First-line Treatment Regimens Research Articles

BTK INHIBITORS IN CNSL AND HIGH‐RISK/REFRACTORY DLBCL PATIENTS: A REAL‐WORLD STUDY

Objective: The effectiveness and prognosis of a BTki-containing regimen in first-line treatment and relapsed/refractory patients were assessed in this study. Methods: There were 26 patients with DLBCL. BTKi was administered to patients with newly diagnosed, relapsed, refractory primary PCNSL and high-risk/refractory systemic DLBCL, and the effectiveness and PFS were evaluated. Results: The BTKi therapy study included 26 participants (16 PCNSL, 10 DLBCL). Among PCNSL,3 patients who had achieved PR following MTX-based first-line chemotherapy were given BTKi as a monotherapy for disease recurrence. BTKi patients lived for an average of 5 (1–8) months before dying from disease progression, which is 5 months longer than the typical patient survival period following chemotherapy recurrence. After three rounds of MTX-based chemotherapy, none of the six patients with refractory PCNSL achieved PR. After BTKi was utilized as second-line therapy, the average survival time was increased by 12 (2–21) months. Three patients received early treatment, while the remaining three received BTKi after the third round of medicine. Early patients had a longer average survival period than late ones (11 months vs. 10 months). The remaining seven high-risk patients received first-line chemotherapy and BTKi treatment. The median follow-up duration was 5 months, the ORR was 100%, and neither the median PFS nor the median OS were achieved. The mean maintenance time was 8 months. Among 10 patients with DLBCL, 8 of them are high risk group, and 2 had refractory disease. When the disease of two SCNSL patients advanced, BTKi was used in conjunction with chemotherapy as a salvage treatment, and BTKi was kept up for an average of 5 months. The efficacy was evaluated as PD. The ORR was 80% (4/5, 1 case was not assessed) and CR rate was 100% in high risk group. Four of these CNS-IPI high-risk DLBCL patients had adrenal involvement and a high IPI score, with BTKi maintained for an average of 6 months, two of them achieved CR, one of PD, and 1 case was not evaluated. The efficacy evaluation was CR in the other two high-risk CD5+ patients, whose BTKi was sustained for 12 months and 6 months, respectively. After receiving standard chemotherapy, the remaining 2 refractory patients kept getting worse. One patient with hepatitis B cirrhosis had elevated AST and ALT levels after one course of medication, so BTKi was stopped. The other patient was kept on BTKi alone for 4 months, but the efficacy was still PD. Patients with PCNSL have a dismal prognosis, in particular, the average survival time for R/R patients is less than two months. The research was funded by: National Natural Science Foundation of China (8226010026), Natural Science Foundation of Gansu Province (22JR11RA053) Keywords: aggressive B-cell non-Hodgkin lymphoma, molecular targeted therapies, combination therapies No conflicts of interests pertinent to the abstract.

Patient-reported outcome (PRO)-based symptom assessment in patients with advanced lung cancer receiving first-line combination immunotherapy: a protocol for a multicenter, prospective, observational study

BackgroundImmunotherapy is currently applied in the first-line treatment regimens for numerous advanced cancers, especially advanced lung cancer. Immune-related adverse events (irAEs) resulting from immunotherapy can vary in severity and cause a substantial symptom burden to patients. However, there are limited data on symptom burden in patients with advanced lung cancer following immunotherapy. To address this deficit, this study aims to provide insight into the symptom burden and severity through patient-reported outcome measurements and conduct an analysis of temporal trends and clinical consequences of symptom burden in patients with advanced lung cancer receiving combination immunotherapy.MethodsWe will prospectively recruit 168 eligible patients from 14 hospitals in China. Eligible patients will be aged ≥ 18 years, pathologically diagnosed with locally advanced or stage IV primary lung cancer without surgical indications, and agreed to receive immunotherapy in combination with other therapies. The primary outcome of this study is the symptom burden of patients during the immunotherapy course. Longitudinal symptom data will be collected using the MD Anderson Symptom Inventory–Lung Cancer module (MDASI-LC) and the symptomatic irAEs scale at baseline (once before treatment) and weekly after treatment, until 1 month after the last treatment cycle has been completed. The trajectory of symptom burden following combination immunotherapy will be depicted, and by linking it to clinical outcomes (the secondary outcome and exploratory outcome of this study), the consequence of symptom burden in patients with advanced lung cancer receiving combination immunotherapy will be examined further.DiscussionThis study intends to establish longitudinal symptom trajectories in patients with lung cancer receiving immunotherapy, and explore its association with clinical outcomes. These findings may serve as an important reference for clinicians in the symptomatic management of patients with lung cancer receiving immunotherapy.Trial registration numberChiCTR2200061540. Registered on June 28, 2022.

