=9) of patients had resection after neoadjuvant therapy. The median progression free and overall survival after neo-adjuvant treatment respectively was 24 months (IQR: 23 – 25 months) and 36 months (IQR: 24 – 36 months), respectively. Presence of comorbidities (OR =7.87, 95% CI: 3.46 – 17.89, p<0.001), tumor staging cT3 (OR = 2.34, 95% CI: 1.13 – 7.49, p =0.013), tumor staging cT4 (OR =4.02, 95% CI: 2.12 – 10.34, p =0.004) and increase in duration of symptoms by one month (OR =1.04, 95% CI: 1.01 – 2.14, p =0.003) were significantly associated with lower overall survival. Conclusions: Our results represent one of the largest series of outcomes for rectal cancer from Sub-Saharan Africa and serves as a baseline for clinical improvement. The long interval from symptom onset to diagnosis represents an area for patient intervention and development of screening protocols. Further exploration into the barriers that limit access to surgery is warranted and development of a non-operative protocol may serve the patient population due to the limited capacity of surgery.
Plasma central carbon metabolite changes associated with KRAS mutation and circulating tumor DNA (ctDNA) status in colorectal cancer (CRC).
Authors: Kim Daniel Myung , Aguirre Francesca Paola , Gangi Alexandra , Alvarez Rocio , Zhou Lisa , ten Hoeve Johanna , Liao Yi Jou , Graeber Thomas , Hendifar Andrew Eugene , Osipov Arsen , Sankar Kamya , Cho May Thet , Abbas Anser , Davelaar John , Hitchins Megan Philippa , Gong Jun
Published: January 2023

181

Background: KRAS mutations have been widely characterized as markers of poor prognosis in CRC. In stage IV CRC, KRAS mutations are predictive of benefit to anti-EGFR therapy. ctDNA has increasingly been recognized as a prognostic biomarker in CRC as well. We evaluated the association between plasma metabolites and KRAS mutation or ctDNA status in a longitudinal, observational cohort of patients with stage I-IV CRC. Methods: This was a retrospective analysis of prospectively collected blood samples from a single-institute cohort of patients with stage I-IV CRC. All blood samples were collected at pre-chemotherapy baseline. A modified Epi proColon 2.0 CE (Epigenomics AG) assay was used for plasma ctDNA testing on the methylated SEPTIN9 gene (mSEPT9). ctDNA positivity was defined as a mSEPT9 percentage of methylation reference (PMR) value greater than zero. Up to 150 metabolites of central carbon metabolism were analyzed by mass spectrometry and high-performance liquid chromatography. Analytes were compared by relative area under the curve (AUC) and differences evaluated by ANOVA. The mean AUC was used in patients with metabolites measured from > 1 timepoint of collection. Patients were stratified by ctDNA status (positive or negative) and KRAS mutant (MT) or wildtype (WT) status. Results: A total of 32 patients were included with median age 65 years (range 20-90). The majority were female (53%) and had stage IV disease (78%). Of 25 patients with stage IV CRC, 88% had pre-chemotherapy blood samples collected in the first-line setting. Most patients were KRAS MT (44%) compared to KRAS WT (37%) or unknown KRAS status (19%). The most common KRAS MT subtypes were G12D (29%), G12V (29%), G13D (21%), and G12C (14%). The mean overall survival in this cohort was 27.4 months while the mean mSEPT9 PMR value was 2553.6. When stratified by ctDNA status, ctDNA positivity was associated with decreased levels of essential amino acids (lysine, methionine, threonine) and the non-essential amino acid arginine (all p < 0.05). Compared to KRAS WT tumors, KRAS MT tumors were associated with increased levels of proline, phenylalanine, and intermediates of glycolysis (lactate), MTA cycle (SAM, 5-Methioadenosine), and O-GlcNAcylation (GlcNac, all p < 0.05). Conclusions: We are the first to demonstrate the feasibility of associating central carbon metabolites with ctDNA and KRAS mutation status. As ctDNA positivity and KRAS MT status have evolving prognostic potential in CRC, associated metabolic signatures may identify metabolic pathways for novel biomarker development. Our findings also show that KRAS MT CRC appears to be enriched in intermediates of glycolytic, methyl donor, and O-GlcNAcylation pathways.
Comparative analysis of tumor immune microenvironment in primary tumors vs metastatic tissue in microsatellite stable metastatic colorectal cancer.
Authors: Fakih Marwan , Ye Jian , Wang Chongkai , Ashok Arya , Mauer Elizabeth , Chao Calvin Y.
Published: January 2023

