Dupilumab improves pruritus and skin lesions in patients with prurigo nodularis: Pooled results from 2 phase 3 trials (LIBERTY-PN PRIME and PRIME2).

Background: Phase 3 PRIME/PRIME2 trials independently demonstrated efficacy and an acceptable safety profile of dupilumab adults with moderate-to-severe prurigo nodularis. Objective: To obtain a more precise estimate of onset and magnitude of treatment effect using PRIME/PRIME2 pooled data. Methods: In PRIME/PRIME2, patients were randomized to dupilumab or placebo for 24 weeks. Pooled analysis assessed proportion of patients achieving clinically meaningful improvement in itch, clear/almost-clear skin, or both; at weeks 12 and 24; overall and by demographic subgroups and changes from baseline to week 24 in symptoms, signs, and quality of life. Results: Patients receiving dupilumab (n = 153) vs placebo (n = 158) experienced significant improvements in all tested endpoints. At week 24, 90 (58.8%) dupilumab-treated vs 30 (19.0%) placebo-treated patients achieved clinically meaningful improvement in itch, 71 (46.4%) vs 27 (17.1%) clear/almost clear skin, and 54 (35.3%) vs 14 (8.9%) achieved both (P < .0001 for all). Treatment benefits were independent of baseline demographics. Safety to week 36 was generally consistent with the known dupilumab safety profile. Limitations: On-treatment data limited to 24 weeks. Conclusions: Pooled analysis confirmed improvements reported in individual trials and revealed earlier effect onset in itch and skin pain. Dupilumab treatment showed benefits across demographics.

Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials.

Prurigo nodularis (PN) is a chronic inflammatory skin disease with intensely pruritic nodules. The LIBERTY-PN PRIME and PRIME2 phase 3 trials enrolled adults with PN with ≥20 nodules and severe itch uncontrolled with topical therapies. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13. Patients were randomized 1:1 to 300 mg dupilumab or placebo subcutaneously every 2 weeks for 24 weeks. The primary endpoint was pruritus improvement, measured by proportion of patients with a ≥4-point reduction in Worst Itch Numeric Rating Scale (WI-NRS) from baseline at week 24 (PRIME) or week 12 (PRIME2). Key secondary endpoints included nodule number reduction to ≤5 at week 24. PRIME and PRIME2 enrolled 151 and 160 patients, respectively. Both trials met all the pre-specified primary and key secondary endpoints. A ≥4-point WI-NRS reduction at week 24 in the dupilumab and placebo arms was achieved by 60.0% and 18.4% of patients, respectively, in PRIME (95% confidence interval (CI), 27.8-57.7 for the difference, P < 0.001) and at week 12 by 37.2% and 22.0% of patients, respectively, in PRIME2 (95% CI, 2.3-31.2; P = 0.022). Dupilumab demonstrated clinically meaningful and statistically significant improvements in itch and skin lesions versus placebo in PN. Safety was consistent with the known dupilumab safety profile.ClinicalTrials.gov identifiers: NCT04183335 and NCT04202679 .

Combination chemotherapy with paclitaxel, cisplatin and fluorouracil for patients with advanced and metastatic gastric or esophagogastric junction adenocarcinoma: a multicenter prospective study.

OBJECTIVE: To evaluate the efficacy and toxicity of the combination regimen of paclitaxel, cisplatin and 5-FU (PCF) as first-line or second-line therapy in patients with advanced gastric and esophagogastric junction (EGJ) adenocarcinoma in China. METHODS: The patients were treated with paclitaxel 150 mg/m(2) on d1; fractionated cisplatin 15 mg/m(2) and continuous infusion 5-FU 600 mg/(m(2)·d) intravenously on d1-d5 of a 21-d cycle until disease progression or unacceptable toxicities. RESULTS: Seventy-five patients have been enrolled, among which, 41 received PCF regimen as the first-line therapy (group A) and 34 received the regimen as the second-line therapy (group B) with the median age of 59 years old and Karnofsky performance status (KPS) score ≥80. Toxicities were analyzed in all 75 patients. Seventy-one patients were evaluable for efficacy. The median overall survival (mOS) was 12.0 months (95% CI: 7.9-16.2 months) in group A and 7.3 months (95% CI: 4.3-10.3 months) in group B, respectively. The median progression-free survival (mPFS) was 5.7 months (95% CI: 4.1-7.2 months) and 5.0 months (95% CI: 3.1-6.9 months), respectively. The response rate (CR+PR) was 40% (16/40; 95% CI: 24.9-56.7%) in group A and 22.6% (7/31; 95% CI: 9.6-41.1%) in group B. Major grade 3 or 4 adverse events include neutropenia (41.3%), febrile neutropenia (9.3%), nausea/anorexia (10.7%), and vomiting (5.3%). There was no treatment-related death. CONCLUSIONS: The combination chemotherapy with PCF is active and tolerable as first-line and second-line therapy in Chinese patients with advanced gastric and EGJ adenocarcinoma. The response and survival of PCF are same as those of DCF, but the tolerance is much better.

Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. METHODS: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. FINDINGS: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference -1·7 [-9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [-6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI -7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. INTERPRETATION: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. FUNDING: Sanofi and Regeneron Pharmaceuticals.

A Phase II trial of oxaliplatin, folinic acid, and 5-fluorouracil (FOLFOX4) as first-line chemotherapy in advanced colorectal cancer: a China single-center experience.

PURPOSE: To evaluate the efficacy and toxicity of leucovorin (LV) plus 5-fluorouracil (5-FU) combined with oxaliplatin every 2 weeks on previously untreated advanced colorectal cancer patients in Chinese population. PATIENTS AND METHODS: Forty-nine patients were enrolled to receive, entirely as inpatients, 2-weekly cycles of oxaliplatin 85 mg/m2 i.v. over 2 hours on Day 1, together with leucovorin 200 mg/m2 over 2 hours, 5-FU 400 mg/m2, bolus, followed by a 22-hours infusion of 5-FU at 600 mg/m2 Days 1-2 (FOLFOX4) every 2 weeks. Treatment was given until progression or unmanageable toxicity. In all, 49 patients received ≥ 1 oxaliplatin dose and a median of 7 treatment cycles (range 1∼27 cycles). RESULTS: Of the 45 eligible patients, 1 complete response (CR) and 18 partial responses (PRs) were observed for an overall response rate of 42.2 percent (95 percent confidence interval 26∼56 percent). Median progression-free survival was 7.2 months (6.4∼8.0) and median overall survival was 14.8 months (13.1∼16.5). Six patients (12.2 percent) reported Grade 3∼4 neutropenia. Thirty-one patients (62.3 percent) experienced Grade 1∼3 neurotoxicity and only 5 patients (10.2 percent) experienced Grade 3 neurotoxicity. CONCLUSION: In our experience, FOLFOX4 regimen is active and well tolerated in patients with previously untreated advanced colorectal cancer in Chinese population.

Bone marrow metastasis of desmoplastic small round cell tumor.

Desmoplastic small round cell tumor is an extremely rare and highly aggressive neoplasm. It usually arises as a single mass or multiple masses in the abdominal cavity, characterized by diffuse peritoneal implants, involvement of regional lymph nodes, and liver and lung metastases. However, bone marrow metastasis has rarely been reported in the literature. We present a case of clinically symptomatic bone marrow metastasis in a 25-year-old woman with a diagnosis of desmoplastic small round cell tumor originating from the pelvic cavity.

Epithelioid malignant mesothelioma presenting with features of gastric tumor in a child.

Localized malignant mesothelioma is very uncommon and mainly arises in pleura and peritoneum, and preferentially occurs in older adults. In this article, we report a case of a Localized malignant mesothelioma that was developed in the stomach of a 6-year-old boy. This boy was admitted to hospital for anemia. An epigastric mass was palpated through systemic physical examination and MR scanning demonstrated an 8×6 cm-sized, well-defined elliptic mass at gastric corpus. Partial resection of the stomach was performed for this boy and no nodules were found on the liver, peritoneum, and other abdominal sites in surgery. In view of the morphological and immunohistochemical findings, a diagnosis of localized malignant mesothelioma, epithelial type was made. This is the first case report of localized malignant mesothelioma arising in the stomach of a child. Accumulation of more cases of malignant mesothelioma involving gastrointestinal tract and longer follow-up of the patients are necessary to further characterize the features of this rare disease.

A study of weekly docetaxel and carboplatin as first-line chemotherapy for advanced non-small cell lung cancer.