Intracranial activity of first-line immune checkpoint inhibitors combined with chemotherapy in advanced non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs) are increasingly used as first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) harboring no actionable mutations; however, data on their efficacy among patients presenting with intracranial lesions are limited. This study aimed to explore the efficacy and safety of ICIs combined with chemotherapy in advanced NSCLC patients with measurable brain metastasis at initial diagnosis. Our study retrospectively analyzed clinical data of a total of 211 patients diagnosed with driver gene mutation-negative advanced NSCLC with measurable, asymptomatic brain metastasis at baseline from Hunan Cancer Hospital between January 1, 2019 and September 30, 2021. The patients were stratified into two groups according to the first-line treatment regimen received: ICI combined with chemotherapy ( n = 102) or chemotherapy ( n = 109). Systemic and intracranial objective response rates (ORRs) and progression-free survival (PFS) were analyzed. Adverse events were also compared between the groups. Compared with the chemotherapy-based regimen, the ICI-containing regimen was associated with a significantly higher intracranial (44.1% [45/102] vs . 28.4% [31/109], χ2 = 5.620, P = 0.013) and systemic (49.0% [50/102] vs . 33.9% [37/109], χ2 = 4.942, P = 0.019) ORRs and longer intracranial (11.0 months vs . 7.0 months, P <0.001) and systemic (9.0 months vs . 5.0 months, P <0.001) PFS. Multivariable analysis consistently revealed an independent association between receiving ICI plus platinum-based chemotherapy as a first-line regimen and prolonged intracranial PFS (hazard ratio [HR] = 0.52, 95% confidence interval [CI]: 0.37-0.73, P <0.001) and systemic PFS (HR = 0.48, 95% CI: 0.35-0.66, P <0.001). No unexpected serious adverse effects were observed. Our study provides real-world clinical evidence that ICI combined with chemotherapy is a promising first-line treatment option for driver gene mutation-negative advanced NSCLC patients who present with brain metastasis at initial diagnosis. https://www.clinicaltrials.gov/ , OMESIA, NCT05129202.

Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non-Small-Cell Lung Cancer.

Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles. Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common. In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Effectiveness and safety of capecitabine, irinotecan and panitumumab in advanced colorectal cancer.

Capecitabine, irinotecan, and panitumumab (CAPIRI-P) is a controversial regimen for metastatic colorectal cancer, with concerns regarding the efficacy and toxicity. However, its toxicity profile has been improved with dose reduction, and concerns regarding efficacy have been extrapolated from other trials. This retrospective study reports the real-world effectiveness and safety of modified CAPIRI-P (mCAPIRI-P). Advanced colorectal cancer patients receiving mCAPIPI-P in the first-line setting between July 2019 and December 2021 were analyzed. The progression-free survival on treatment (PFSOT) and overall survival (OS) were estimated using the Kaplan-Meier method, and the association with clinical and disease factors was analyzed using the Cox regression model. Serial changes in carcinoembryonic antigen (CEA) level and treatment toxicity were also evaluated. A total of 106 patients were included, of whom 97 (92%) and 31 (29%) had left-sided primary and unresectable liver-only disease, respectively. The median PFSOT and OS were 15.4 (95% CI 12.5-18.3) and 25.5 (95% CI 17.6-33.4) months, respectively. Sixteen (51.6%) and 10 (32.3%) liver-only disease patients underwent secondary liver treatment and R0 resection, respectively. In multivariable Cox regression, CEA responders (PFSOT: HR 0.53) and CEA normalization (PFSOT: HR 0.27; OS: HR 0.28) were independent favorable prognostic factors for PFSOT and OS. Grade ≥3 toxicity rate was 43%, mainly related to uncomplicated hematological toxicities. The real-world data show that mCAPIRI-P is safe and effective as the first-line treatment regimen for RAS wild-type advanced colorectal cancer and warrants further study.

Abstract 6485: Oxidative phosphorylation-associated radiomic feature and survival of women with serous ovarian cancer

