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BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Xinghao Ai ◽  
Zhengbo Song ◽  
Hong Jian ◽  
Zhen Zhou ◽  
Zhiwei Chen ◽  

Abstract Background Standard therapy for human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC) is lacking. The clinical benefits with pan-HER inhibitors (afatinib, neratinib, and dacomitinib), anti-HER2 antibody drug conjugate (ADC) trastuzumab emtansine, and an emerging irreversible tyrosine kinase inhibitor (TKI) poziotinib were modest. Another new ADC trastuzumab deruxtecan showed encouraging outcomes, but only phase I study was completed. Pyrotinib, another emerging irreversible epidermal growth factor receptor (EGFR)/HER2 dual TKI, has been approved in HER2-positive breast cancer in 2018 in China. It has shown promising antitumor activity against HER2-mutant NSCLC in phase II trials, but pyrotinib-related diarrhea remains an issue. The antiangiogenic and immunomodulatory drug thalidomide is a cereblon-based molecular glue that can induce the degradation of the IKAROS family transcription factors IKZF1 and IKZF3. The use of thalidomide can also decrease gastrointestinal toxicity induced by anti-cancer therapy. Methods This is an open-label, single-arm phase II trial. A total of 39 advanced NSCLC patients with HER2 exon 20 insertions and ≤ 2 lines of prior chemotherapy will be recruited, including treatment-naïve patients who refuse chemotherapy. Patients are allowed to have prior therapy with immune checkpoint inhibitors and/or antiangiogenic agents. Those who have prior HER2-targeting therapy or other gene alterations with available targeted drugs are excluded. Eligible patients will receive oral pyrotinib 400 mg once daily and oral thalidomide 200 mg once daily until disease progression or intolerable toxicity. The primary endpoint is objective response rate. Discussion The addition of thalidomide to pyrotinib is expected to increase the clinical benefit in advanced NSCLC patients with HER2 exon 20 insertions, and reduce the incidence of pyrotinib-related diarrhea. We believe thalidomide is the stone that can hit two birds. Trial registration Identifier: NCT04382300. Registered on May 11, 2020.

2021 ◽  
Ji Hyun Lee ◽  
Seong Gu Heo ◽  
Beung‐Chul Ahn ◽  
Min Hee Hong ◽  
Byoung Chul Cho ◽  

2021 ◽  
Jens Peter Klussmann ◽  
Clara Lehmann ◽  
Maria Grosheva ◽  
Kurtulus Sahin ◽  
Eszter Nagy ◽  