BACKGROUND: Weekly docetaxel demonstrated similar efficacy but better tolerability than standard triweekly docetaxel, and carboplatin was less nephrotoxic, neurotoxic and emetogenic than cisplatin. This study aimed to evaluate the efficacy and safety of weekly docetaxel with carboplatin as first-line chemotherapy for advanced non-small cell lung cancer (NSCLC). METHODS: Forty-three Chinese patients have been included. Patients were administered docetaxel at a dose of 35 mg/m(2) on days 1, 8, 15 and carboplatin at an area under the curve (AUC) 5 on day 1 every 28-day cycle (maximum six cycles). RESULTS: Of the 43 eligible patients, the assessed overall response rate (RR) was 30.2% with 30.2% partial response (PR) in 13 patients, 48.8% stable disease (SD) in 21 patients and 20.9% progressive disease (PD) in 9 patients. The estimated median progression free survival and median overall survival (OS) time were respectively, 120 days (95% CI: 80-160 days) and 340 days (95% CI: 224-456 days) with the patients surviving of 46.5% (95% CI: 31.6-61.4%) at one year and 20.0% (95% CI: 7.1-33.3%) at two years. The major grade 3/4 hematological toxicities were included leucocytopenia in 6 patients (13.9%) and neutropenia in 8 patients (18.6%). One patient (2.3%) suffered grade 1 febrile neutropenia. All grade of the nonhematological toxicities, such as nausea, vomiting, alopecia and fatigue held the proportion of 48.8% (grade 3/4 4.6%), 27.9%, 55.8% and 53.5% (grade 3/4 9.3%), respectively. CONCLUSIONS: The combination of weekly docetaxel and carboplatin showed feasible efficacy with acceptable hematologic toxicities for advanced lung cancer.

Association between KRAS codon 13 mutations and clinical response to anti-EGFR treatment in patients with metastatic colorectal cancer: results from a meta-analysis.

PURPOSE: To comparatively evaluate whether metastatic colorectal cancer (mCRC) patients with KRAS codon 13 mutations (codon 13 muts) can benefit from anti-EGFR treatment. METHODS: We performed a meta-analysis of relevant studies. Systematic searches of the PubMed, Embase, and Cochrane databases, as well as ASCO conference papers up to July 30, 2012, were retrieved, and the authors of included studies were contacted to obtain more individual data. Fixed effects meta-analytical models were used where indicated, and between-study heterogeneity was assessed. The primary study end points were the overall response rate (ORR). Secondary end points were progress-free survival (PFS) and overall survival (OS). RESULTS: A total of 7 studies were included in the final meta-analysis, consisting of 2,802 mCRC patients, 1,679 of whom were treated with anti-EGFR monoclonal antibodies. The ORR of mCRC patients with codon 13 mutation was 25.2 % (29/115), compared to 17.6% (98/558) for other KRAS mutations (other mut) and 42.6% (429/1,006) for KRAS WT patients. The overall pooled RR for ORRs of codon 13 mut versus other mut was 1.52 (95% CI 1.10-2.09, P = 0.003), whereas the pooled RR for codon 13 mut versus WT was 0.61 (95% CI 0.45-0.83, P = 0.002). The pooled progression-free survival (PFS) times were 6.4 months for codon 13 mut, 4.1 months for other mut, and 6.6 months for WT, whereas the pooled OS durations were 14.6, 11.8, and 17.3 months, respectively. Subgroup analysis was conducted on the basis of the line of treatment, anti-EGFR drug, study design, and detection method, respectively. The results implicated that KRAS codon 13 mut patients gain more benefit from Cetuximab in further line treatment. CONCLUSIONS: Metastatic colorectal cancer patients with KRAS codon 13 mutations demonstrate a greater clinical response to anti-EGFR treatment than patients with other KRAS mutations.

XRCC1 Arg399Gln and clinical outcome of platinum-based treatment for advanced non-small cell lung cancer: a meta-analysis in 17 studies.