Abstract Novel biomarkers that can be utilized for clinical decision support to improve patient outcomes are critically needed for ovarian cancer. At present, there are no standard of care biomarkers to inform the first-line treatment regimen (neoadjuvant chemotherapy vs. upfront surgical debulking) best suited for each patient or which patients are at the highest risk of recurrence. To address this unmet need, we identified pre-treatment computed tomography (CT) image-based radiomic features predictive of outcomes and primary treatment response among 298 women diagnosed with serous ovarian cancer from 2008 to 2019. A decision tree analysis identified a single volumetric feature, region of interest (ROI) volume center of mass (CoM) in the X direction, as the most informative radiomic feature that stratified patients with upfront surgery into high- and low-risk groups for overall survival. The high-risk group consists of patients with higher values of the radiomic feature. In the training (N=91) and test (N=91) cohorts of women treated with upfront surgery, high-risk patients had worse survival compared to low-risk patients (HR=2.01, 95% CI=1.07, 3.77 and HR=2.23, 95% CI=1.19, 4.17, respectively). This radiomic feature was not associated with survival among women treated with neoadjuvant chemotherapy (N=116; HR=1.23, 95% CI=0.73, 2.07). To reveal potential underlying biology of this radiomic feature, we performed RNAseq gene expression profiling on 47 formalin-fixed paraffin-embedded tumor specimens and correlated gene expression with the radiomic feature using DESeq2 from RSEM estimates. Dichotomized analysis (high- vs. low-risk) yielded 7 significant genes and continuous analysis yielded 15 significant genes (adjusted p&amp;lt;0.05), with both approaches identifying AKT2 and PSMC4. Gene set enrichment analysis (GSEA) was used to identify enriched gene sets from continuous associations using the MSigDB Hallmarks pathways (adjusted p&amp;lt;0.05). GSEA identified the oxidative phosphorylation (OXPHOS) pathway as one of the gene sets most negatively associated with the predictive radiomic feature (Hallmark Normalized Enrichment Score=-2.28, adjusted p&amp;lt;0.001). We derived a PCA-based gene signature from significantly associated OXPHOS genes (p&amp;lt;0.01) resulting in a negative correlation with the radiomic feature (R=-0.65, p&amp;lt;0.001). Prior studies have shown that high OXPHOS ovarian tumors are associated with an increased response to conventional chemotherapy, suggesting that OXPHOS may be a key pathway for chemoresistance in ovarian cancer. In summary, we identified an OXPHOS-associated radiomic feature predictive of survival among women with serous ovarian cancer treated with upfront surgery. Further research is needed to elucidate the biologic and mechanistic underpinnings of the identified radiomic feature and to validate these findings in a larger cohort of women with ovarian cancer. Citation Format: Christelle Colin-Leitzinger, Jaileene Perez-Morales, Steven Eschrich, Jamie K. Teer, Sweta Sinha, Melissa J. McGettigan, Daniel K. Jeong, Olya Stringfield, Mahmoud A. Abdalah, Natarajan Raghunand, Robert J. Gillies, Jing-Yi Chern, Matthew Schabath, Lauren Cole Peres. Oxidative phosphorylation-associated radiomic feature and survival of women with serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6485.

Systematic Literature Review (SLR) and Network Meta-Analysis (NMA) of First-Line Therapies (1L) for Locally Advanced/Metastatic Urothelial Carcinoma (la/mUC).

To compare efficacy outcomes for all approved and investigational first-line (1L) treatment regimens for locally advanced or metastatic urothelial carcinoma (la/mUC) with standard of care (SOC), a network meta-analysis (NMA) was conducted. A systematic literature review (SLR) identified phase 2 and 3 randomized trials investigating 1L treatment regimens in la/mUC published January 2001-September 2021. Three networks were formed based on cisplatin (cis) eligibility: cis-eligible/mixed (cis-eligible patients and mixed populations of cis-eligible/ineligible patients), cis-ineligible (strict; exclusively cis-ineligible patients), and cis-ineligible (wide; including studies with investigator's choice of carbo). Analyses examined comparative efficacy by hazard ratio (HR) for overall survival (OS), and progression-free survival (PFS), and odds ratio (OR) for overall response rate (ORR), with 1L regimens vs. SOC. SOC was gemcitabine + cis (GemCis) or carboplatin (GemCarbo), cis-eligible/mixed network, and GemCarbo cis-ineligible networks. Of 1906 SLR identified citations, 55 trials were selected for data extraction. The NMA comprised 11, 6, and 8 studies in the cis-eligible/mixed, cis-ineligible (strict), cis-ineligible (wide) networks, respectively. In a meta-analysis of SOC control arms, median (95% CI) overall survival (OS) in months varied by network: 13.19 (12.43, 13.95) cis-eligible/mixed, 11.96 (10.43, 13.48) cis-ineligible (wide), and 9.74 (6.71, 12.76) cis-ineligible (strict). Most differences in OS, PFS, and ORR with treatment regimens across treatment networks were not statistically significant compared with SOC. Outcomes with current 1L regimens remain poor, and few significant improvements over SOC have been made, despite inclusion of recent clinical trial data, highlighting an unmet need in the la/mUC patient population.

Superiority of ibrutinib plus bendamustine and rituximab in newly diagnosed patients with mantle-cell lymphoma ineligible for intensive therapy: A network meta-analysis.