187

Background: We previously demonstrated differences in responses to checkpoint inhibitors between liver and non-liver metastases (mets) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Here, we investigate differences in tumor microenvironment (TME) and mutational landscape of primary and mCRC sites. Methods: We used the Tempus clinicogenomic database to select de-identified cases of MSS mCRC which underwent Tempus xT testing. Tempus xT is a 648-gene NGS panel that detects somatic alterations and includes RNA sequencing. Gene expression patterns of different immune cells were used to predict their relative abundance within the tumor. Analyzed tumors were divided into 4 categories based: primary tumor (colon), liver, lung, and peritoneal mets. Demographics, genomic alterations, tumor mutational burden (TMB), PD-L1 expression, and proportions of B, T (CD4+, CD8+), NK cells, and macrophages were compared between all 4 categories. Chi-squared/Fisher’s exact tests or Kruskal-Wallis tests were used to assess statistical significance. Results: Genomic profiles from 4,345 unique mCRC patients were analyzed (Primary CRC = 1734; Liver = 1825; Lung = 443; Peritoneal = 343). Median TMB and PD-L1 expressions had small differences across sites that were statistically significant. KRAS mutations were more frequent and SMAD4 mutations were less prevalent in lung mets. RNA-Seq revealed significant differences in immune cell composition. Lung mets exhibited a higher percentage of B cells and lower percentage of macrophages than liver and peritoneum (p< 0.001), similar to primary tumors. CD4+ T cells were highest in primary tumors, whereas CD8+ T cells were highest in lung mets (p < 0.001). Conclusions: The TME of lung mets has a more favorable immune composition (increased CD8+ T cells and B cells, decreased macrophages) than that of liver and peritoneal mets, suggesting that MSS mCRC to the lung may potentially be more responsive to immunotherapy.[Table: see text]
Biomarker analysis from a phase I/I1b study of regorafenib and nivolumab (rego/nivo) in microsatellite stable (MSS) colorectal cancer (CRC).
Authors: Yu James , Kim Youngchul , Mehta Rutika , Miao Ruoyu , Strosberg Jonathan R. , Imanirad Iman , Kim Dae Won , Kim Richard D.
Published: January 2023

188

Background: Our previous phase I/Ib study revealed modest clinical efficacy of rego/nivo in refractory MSS-CRC, implying benefits in selected populations. This has prompted us to investigate predictive biomarkers. Methods: Pre-treatment tumor samples from the previous phase Ib rego/nivo study were obtained and assessed for mRNA sequencing (RNAseq). Response-associated transcripts were identified using DESeq2 method and annotated using gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. Results: A total of 19 pretreatment tumor samples were analyzed including 14 patients (pts) with disease control (DC) (2 partial response and 12 stable disease) and 5 pts with progression disease (PD). We observed significant upregulation of 89 genes including SFTPB ( P<0.001), SFTPA1 ( P<0.001), ERICH6B ( P<0.001) , XIST ( P<0.001), IGHV2-26 ( P<0.001), RETNLB ( P=0.005), VWA5B1 ( P=0.033), IGHV3-53 ( P<0.001), POTEH ( P=0.015), IGHV1-3 ( P=0.001) and downregulation of 70 genes including AFAP1-AS1 ( P=0.022), PRSS21( P<0.001), NTSR1 ( P<0.001), CALB1 ( P=0.033), FAM83A ( P=0.013), TBL1Y ( P=0.045), WNT7A ( P=0.022), PADI1 ( P<0.001), KRT6A ( P=0.030), KRT17 ( P=0.002) on RNA sequencing in the DC compared to PD. GO pathway enrichment analyses revealed 44 significantly upregulated pathways including positive regulation of B cell activation ( P<0.001), B cell receptor signaling pathway ( P<0.001), Phagocytosis engulfment ( P<0.001), Fc-gamma receptor signaling pathway involved in phagocytosis ( P<0.001), endocytosis ( P<0.001), immunoglobulin receptor binding ( P<0.001), serine-type endopeptidase activity ( P<0.001) in the DC compared with PD group. Nine downregulated pathways including cell-substrate junction assembly ( P<0.001), extracellular matrix (ECM) organization ( P=0.030), and ephrin receptor activity ( P=0.046) were observed in the DC compared with PD. KEGG pathway enrichment analysis revealed 8 significantly downregulated pathways including PI3K-Akt signaling ( P=0.009), ECM-receptor interaction ( P=0.006), Focal adhesion ( P=0.028), and Glycine, serine and threonine metabolism ( P=0.007) pathways in the DC compared with PD. Conclusions: RNAseq and following gene set enrichment analysis between pts with DC and PD revealed several dysregulated pathways involving immune regulation including macrophage and B cell activation, and also PI3-Akt signaling, ECM organization/receptor interaction, and adhesion, which are consistent with previous translational studies in other solid tumors. These dysregulated genes and pathways related to differentially expressed genes may need to be further evaluated as potential predictive biomarkers for rego/nivo or other tyrosine kinase inhibitor plus PD-1 blockade in MSS-CRC.
Comparison of treatment utilization and clinical outcomes among elderly patients with colon cancer from a limited-resource and high-resource setting.
Authors: El Hajj Joanna , Sanjeevaiah Aravind , Kainthla Radhika , Al Mutar Salwan , Kazmi Syed Mohammad Ali
Published: January 2023