OBJECTIVE: XRCC1 polymorphism is a research hotpot in individual treatment for non-small cell lung cancer (NSCLC). To obtain the association between XRCC1 polymorphism and clinical outcome of platinum-based treatment for NSCLC, a meta-analysis was conducted. METHODS: Databases including PubMed, Embase, Cochrane, and Chinese National Knowledge Infrastructure (CNKI) were searched for publications that met the inclusion criteria. A fixed effect model was used to estimate pooled odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (CI) for the association between XRCC1 Arg399Gln and response or survival of platinum-based treatment for advanced NSCLC. A chi-squared-based Q-test was used to test the heterogeneity hypothesis. Egger's test was used to check publication bias. RESULTS: Seventeen published case-control studies that focus on the association between XRCC1 Arg399Gln and response or survival of platinum-based treatment for advanced NSCLC in 2256 subjects were included in this meta-analysis, of whom 522 were AA genotypes (23.2% frequency), 916 AG genotypes (40.6% frequency), and 818 GG genotypes (36.2% frequency). The overall response rate (ORR) was 45.2% (110/243) for AA genotype patients, 29.9% for AG genotype (73/244), and 30.7% for GG genotype (124/403). The heterogeneity test did not show any heterogeneity and the Egger's test did not reveal an obvious publication bias among the included studies. The meta-analysis indicated that AA genotype patients presented higher response rates toward platinum drug treatment compared with G model (GG+GA) patients (GG vs. AA model: OR=0.489, 95% CI 0.266-0.900, P=0.021; AG vs. AA model: OR=0.608, 95% CI 0.392-0.941, P=0.026; GA+AA vs. GG model: OR=1.259, 95% CI 0.931-1.701, P=0.135; GG+GA vs. AA model: OR=0.455, 95% CI 0.313-0.663, P=0.0001). However, no evidence validates XRCC1 associates with the survival following platinum drug therapy. CONCLUSIONS: Our meta-analysis suggested that XRCC1 Arg399Gln is related with the sensitivity of NSCLC patients to platinum-based treatment. AA genotype patients present more desirable curative effectiveness compared with other patients.

Chemosensitivity of radioresistant cells in the multicellular spheroids of A549 lung adenocarcinoma.

BACKGROUND: The relapse of cancer after radiotherapy is a clinical knotty problem. Previous studies have demonstrated that the elevation of several factors is likely in some way to lead to the development of treatment tolerance, so it is necessary to further explore the problem of re-proliferated radioresistant cells to chemotherapeutic agents. In the present study, we aimed to investigate the chemosensitivity of radioresistant cells originated from the multicellular spheroids of A549 lung adenocarcinoma. METHODS: After irradiated with 25 Gy of 6 MV X-ray to A549 multicellular spheroids, whose 10th re-proliferated generations were employed as radioresistant cells, and the control groups were A549 parental cells and MCF7/VCR resistant cells. The chemo-sensitivity test was made by six kinds of chemotherapeutic drugs which were DDP, VDS, 5-Fu, HCP, MMC and ADM respectively, while verapamil (VPL) was used as the reversal agent. Then the treatment effect was evaluated by MTT assay, and the multidrug resistant gene expressions of mdr1 and MRP were measured by RT-PCR. RESULTS: Both A549 parental cells and A549 derived radioresistant cells were resistant to DDP, but sensitive to VDS, 5-Fu, HCP, MMC and ADM. The inhibitory rates of VPL to these two types of cell were 98% and 25% respectively (P < 0.001). In addition, without drugs added, the absorbance value (A value) of A549 parental cells was 2-folds higher than that of their radioresistant cells (P < 0.001). As to the MCF7/VCR cells, they were resistant to DDP and VDS, but slight sensitive to MMC, ADM, 5-Fu, and HCP with 80% of inhibitory rate to VPL. The subsequent RT-PCR demonstrated that the Mdr1/beta2-MG and MRP/beta2-MG of all A549 cells were about 0 and 0.7 respectively, and those of MCF7/VCR cells were 35 and 4.36. CONCLUSION: The chemosensitivity of A549 radioresistant cells had not changed markedly, and the decreased sensitivity to VPL could not be explained by the gene expression of mdr1 and MRP. It is possible that the changes in the cell membrane and decreased proliferate ability might be attributed to the resistance. Unlike multidrug resistance induced by chemotherapy, VPL may be not an ideal reverser to radioresistant cells. Therefore, the new biological strategy needs to be developed to treat recurring radioresistant tumor in combination with chemotherapy.

Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia.

OBJECTIVES: The study evaluated the efficacy and safety of long-term coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia (HeFH). BACKGROUND: Aggressive intervention to achieve lipid goals for adolescents with HeFH is recommended to reduce risk of premature cardiovascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled study, 248 male and female subjects ages >or=10 and