Because of lacking of head-to-head comparison among recently effective novel agents' combination regimens for newly diagnosed patients with mantle-cell lymphoma (MCL) who are ineligible for intensive therapy like autologous stem-cell transplantation, the optimal option for these patients still remains undefined. We searched relevant published reports. Three randomized controlled trials with 1459 subjects were identified. In the network meta-analysis, ibrutinib plus bendamustine and rituximab (Ibru + BR) significantly improved progression-free survival (PFS) when compared to bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP; hazard ratio [HR]: 0.55, p=.03) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; HR: 0.35, p < .001) for newly diagnosed patients with MCL ineligible for intensive therapy. Among these first-line treatment regimens (Ibru + BR, VR-CAP, R-CHOP, and BR), Ibru + BR had the highest probability of 94.9% to be the best intervention in PFS analysis. No significant difference was found in adverse events analysis. Our data indicated that Ibru + BR seemed to prolong the PFS when compared to VR-CAP and R-CHOP for newly diagnosed patients with MCL ineligible for intensive therapy. Considering our limits, prospective clinical trials directly comparing these regimens are warranted.

From Antibiotic Resistance to Antibiotic Renaissance: A New Era in Helicobacter pylori Treatment.

Helicobacter pylori (H. pylori) is a common bacterial infection that can cause gastric diseases, including gastric cancer. The standard treatment for H. pylori infection is a combination of antibiotics and acid suppressants, but antibiotic resistance has become a significant problem that can reduce treatment efficacy. The development of novel treatment strategies for H. pylori is necessary to reduce the burden of this infection on public health.This review article examines H. pyloriantibiotic resistance and future treatment possibilities. We discuss transitioning from trial and error to antimicrobial stewardship and using multi-strain probiotics as an adjunct therapy for H. pylori eradication. This review article provides an extensive overview of H. pylori antibiotic resistance and future treatment possibilities. It begins with an introduction and background of the topic, followed by a literature review. The review of the literature covers the transition from trial and error to antimicrobial stewardship, the diagnosis and treatment of H. pylori, the comparative effectiveness of multiple first-line treatment regimens, the ideal H. pylori treatment for the present and future, the use of probiotics to reduce adverse events and improve eradication rates, and the use of novel and effective therapeutic regimens in an era of increasing antibiotic resistance. The conclusion summarizes the review's findings and provides recommendations for future research. The terms Helicobacter pylori, infection, antibiotic resistance, clarithromycin, macrolide resistance, proton pump inhibitors, vonoprazan, triple regimen, susceptibility, and stewardship were used in a PubMed literature search. Finally, the article highlights the urgent need for a global collaborative approach toward tackling antibiotic resistance in H. pylori infections.

Survival comparison of first-line treatment regimens in patients with braf-mutated advanced colorectal cancer: a multicenter retrospective study

BackgroundPatients with V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E-mutated advanced colorectal cancer (CRC) have a poor prognosis, and treatment options that can improve outcome are still under investigation. The purpose of this study was to discuss the differences of overall survival (OS) and progression-free survival (PFS) between patients with BRAF V600E-mutated advanced CRC who were treated with chemotherapy alone and chemotherapy combined with targeted therapy in advanced first-line therapy.MethodsGrouping of 61 patients according to first-line treatment regimen (chemotherapy alone/chemotherapy combined with bevacizumab). Kaplan–Meier method and log-rank test were used to compare OS and PFS. Cox proportional hazards regression model was used to measure the risk of first-line medication therapies while correcting for confounding factors that may affect PFS and OS.ResultsThere was no significant difference in OS between patients treated with chemotherapy alone and those treated with chemotherapy combined with bevacizumab (P = 0.93; HR, 1.027; 95% CI, 0.555–1.901). Likewise, there was no significant difference in PFS between the two groups (P = 0.29; HR, 0.734; 95% CI, 0.413–1.304). Subgroup analysis showed that OS and PFS of different treatment regimens were not significantly different among subgroups. Multivariate analysis suggested that surgical treatment of primary tumor (P = 0.001; HR, 0.326; 95% CI, 0.169–0.631) and presence of liver metastasis (P = 0.009; HR, 2.399; 95% CI, 1.242–4.635) may serve as independent prognostic indicators in patients with BRAF-mutated advanced CRC. Surgical treatment of the primary tumor (P = 0.041; HR, 0.523; 95% CI, 0.280–0.974) was significantly associated with PFS too.ConclusionFor patients with BRAF V600E-mutated advanced CRC, chemotherapy alone did not differ significantly in OS and PFS compared with chemotherapy + bevacizumab for advanced first-line therapy. Chemotherapy combined with targeted therapy did not render a survival benefit to these patients, demonstrating that the importance of developing new treatment options for this population.