20

Background: Elderly colon cancer patients face unique age-specific challenges during their treatments. The resource availability at the healthcare facility can affect their cancer-related outcomes. We evaluated the utilization of therapies and compared outcomes among elderly colon cancer patients treated in a limited-resource versus a high-resource healthcare setting. Methods: Patients >70 years of age with stage II-IV colon adenocarcinoma diagnosed between 2011 and 2017 were identified from the tumor registry of a large safety-net hospital (limited-resource setting), and an NCI-designated Comprehensive Cancer Center (high-resource setting). We compared the frequencies of categorical variables using Chi-square and Fisher’s exact tests and used a t-test to compare continuous variables between the limited-resource and high-resource setting patients. A multivariate survival analysis was performed using the Cox proportional hazard models adjusting for age, race/ethnicity [Hispanic, non-Hispanic White (NHW), and non-Hispanic Black (NHB)], BMI (<18.5 and > 18.5), gender, hospital setting (limited-resource vs. high-resource setting), staging (II, III, and IV), laterality of the tumor (right or left) and performance of surgery. Results: One-hundred-twenty-one elderly colon cancer patients were identified; the median age at diagnosis was 75 years (IQR 72-80.5), predominantly females (53%). Fifty-four patients (44.6%) received treatment in the limited-resource setting while sixty-seven (55.4%) were treated in the high-resource setting. Most patients were NHW (46%), followed by NHB (25%) and Hispanics (23%). Hispanic patients were more frequent in the limited-resource setting (44% vs 6%) while NHW were more frequent in the high-resource setting (73.8% vs. 14.8%). Utilization of surgery (83% vs. 85%, p-value = 0.8), the use of adjuvant chemotherapy for stage III colon cancer (34.8% vs. 65.2%; p-value = 0.295) and palliative chemotherapy among stage IV (39% vs. 61%; p-value = 0.5) was not significantly different among the elderly patients treated in the limited-resource setting as compared to high-resource setting. On the multivariate survival analysis, stage IV disease (p-value = 0.002) and limited-resource setting (HR = 0.37, 95% CI = 0.19-0.71, p-value = 0.003) were independently associated with survival in this cohort. Conclusions: Elderly patients treated in the limited-resource setting had lower survival as compared to those treated in the high-resource setting. There was a trend toward lower utilization of chemotherapy for stage III and IV elderly colon cancer patients in the limited-resource setting compared to the high-resource setting. The patient or system-related factors that may contribute to this disparity should be further explored.
What genes predict response to neoadjuvant chemoradiation in locally advanced rectal cancer? A systematic review based on gene expression profiling.
Authors: Or Michelle , Lin Jessica , Lam Johnson , Hau Eric , Sundaresan Puma
Published: January 2023

200

Background: Curative management of locally advanced rectal cancer (LARC) involves neoadjuvant chemoradiation therapy (nCRT) followed by radical surgery. Pathological complete response (pCR) is seen in 15-27% of patients. The response to nCRT may be influenced by genetic variations. Gene signatures therefore may serve as biomarkers for predicting response or resistance to nCRT. We conducted a systematic review on genetic biomarkers for response prediction to nCRT in LARC and identify common genes or ontology pathways. Methods: A systematic search of electronic databases (MEDLINE, PubMed and EMBASE) was performed for relevant recent studies. Studies were screened as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with search terms “rectal neoplasm”, “rectal cancer”, “gene”, “gene expression”, “gene expression profile”. The relevant studies were selected for full-text review. Studies that reported gene expression profile to predict response to nCRT were included. Results: Twelve of 367 studies screened were included. Most studies used microarray or real-time reverse transcription PCR. Six of these assessed for gene predictors of pCR with 2 studies reporting correlation between certain genes and pCR: thymidylate synthetase; gene set (including LMNB2, MLF2, DDX1, EIF4A1, FOXO3A, ILF3 and SEMA3C); 19 genes including (NPSR1, HYAL1, FGFBP1, PLLP and MALL). Common gene ontology pathways identified included DNA break repair via homologous recombination and apoptotic pathways. Conclusions: Multiple genes were identified as prospective biomarkers for nCRT in LARC patients. Further studies are required to validate these identified genes to personalize treatment for LARC patients.