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Atypical L858R or other L858X mutations in the epidermal growth factor receptor (EGFR) gene, beyond the classical EGFRL858R mutation caused by c.2573 T > G, have been identified in non‐small cell lung cancer (NSCLC), yet their genomic features and survival benefits with EGFR tyrosine kinase inhibitor (TKI) treatment have not been fully explored. We retrospectively enrolled 489 NSCLC patients with baseline tumor tissue/plasma samples carrying uncommon EGFRL858R (N = 124), EGFRL858Q/M (N = 17), or classical EGFRL858R mutations (N = 348). The comparison of molecular features was performed using treatment‐naïve tumor tissues. Survival benefits and resistance mechanisms of first‐line EGFR TKI treatment were studied in an advanced disease subcohort. NSCLCs harboring uncommon EGFRL858R had lower TP53 mutation prevalence (p = 0.04) and chromosome instability scores (p = 0.02) than those with classical EGFRL858R. Concomitant EGFRL861Q mutations were enriched in NSCLCs with EGFRL858Q/M (p < 0.01), with cooccurrence in those carrying EGFRL858M. Patients with uncommon EGFRL858R experienced improved progression‐free survival (PFS) compared to those with classical EGFRL858R (median: 13.0 vs. 10.0 months, hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.41–0.80). The association remained significant when adjusting for sex, age, histological subtype, TKI category, and anti‐vascular therapy (HR: 0.55, 95% CI: 0.39–0.77). Furthermore, EGFRL858Q/M patients showed enhanced first‐line PFS (vs. classical EGFRL858R, HR: 0.26, 95% CI: 0.10–0.67), potentially benefiting more from afatinib. Additionally, NSCLCs with uncommon EGFRL858R and classical EGFRL858R had similar resistance profiles to EGFR TKIs. In conclusion, NSCLCs carrying atypical EGFR L858 aberrations, which had fewer TP53 mutations and higher chromosome stability, exhibited improved PFS under first‐line EGFR TKIs than those with the classical EGFRL858R. This study reveals that NSCLC patients with uncommon EGFR L858R mutations experience improved outcomes with EGFR TKIs compared to those with the classical EGFR L858R mutation, evidenced by longer PFS, fewer TP53 mutations, and higher chromosome stability. Furthermore, patients with EGFR L858Q/M showed enhanced first‐line PFS, potentially benefiting more from afatinib.

Incidence and mortality of biliary tract carcinoma (BTC) are increasing, especially in South America and Asia. Such a disease often bears a dismal prognosis because of diagnosis occurring at late stages and for the frequent relapses after surgery. The aims of this review were to summarize the state of the art of the treatment of BTC and give a view at possible future prospects linked with molecular profiling, immunotherapy, and targeted therapies. We conducted a systematic literature search using MEDLINE and the 2018 ASCO Meeting abstract databases to identify published clinical trials, translational series, and meeting abstracts. All significant papers and abstracts available to date were included. For resected BTC, thanks to the BILCAP study, adjuvant chemotherapy (CT) with capecitabine should be regarded as the new standard of care. For locally advanced inoperable and metastatic diseases, the use of chemoradiotherapy and radioembolization has not been supported by any randomized Phase III study. The standard of care remains the combination of CT with gemcitabine and cisplatin, as reported by the ABC-02 trial. All targeted therapies have failed to improve the survival outcomes, either in combination with CT or as single agents and are not recommended in the treatment of BTC. Whole-exome sequencing and molecular profiling have helped in identifying genetic signatures typical of different BTC subtypes. With this support, new trials with targeted agents and immunotherapy have been designed, and results are awaited. BTC still remains a disease with very few treatment options. Different BTC subtypes own peculiar gene mutations and pathways alterations. Therefore, molecular profiling may be the only key to enable new tailored strategies with targeted agents and immunotherapy.

Background The current standard of care for advanced human epidermal growth factor receptor 2 (HER2)‐positive breast cancer is pertuzumab plus trastuzumab and docetaxel as first‐line therapy. However, with the development of newer treatment regimens, there is a lack of evidence regarding which is the optimal treatment strategy. The aim of this network meta‐analysis was to evaluate the efficacy and safety of first‐line regimens for advanced HER2‐positive breast cancer by indirect comparisons. Methods A systematic review and Bayesian network meta‐analysis were conducted. The PubMed, EMBASE, and Cochrane Library databases were searched for relevant articles published through to December 2023. The hazard ratio (HR) and 95% credible interval (CrI) were used to compare progression‐free survival (PFS) between treatments, and the odds ratio and 95% CrI were used to compare the objective response rate (ORR) and safety. Results Twenty randomized clinical trials that included 15 regimens and 7094 patients were analyzed. Compared with the traditional trastuzumab and docetaxel regimen, PFS was longer on the pyrotinib and trastuzumab plus docetaxel regimen (HR: 0.41, 95% CrI: 0.22–0.75) and the pertuzumab and trastuzumab plus docetaxel regimen (HR: 0.65, 95% CrI: 0.43–0.98). Consistent with the results for PFS, the ORR was better on the pyrotinib and trastuzumab plus docetaxel regimen and the pertuzumab and trastuzumab plus docetaxel regimen than on the traditional trastuzumab and docetaxel regimen. The surface under the cumulative ranking curve indicated that the pyrotinib and trastuzumab plus docetaxel regimen was most likely to rank first in achieving the best PFS and ORR. Comparable results were found for grade ≥3 AE rates of ≥10%. Conclusions Our results suggest that the pyrotinib and trastuzumab plus docetaxel regimen is most likely to be the optimal first‐line therapy for patients with HER2‐positive breast cancer. We conducted a network meta‐analysis to compare all treatment regimens from randomized controlled trials for advanced HER2‐positive breast cancer in first‐line setting.