Real-world outcomes in patients with metastatic renal cell carcinoma (mRCC) receiving dual immune checkpoint inhibitor (ICI-ICI) regimens or immune checkpoint inhibitor and tyrosine kinase inhibitor (ICI-TKI) combinations as first-line therapy: A British Columbia (BC) population-based analysis.

646 Background: Currently available first-line treatment regimens for mRCC include pembrolizumab-axitinib (ICI-TKI) and ipilimumab-nivolumab (ICI-ICI). Although both regimens are superior to sunitinib, direct comparisons between ICI-ICI and ICI-TKI are lacking and real-world data are sparse. Methods: Through BC Cancer pharmacy data and patient access programs queries, we identified 319 mRCC patients who were treated with first line ICI-TKI or ICI-ICI between May 2019 and March 2022. Patients’ charts were reviewed for baseline characteristics, including International mRCC Database Consortium (IMDC) risk criteria, pharmacy data, pathology and radiology reports, treatment toxicity, rationale for treatment choice when available, progression and survival outcomes. Treatment groups were compared using standard descriptive statistics; survival outcomes were compared using Kaplan Meier and Cox Regression analyses. Results: Among the first 214 patients, 64.9% and 35.1% received first line ICI-ICI and ICI-TKI, respectively. The most commonly cited reason for choosing ICI-ICI was unavailability of a publicly funded alternative at the time of prescription. IMDC risk group distribution was markedly different between regimens; in ICI-TKI patients, favorable, intermediate and poor-risk patients respectively represented 60.3%, 28.8% and 10.9%, versus 10.2%, 56.9% and 32.9% in ICI-ICI patients (p&lt;0.001). Response rates in ICI-TKI compared favorably to ICI-ICI in the overall population with objective response rates (ORR) of 69% vs 50.4% (p=0.012) and primary progression rates of 12.7% vs 33.1% (p=0.001). However, in the intermediate-poor risk patients, survival outcomes were similar between ICI-TKI and ICI-ICI, with median progression-free survival (mPFS) of 7.5 versus 4.5 months respectively (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.41 to 1.09, p=0.107) and median overall survival (mOS) of not reached (NR) vs 22.6 months (HR 0.86, 95% CI 0.44 to 1.69, p=0.665). Of interest, in patients treated with ICI-ICI, more ipilimumab infusions in the induction phase was associated with improved mOS, rising from 3.9 to 13.6, 21.8 and 37.5 months for 1, 2, 3 or 4 infusions respectively (statistically significant by Log Rank [Mantel-Cox], p&lt;0.001). Conclusions: In the real-world mRCC experience from BC, Canada, ICI-TKI was associated with statistically significantly improved ORR over ICI-ICI although the treated population was comparatively enriched for favorable risk patients by IMDC. PFS and OS did not differ between the two regimens in the intermediate-poor risk population. Updated results on all 319 patients will be presented.

Analysis of the impact of eliminating bolus 5-fluorouracil in metastatic colorectal cancer.

59 Background: 5-Fluorouracil (5-FU) is a component of first-line treatment regimens for metastatic colorectal cancer (mCRC). Historically, 5-FU is administered as a bolus followed by an infusion. However, the bolus dose adds substantial toxicity and is often withheld in patients with limited functional status or high-risk comorbidities, but its impact on treatment outcomes remains unclear. Small studies suggest that it may be omitted. The aim of this study was to determine whether omission of the 5-FU bolus is associated with a difference in overall survival (OS). Methods: An electronic health record-derived national multicenter oncology database from Flatiron Health was queried to select patients with mCRC who received a first-line 5-FU-containing regimen. Demographics, relevant labs, treatment details, and survival outcomes were collected. Propensity score (PrS) matching and OS analysis were performed incorporating age, race, sex, ECOG score, combination drug regimen, and baseline creatinine and bilirubin. Variables with p &lt; 0.10 in univariable Cox proportional hazards models were included in the multivariable analysis. Results: We included 9741 patients with mCRC who received 5-FU-based regimens. All individuals received a 5-FU infusion, and 7901 (81%) also received a 5-FU bolus. Among our entire cohort, 43% were female, 23% were &gt; 70 years, 66% were white, and 89% had ECOG ≤ 1. Over a median follow-up time of 19 months, 5847 patients (60%) died. In the unmatched univariable (HR 0.94, 95% CI 0.88-1.00, p = 0.06) and multivariable (aHR 0.85, 95% CI 0.93-1.06, p = 0.85) analyses, there was no association between the use of bolus 5-FU and OS. A number of factors were associated with an increased risk of death, including older age, high ECOG scores, and elevated bilirubin or creatinine levels. Similarly, in our PrS-matched dataset (n = 6126), the use of a 5-FU bolus was not associated with OS (HR 0.98; 95% CI 0.91-1.06; p = 0.64). Conclusions: The findings of our PrS-matched multicenter cohort study indicate that, after adjusting for host and treatment factors, 5-FU bolus dosing was not associated with an overall survival benefit among patients with mCRC. These results suggest that, in mCRC, the addition of a 5-FU bolus does not appear to add efficacy to regimens utilizing infusional 5-FU. Future work is necessary to determine the role of bolus dosing in the adjuvant setting and its impact on other clinically-relevant outcomes.