Abstract Background:The current COVID-19 pandemic has had a major influence on our daily lives. The most frequent early symptoms associated with SARS-CoV-2 infection are coughing, fever, rhinitis, and loss of smell and taste. If the infection progresses to the lower respiratory tract, it can cause massive inflammation of the pulmonary system, which can be life threatening. There is urgent need for a broadly available and effective therapy for the treatment of early infections with SARS-CoV-2 in order to prevent progression to severe disease. Methodology:CARVIN is a phase II proof of concept, randomized, parallel, double-blind, placebo-controlled, interventional clinical trial. 90 SARS-CoV-2 positive volunteers were randomized into three groups to receive either placebo, azelastine 0.02% or azelastine 0.1% nasal spray for a period of 11 days. Seven nasopharyngeal swabs were taken during this period for quantitative PCR measurements assessing the viral load via the ORF 1a/b and E genes. Investigators also assessed patients’ status continuously throughout the trial, and the intensity of individual symptoms were reported by the patients using an electronic diary. Two safety follow-ups were performed at days 16 and 60 of study participation. Results:Since the data of the primary outcome did not show a normal distribution, all statistical tests presented here were done non-parametrically and all p-values are descriptive and without adjustment for multiple testing. A broader descriptive analysis will be performed at a later date on all variables and it will be published in a peer-reviewed publication. A wide range of initial viral loads in the nasopharyngeal swabs of the study population was observed with an overall median/mean + SD Ct value of approximately 21.9 / 23.6 + 5.8, corresponding to log10 6.6 + 1.8 copies per /ml. Out of the 90 enrolled subjects, at least 54 carried the Alpha (B.1.1.7, UK) variant.Treatment with azelastine nasal sprays resulted in a greater but non-significant decrease in mean viral load compared to that measured in the placebo group at all 6 timepoints after initiation of treatment. This tendency was stable and most pronounced on day 8 (after 7 days treatment), when in the 0.1% and 0.02% azelastine nasal spray groups, an approximately 8- and 29-fold greater clinically meaningful reduction of the baseline viral load, respectively, compared to placebo was observed (based on the ORF1a/b gene). On days 4 and 11, approximately 4-fold greater mean viral load reduction was seen in the 0.1% azelastine group.Differences in mean viral load compared to baseline values were seen starting on the second day (after one day of treatment) in the azelastine 0.1% and azelastine 0.02% group for ORF 1a/b gene, and with azelastine 0.1% for the E gene, while this reduction was less pronounced in the placebo group.The effects of 0.1% azelastine nasal spray treatment to accelerate viral load reduction were even more pronounced in patients with initial high viral load (subgroup analyses in patients exhibiting initial Ct values below 25 and below 20, respectively). Of note, by day 8 the PCR-test had turned negative in more patients in the 0.1% azelastine group (n=6, p= 0.01 for the ORF 1a/b gene and n = 3, p= 0.08 for the E gene) and in the 0.02% azelastine group (n=8, p< 0.01 for the ORF 1a/b gene and n = 5, p= 0.02 for the E gene) than in the placebo group (n=0 for the ORF 1a/b gene and n = 0, for the E gene).Discussion:This study provides the first clinical hints of the effects of an azelastine nasal spray in SARS-CoV-2 positive patients. Subgroup analyses performed in patients exhibiting high initial viral loads are further suggestive of azelastine’s potential as an antiviral treatment.

2021 ◽  
Vol 16 (1) ◽  
Jianjiao Ni ◽  
Yue Zhou ◽  
Lin Wu ◽  
Xinghao Ai ◽  
Xiaorong Dong ◽  

Abstract Objectives The SWORD trial is the first multicenter, single arm, phase II study assessing the safety and efficacy of a PD-1 inhibitor (Sintilimab), stereotactic body radiotherapy (SBRT) and granulocyte–macrophage colony stimulating factor (GM-CSF) in advanced non-small cell lung cancer (NSCLC) without sensitizing driver mutations. A safety run-in phase was conducted to determine the tolerability of the experimental treatment. Materials and methods Twenty metastatic NSCLC patients who failed first-line chemotherapy were enrolled, and they received SBRT (8 Gy × 3) to one lesion, followed by Sintilimab (200 mg d1, every 3 weeks, until disease progression, unacceptable toxicity, or up to 35 cycles) and GM-CSF (125 μg/m2 d1-d14, cycle 1) within 2 weeks after SBRT. In addition, blood and tissue samples were serially collected for translational research. Results Median age of the patients was 61 and all of them had more than 5 lesions at baseline. The sites of SBRT included lung (n = 11), mediastinal lymph node (n = 5), liver (n = 1), abdominal lymph node (n = 1), pleural nodule (n = 1) and vertebra (n = 1). No patients had dose-limiting toxicities (DLTs) and 18 patients experienced treatment-related adverse event (TRAE). The most common TRAEs were fatigue (50%), fever (30%), and ostealgia (20%), and they all were grade 1. Only 2 grade 3 TRAEs were observed, including elevation of liver enzymes in one and transient acute heart failure in another. No grade 4 or 5 AE was observed. Conclusion Sintilimab, SBRT and GM-CSF for advanced NSCLC is safe with manageable TRAEs and the trial continues to recruit participants. Trial registration, NCT04106180. Registered 26 September 2019, SBRT in Combination With Sintilimab and GM-CSF for the Treatment of Advanced NSCLC-Tabular

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Edward T. Pring ◽  
Laura E. Gould ◽  
George Malietzis ◽  
Philip Lung ◽  
Mina Bharal ◽  