The selection of initial systemic treatment for advanced non‐small cell lung cancer (NSCLC) depends on histological subtypes, oncogenic driver identification through genomic profiling, and programmed death‐ligand 1 (PD‐L1) expression quantification. The choice of first‐line treatment is crucial as patients with advanced NSCLC may not have the opportunity to receive second‐ or later‐line therapies due to the rapid progression of the disease. Current guidelines recommend pretreatment PD‐L1 expression quantification evaluation prior to initiating systemic therapy in advanced NSCLC. Except for histology, PD‐L1 expression, and absence of actionable driver mutations, single‐agent immune checkpoint inhibitors (ICIs) are foundational first‐line interventions. ICIs combined with chemotherapy or other ICIs have shown improved survival outcomes compared to ICI monotherapy. However, choosing the best option can be challenging due to limited head‐to‐head comparisons. Treatment decisions are often influenced by drug availability, reimbursement coverage, and patient's economic conditions. Despite the development of new ICI therapies, overall survival data seem to have plateaued, highlighting the need for sustained investigations and extensive clinical validation studies to develop novel therapies, optimize ICI combinations, and monitor adverse effects. Collaboration among data scientists, clinicians, biologists, and policymakers is essential to establish biomarkers that enhance patient selection and overall survival in NSCLC. Immune checkpoint inhibitor‐based first‐line therapy improves survival in advanced NSCLC, yet its efficacy is moderated by PD‐L1 expression and genomic profiles. Real‐world challenges, including limited comparative data and accessibility disparities, demand multidisciplinary collaboration to explore biomarkers, develop novel treatment combinations, and make policy optimization, which would ultimately transcend the current therapeutic plateau.

Background and Aims The optimal management of naïve and not naïve Helicobacter pylori patients remains unclear. Therefore, it is essential to evaluate whether the actual clinical practice mirrors the indications suggested by the guidelines. This study aimed to assess the effectiveness and the safety of the empirical first‐ and second‐line treatments prescribed to patients enroled at Italian centres participating in the European Registry on H. pylori Management (Hp‐EuReg). Methods The Hp‐EuReg is an international multicentre prospective non‐interventional registry starting in 2013 aiming to evaluate the management of H. pylori infection by European gastroenterologists. Patients were registered in an e‐CRF by AEG‐REDCap. Variables assessed included demographics, previous eradication attempts, treatment regimen, effectiveness, and tolerance. Results Overall, 3723 patients from 2013 to February 2021 were included: 2996 and 727 received an empirical first‐ and second‐line treatment, respectively. According to the modified ITT analysis, among the first‐line regimens, only the bismuth quadruple therapy with three‐in‐one‐single capsule (BQT‐TSC), the concomitant, and the sequential treatment ‐ all lasting 10 days ‐ achieved an eradication rate >90%. Among the second‐line regimens, only the 10‐day BQT‐TSC reported an effectiveness >90%. High‐dose PPI twice daily also significantly increased the effectiveness of some therapies. The BQT‐TSC was the regimen with the highest incidence of adverse events. Conclusions Only quadruple therapies lasting at least 10 days achieved over 90% eradication rates among the empirical first‐ and second‐line regimens. It remains unclear whether high‐dose PPI twice daily can improve the efficacy of quadruple treatment.