A real-world exploratory study on the feasibility of vonoprazan and tetracycline dual therapy for the treatment of Helicobacter pylori infection in special populations with penicillin allergy or failed in previous amoxicillin-containing therapies.

The treatment of Helicobacter pylori (H. pylori) infection is a challenge for those who cannot use amoxicillin. To evaluate the eradication rate and adverse effects of vonoprazan and tetracycline dual therapy as first-line and rescue treatment regimens used in special populations with penicillin allergy or failed in previous amoxicillin-containing therapies. Patients enrolled were those who were H. pylori-positive with selected conditions: (1) allergic to penicillin, either naïve to treatment or had failed before; or (2) failed in previous amoxicillin-containing therapies. All enrolled patients accepted 14-day vonoprazan and tetracycline dual therapy (VT dual therapy) as follows: vonoprazan (20 mg b.i.d.) and tetracycline (500 mg t.i.d. [body weight < 70 kg] or 500 mg q.i.d. [body weight ≥ 70 kg]). H. pylori status was evaluated by 13 C-urease breath test 6 weeks after treatment. All adverse effects were recorded. Some patients underwent bacterial culture and antibiotic susceptibility testing. A total of 62 patients were enrolled; 18 of them received VT dual therapy as first-line treatment, 44 patients received VT dual therapy as rescue treatment. Overall, 58 of 62 patients achieved successful eradication (93.5%), while all involved (100%,18/18) succeeded in the first-line treatment group and 40 cases (90.9%, 40/44) succeeded in the rescue treatment group. Sixty-one (61/62, 98.4%) patients completed the whole course of treatment. Adverse events occurred in 6 patients (6/62, 9.7%), while one patient quit because of skin rash. All adverse effects were mild and relieved spontaneously after H. pylori treatment. Five patients achieved successful H. pylori culture, and all strains isolated were sensitive to tetracycline. For the treatment of H. pylori infection in special populations with penicillin allergy or failed in previous amoxicillin-containing therapies, a 14-day vonoprazan and tetracycline dual therapy was effective and safe as first-line and rescue treatment in our study. Further study is warranted to verify its efficacy, especially for those who cannot use amoxicillin.

Retrospective study of the combination of TP and PF regimens with or without immune checkpoint inhibitors for the first-line treatment of locally advanced or advanced esophageal squamous cell carcinoma.

To investigate the efficacy and safety differences between the cisplatin + paclitaxel (TP) and cisplatin + fluorouracil (PF) regimens in combination with or without immune checkpoint inhibitors (ICIs) in advanced esophageal squamous cell carcinoma (ESCC) first-line treatment and prognostic factors. We selected the medical records of patients with late stage ESCC admitted to the hospital between 2019 and 2021. Based on the first-line treatment regimen, control groups were divided into chemotherapy plus ICIs (n = 243) and non-ICIs (n = 171), 119 (49%) in the TP + ICIs group, 124 (51%) in the PF + ICIs group, 83 (48.5%) in the TP group, and 88 (51.5%) in the PF group in the control group. We analyzed and compared factors related to efficacy, safety, or response to toxicity and prognosis across four subgroups. The overall objective response rate (ORR) and disease control rate (DCR) of the TP plus ICIs group were 42.1% (50/119) and 97.5% (116/119), respectively, which were 6.6% and 7.2% higher than those of the PF plus ICIs group. Patients in the TP combined with ICIs group had higher overall survival (OS) and progression-free survival (PFS) than those in the PF combined with ICIs group [hazard ratio (HR) = 1.702, 95% confidence interval (CI): 0.767-1.499, p = 0.0167 and HR = 1.158, 95% CI: 0.828-1.619, p = 0.0055] ORR and DCR were 15.7% (13/83) and 85.5% (71/83) in the TP chemotherapy alone group, significantly higher than the PF group [13.6% (12/88) and 72.2% (64/88)] (p < 0.05), OS and PFS were also better in patients treated with TP regimen chemotherapy than PF (HR = 1.173, 95% CI: 0.748-1.839, p = 0.0014 and HR = 0.1.245, 95% CI: 0.711-2.183, p = 0.0061). Furthermore, following the combination of TP and PF diets with ICIs, the OS of the patients was higher than that of the group treated with chemotherapy alone (HR = 0.526, 95% CI: 0.348-0.796, p = 0.0023 and HR = 0.781, 95% CI: 0.0.491-1.244, p < 0.001). Regression analysis showed that the neutrophil-to-lymphocyte ratio (NLR), the control nuclear status score (CONUT), and the systematic immune inflammation index (SII) were independent prognostic factors for the efficacy of immunotherapy (p < 0.05). The overall incidence of treatment-associated adverse events (TRAEs) was 79.4% (193/243) and 60.8% (104/171) in the experimental and control groups, respectively, and there was no statistically significant difference in TRAEs between TP + ICIs (80.6%) and PF + ICIs (78.2%) (61.4%) and PF groups (60.2%) (p > 0.05). Overall, 21.0% (51/243) of patients in the experimental group experienced immune-related adverse events (irAEs), and all of these adverse effects were tolerated or remitted following drug treatment without affecting follow-up. The TP regimen was associated with better PFS and OS with or without ICIs. Furthermore, high CONUT scores, high NLR ratios, and high SII were found to be associated with poor prognosis in combination immunotherapy.