Abstract Background Colorectal cancer is associated with secondary sarcopenia (muscle loss) and myosteatosis (fatty infiltration of muscle) and patients who exhibit these host characteristics have poorer outcomes following surgery. Furthermore, patients, who undergo curative advanced rectal cancer surgery such as pelvic exenteration, are at risk of skeletal muscle loss due to immobility, malnutrition and a post-surgical catabolic state. Neuromuscular electrical stimulation (NMES) may be a feasible adjunctive treatment to help ameliorate these adverse side-effects. Hence, the purpose of this study is to investigate NMES as an adjunctive pre- and post-operative treatment for rectal cancer patients in the radical pelvic surgery setting and to provide early indicative evidence of efficacy in relation to key health outcomes. Method In a phase II, double-blind, randomised controlled study, 58 patients will be recruited and randomised (1:1) to either a treatment (NMES plus standard care) or placebo (sham-NMES plus standard care) group. The intervention will begin 2 weeks pre-operatively and continue for 8 weeks after exenterative surgery. The primary outcome will be change in mean skeletal muscle attenuation, a surrogate marker of myosteatosis. Sarcopenia, quality of life, inflammatory status and cancer specific outcomes will also be assessed. Discussion This phase II randomised controlled trial will provide important preliminary evidence of the potential for this adjunctive treatment. It will provide guidance on subsequent development of phase 3 studies on the clinical benefit of NMES for rectal cancer patients in the radical pelvic surgery setting. Trial registration Protocol version 6.0; 05/06/20. NCT04065984. Registered on 22 August 2019; recruiting.

2021 ◽  
pp. JCO.21.01032
Yukihide Kanemitsu ◽  
Yasuhiro Shimizu ◽  
Junki Mizusawa ◽  
Yoshitaka Inaba ◽  
Tetsuya Hamaguchi ◽  

PURPOSE Adjuvant chemotherapy after hepatectomy is controversial in liver-only metastatic colorectal cancer (CRC). We conducted a randomized controlled trial to examine if adjuvant modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) is superior to hepatectomy alone for liver-only metastasis from CRC. PATIENTS AND METHODS In this phase II or III trial (JCOG0603), patients age 20-75 years with confirmed CRC and an unlimited number of liver metastatic lesions were randomly assigned to hepatectomy alone or 12 courses of adjuvant mFOLFOX6 after hepatectomy. The primary end point of phase III was disease-free survival (DFS) in intention-to-treat analysis. RESULTS Between March 2007 and January 2019, 300 patients were randomly assigned to hepatectomy alone (149 patients) or hepatectomy followed by chemotherapy (151 patients). At the third interim analysis of phase III with median follow-up of 53.6 months, the trial was terminated early according to the protocol because DFS was significantly longer in patients treated with hepatectomy followed by chemotherapy. With median follow-up of 59.2 months, the updated 5-year DFS was 38.7% (95% CI, 30.4 to 46.8) for hepatectomy alone compared with 49.8% (95% CI, 41.0 to 58.0) for chemotherapy (hazard ratio, 0.67; 95% CI, 0.50 to 0.92; one-sided P = .006). However, the updated 5-year overall survival (OS) was 83.1% (95% CI, 74.9 to 88.9) with hepatectomy alone and 71.2% (95% CI, 61.7 to 78.8) with hepatectomy followed by chemotherapy. In the chemotherapy arm, the most common grade 3 or higher severe adverse event was neutropenia (50% of patients), followed by sensory neuropathy (10%) and allergic reaction (4%). One patient died of unknown cause after three courses of mFOLFOX6 administration. CONCLUSION DFS did not correlate with OS for liver-only metastatic CRC. Adjuvant chemotherapy with mFOLFOX6 improves DFS among patients treated with hepatectomy for CRC liver metastasis. It remains unclear whether chemotherapy improves OS.