Therapeutic drug monitoring in optimizing tuberculosis treatment outcomes: A review on the first-line four-drug standard treatment regimen

Therapeutic drug monitoring in optimizing tuberculosis treatment outcomes: A review on the first-line four-drug standard treatment regimen

Knowledge on the risk factors of drug-resistant tuberculosis among newly diagnosed patients of tuberculosis with first-line antitubercular treatment regimen

Knowledge on the risk factors of drug-resistant tuberculosis among newly diagnosed patients of tuberculosis with first-line antitubercular treatment regimen

Establishment and evaluation of a nomogram for predicting the survival outcomes of patients with diffuse large B-cell lymphoma based on International Prognostic Index scores and clinical indicators.

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma, treatment outcomes of patients vary greatly. The current International Prognostic Index (IPI) is not enough to distinguish patients with poor prognosis, and genetic testing is very expensive, so a inexpensive risk prediction tool should be developed for clinicians to quickly identify the poor prognosis of DLBCL patients. DLBCL patients (n=420; 18-80 years old) who received a combination of cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) with or without rituximab (R-CHOP) at our hospital between 2008 and 2017 were included in the study. Potential predictors of survival were determined by univariate and multivariate Cox regression analyses, and significant variables were used to construct predictive nomograms. The new prediction models were assessed using concordance indexes (C-indexes), calibration curves, and their clinical utility was assessed by decision curve analyses (DCAs). The 5-year overall survival (OS) rate was 70.62% and the 5-year progression-free survival (PFS) rate was 59.02%. The multivariate Cox analysis indicated that IPI, Ki-67, the lymphocyte/monocyte ratio, and first-line treatment with rituximab were significantly associated with survival. The C-index results indicated that a predictive model that included these variables had better discriminability for OS (0.73 vs. 0.67) and PFS (0.68 vs. 0.63) than the IPI-based model. The calibration plots showed good agreement with observations and nomogram predictions. The DCAs demonstrated the clinical value of the nomograms. Our study identified prognostic factors in patients who were newly diagnosed with DLBCL to construct an individualized risk prediction model, combined IPI with common clinical indicators. Our model might be a valuable tool that could be used to predict the prognosis of DLBCL patients who receive standard first-line treatment regimens. It enables clinicians to quickly identify some patients with possible poor prognosis and choose more active treatment for patients, such as chimeric antigen receptor T-cell (CART) Immunotherapy and other new drugs therapy, so as to prolong the PFS and OS of patients.

IFT20 Confers Paclitaxel Resistance by Triggering β-arrestin-1 to Modulate ASK1 Signaling in Breast Cancer.

System paclitaxel-based chemotherapy is the first-line treatment regimen of defense against breast cancer, but inherent or acquired chemotherapy resistance remains a major obstacle in breast cancer therapy. Elucidating the molecular mechanism of chemoresistance is essential to improve the outcome of patients with breast cancer. Here, we demonstrate that intraflagellar transport 20 (IFT20) is positively associated with shorter relapse-free survival in patients with system paclitaxel-based chemotherapy. High-expressed IFT20 in breast cancer cells increases resistance to cell death upon paclitaxel treatment; in contrast, IFT20 knockdown enhances apoptosis in breast cancer cells in response to paclitaxel. Mechanistically, IFT20 triggers β-arrestin-1 to bind with apoptosis signal-regulating kinase 1 (ASK1) and promotes the ubiquitination of ASK1 degradation, leading to attenuating ASK1 signaling and its downstream JNK cascades, which helps cells to escape from cell death during paclitaxel treatment. Our results reveal that IFT20 drives paclitaxel resistance through modulating ASK1 signaling and identifies IFT20 as a potential molecular biomarker for predicting the response to paclitaxel therapeutic in breast cancer. IFT20 drives paclitaxel resistance through modulating ASK1 signaling and IFT20 may act as a potential molecular biomarker for predicting the response to paclitaxel therapeutic in breast cancer.