Blood ◽  
2021 ◽  
Muzaffar H Qazilbash ◽  
Neeraj Y Saini ◽  
Cha Soung-chul ◽  
Zhe Wang ◽  
Edward Stadtmauer ◽  

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding anti-myeloma idiotype-keyhole limpet hemocyanin (Id-KLH) vaccine to vaccine-specific co-stimulated T cells. In this randomized, phase II trial, eligible patients received either the control (KLH only) or Id-KLH vaccine, an auto-transplant, vaccine-specific co-stimulated T-cells expanded ex-vivo, and two booster doses of the assigned vaccine. In 36 patients (20 in KLH, 16 in Id-KLH) enrolled, no dose-limiting toxicity was seen in either arm. At last evaluation, 6 (30%) and 8 (50%) had achieved complete remission in KLH-only and Id-KLH, respectively (p=0.22) and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; p=0.32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with KLH-only patients, there was a greater change in IR genes in T-cells in Id-KLH patients relative to baseline. Specifically, upregulation of genes associated with activation, induction of effector function, and generation of memory CD8+ T cells after Id-KLH, but not after KLH control vaccination, was observed. Similarly, responding patients across both arms were associated with upregulation of genes associated with T-cell activation. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of Id-KLH patients analyzed. In conclusion, in this combination immunotherapy approach, we observed a significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies.

2021 ◽  
Vol 8 ◽  
Ziyan Yan ◽  
Wenfeng Deng ◽  
Yuchen Wang ◽  
Yanna Liu ◽  
Hengbiao Sun ◽  

Background: Colonization of Cryptococcus rarely occurs in a graft. This study reports a case of malacoplakia and cryptococcoma caused by E. coli and Cryptococcus albidus in a transplanted kidney, with detailed pathology and metagenome sequencing analysis.Case Presentation: We presented a case of cryptococcoma and malacoplakia in the genitourinary system including the transplant kidney, bladder, prostate, and seminal vesicles caused by Cryptococcus albidus and Escherichia coli in a renal-transplant recipient. Metagenome sequencing was conducted on a series of samples obtained from the patient at three different time points, which we termed Phase I (at the diagnosis of cryptococcoma), Phase II (during perioperative period of graftectomy, 3 months after the diagnosis), and Phase III (2 months after graftectomy). Sequencing study in the Phase I detected two and four sequences of C. albidus respectively in cerebrospinal fluid (CSF) and feces, with resistant Escherichia coli 09-02E presented in urine and renal mass. A 3-month antibiotic treatment yielded a smaller bladder lesion but an enlarged allograft lesion, leading to a nephrectomy. In the Phase II, two sequences of C. albidus were detected in CSF, while the E. coli 09-02E continued as before. In the Phase III, the lesions were generally reduced, with one C. albidus sequence in feces only.Conclusions: The existence and clearance of Cryptococcus sequences in CSF without central nervous system symptoms may be related to the distribution of infection foci in vivo, the microbial load, and the body's immunity. Overall, this study highlights the need for enhanced vigilance against uncommon types of Cryptococcus infections in immunocompromised populations and increased concern about the potential correlation between E. coli and Cryptococcus infections.

2021 ◽  
pp. JNM-D-20-00018
Hannah Fraley ◽  
Teri Aronowitz

Background and PurposeEstimates suggest approximately 244,000–360,000 schoolaged children in the United States are at risk of being trafficked. The purpose of this study was to test the psychometric properties of the School Nurses' Awareness and Perceptions Survey (SNAPS).MethodsA multi-phase approach for reliability and validity using correlation, exploratory, and confirmatory factor analysis (CFA) with samples of school nurses from Massachusetts (Phase I) and nationally (Phase II).ResultsSNAPS is a 32-item 5-point Likert scale with a potential score range of 32–160. Cronbach's alpha was .94 with sub-scales ranging from 0.84–0.94. CFA revealed a three-factor scale with a cumulative variance of 70.79% (Chisquare 3.13, df 461, p < .001; RMSEA .10; GFI .80; CFI .78; TLI .76).ConclusionsStrong psychometric properties were found for the new measure allowing assessment of school nurses' knowledge of youth trafficking.

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