Comparative effectiveness of first-line therapies for eradication of antibiotic-resistant Helicobacter pylori strains: A network meta-analysis.

As a first-line treatment regimen for Helicobacter pylori (H. pylori) infection, antibiotic therapy is widely used worldwide. However, the question of increasing antibiotic resistance must be considered. Given this issue, we need to find ways to reduce drug resistance. This study examined all currently available first-line regimens and compared them with standard triple treatment through a network meta-analysis of randomized controlled trials (RCTs). To compare first-line treatment regimens for eradication of antibiotic-resistant H. pylori strains. To compare the effectiveness of the first-line regimens for treating H. pylori infection, a Bayesian network meta-analysis was applied to process data extracted from RCTs. The plausible ranking for each regimen was assessed by the surface under the cumulative ranking curve (SUCRA). In addition, we conducted a relevant search by reference citation analysis. Twenty-five RCTs involving 12029 participants [including 1602 infected with clarithromycin (CAM)-resistant strains and 1716 infected with metronidazole (MNZ)-resistant strains] were included, in which a total of seven regimens were used for H. pylori eradication. The results showed that dual therapy containing a high-dose proton pump inhibitor (HDDT) [odds ratio (OR): 4.20, 95% confidence interval (CI): 2.29-8.13] was superior to other therapies for all patients, including those with CAM/MNZ-resistant H. pylori infection. In the comparative effectiveness ranking, for CAM-resistant H. pylori, HDDT (OR: 96.80, 95%CI: 22.46-521.9) had the best results, whereas standard triple therapy ranked last (SUCRA: 98.7% vs 0.3%). In the subgroup of high cure rates (≥ 90%), HDDT was also generally better than other therapies. For the eradication of CAM- and MNZ-resistant H. pylori strains, HDDT exhibited considerable advantages. The studies of CAM-resistant H. pylori were based on small samples due to a lack of antibiotic sensitivity tests in many RCTs, but the results showed that all patients, including those with CAM-resistant H. pylori infection, had a concordant trend. Overall, HDDT may be a reference for RCTs and other studies of H. pylori eradication.

Differences between complex epithelial neoplasms of the ovary and high-grade serous ovarian cancer: a retrospective observational cohort study

BackgroundComplex epithelial neoplasms of the ovary (CENO), an uncommon pathological histotype in ovarian cancer, comprises adenosquamous carcinoma and adenocarcinoma with metaplasia. Owing to the rarity of relevant reports, there are currently no statistics on outcomes based on large samples. Meanwhile high-grade serous ovarian cancer (HGSOC) is the most common histotype in ovarian cancer which has a recognized first-line treatment regimen and poor prognosis. Thus, we aimed to determine the characteristics, prognosis, and independent predictors of survival for CENO, compare them with those of HGSOC and construct prognostic predictive models and nomograms.MethodsWe used the Surveillance, Epidemiology, and End Results (SEER) database to determine patients diagnosed with CENO or HGSOC from 2000 to 2017. Clinical, demographic, and treatment characteristics were compared between these groups. Propensity score matching, Cox risk regression analysis, Kaplan–Meier survival curves, and the Least Absolute Shrinkage and Selection Operator regression analysis were employed for analyzing the data.ResultsHere, 31,567 patients with HGSOC and 216 patients with CENO between 2000 and 2017 in the SEER database were enrolled. Age < 57 years, unmarried, and early-stage diseases were more common in patients with CENO than in those with HGSOC. Women with CENO were less likely to receive adjuvant chemotherapy (65.7% vs. 79.4%) but more likely to receive radiotherapy (6.0% vs. 0.8%; both p < 0.001) than those with HGSOC. Year of diagnosis, surgery status, number of primary tumors, grade, and FIGO stage were independent prognostic factors for overall and cancer-specific survival in CENO. Overall survival rates were significantly lower for CENO than for more malignant HGSOC.ConclusionsIn summary, CENO was rare in ovarian cancer, while the year of diagnosis, surgery status, number of primary tumors, grade, and FIGO stage were independent prognostic factors. Compared with other common malignant ovarian tumors, CENO had a poor prognosis. Prognostic predictive models and nomograms had been determined to predict the individual survival rates of patients with CENO. These methods could improve evaluations of survival and therapeutic decisions for patients.