Background Understanding the symptom burden experienced by patients with cancer can enable appropriate supportive care. Our aim was to describe patient‐reported outcomes (PROs) for patients with metastatic NSCLC initiating first‐line (1L) systemic therapy under usual care at a large academic center. Methods Patients eligible for this prospective observational study were ≥ 18 years old when initiating 1L systemic therapy for stage IV NSCLC from January 1, 2017 to December 31, 2020. Patients completed two PRO questionnaires before 1L therapy initiation (baseline) and every ~6 weeks at imaging visits thereafter: the MD Anderson Symptom Inventory for lung cancer (MDASI‐LC) and EuroQol EQ‐5D‐5L. Study follow‐up ended on June 30, 2021. Results The 609 eligible patients (median age, 63 years; range, 24–87; 51% men) received 1L chemotherapy plus immunotherapy (38%), targeted therapy (29%), chemotherapy (19%), or immunotherapy (13%). The five most severe MDASI‐LC symptoms among all assessments were fatigue, pain, shortness of breath, disturbed sleep, and dry mouth; 17%–32% of assessments were rated as moderate or severe. Of all assessments, 39% recorded moderate to severe symptom interference with physical aspects of daily life, and 22% reported moderate to severe interference with affective aspects. Symptom and interference subscale scores generally declined from baseline to 102 weeks overall and for the four 1L regimens. Conclusion Our findings confirm previous findings that patients with a new diagnosis of metastatic NSCLC experience a moderate symptom burden. More research is needed to identify predictors and causes of this symptom burden so that it can be effectively addressed. This prospective observational study at an academic center enabled a detailed description of the symptom burden before and during first‐line systemic therapy for 609 patients with metastatic NSCLC. Study findings align with prior research indicating that patients with a new diagnosis of metastatic NSCLC experience a moderate symptom burden.

Background Immunotherapy has afforded new treatment options for extensive small cell lung cancer (ES‐SCLC). However, reports on the effectiveness of immune checkpoint inhibitors (ICIs) combined with chemotherapy on survival in ES‐SCLC patients are inconsistent. Therefore, we conducted a meta‐analysis on the efficacy and safety of ICI combined with chemotherapy for ES‐SCLC. Methods We searched for randomized controlled clinical trials related to first‐line treatment of ES‐SCLC with ICI combined with chemotherapy in PUBMED, ESMO, ASCO, and WCLC since 2018. The primary outcome was overall survival (OS). Results Four studies were included. Compared to chemotherapy alone, ICI in combination with chemotherapy as first‐line treatment reduced the risk of death (hazard ratio [HR]: 0.76; 95% CI: 0.68–0.86; P < 0.00001) and disease progression (HR: 0.76; 95% CI: 0.68–0.84; P < 0.00001). The objective response rate (ORR) with ICI plus chemotherapy was significantly higher than that with chemotherapy alone (HR: 1.10; 95% CI: 1.02–1.19, P = 0.01). The duration of response (DoR) rate at one year was also better with ICI plus chemotherapy (HR: 3.46; 95% CI: 2.24–5.33; P < 0.00001). Security analysis revealed that the incidence of immune‐mediated adverse events (imAEs) (HR: 3.77; 95% CI: 1.99–7.15, P < 0.0001) and grade 3/4 imAEs (HR: 7.01; 95% CI: 2.48–19.81; P = 0.0002) increased significantly with ICI plus chemotherapy. Conclusions ICI combined with chemotherapy as first‐line treatment can significantly improve the OS and progression‐free survival (PFS) of ES‐SCLC patients, but the toxicity caused by immunotherapy should be carefully considered. Key points Significant findings of the studyOur meta‐analysis shows that PD‐L1/PD‐1 plus chemotherapy can significantly improve the OS and PFS of ES‐SCLC patients when used as first‐line therapy. What this study adds This study fills gaps regarding the efficacy of immunotherapy combined with chemotherapy as first‐line treatment for ES‐SCLC, and provides better evidence for the use of PD‐L1/PD‐1 immunotherapy plus chemotherapy for patients with ES‐SCLC. This is a meta‐analysis evaluated the efficacy and safety of PD‐L1/PD‐1 immunotherapy combined with first‐line chemotherapy for extensive small cell lung cancer. A total of 1538 patients from four trials were included in our meta‐analysis. Our study proved that PD‐L1/PD‐1 immunotherapy combined with chemotherapy can significantly improve the OS and PFS of first‐line ES‐ SCLC.

Background To evaluate the outcomes of first‐line imatinib versus nilotinib treatment for chronic myeloid leukemia in the chronic phase (CML‐CP) in real‐world clinical practice. Methods A propensity score analysis was performed to eliminate imbalances between the treatment groups. In the analysis, 163 patients in the nilotinib group and 163 patients in the matched imatinib group were retrospectively evaluated. Results Nilotinib‐treated patients achieved complete cytogenetic response (CCyR) and major molecular response more rapidly than imatinib‐treated patients. However, there was no significant difference in 5‐year overall survival (OS) or progression‐free survival (PFS) between the two groups (OS: 94.3% vs. 90.5%, p = 0.602; PFS: 92.9% vs. 88.0%, p = 0.614). Nilotinib‐treated patients had a higher failure‐free survival (FFS) and event‐free survival (EFS) than imatinib‐treated patients (FFS: 71.7% vs. 54.3%, p = 0.040; EFS: 71.7% vs. 53.5%, p = 0.025). Conclusions This retrospective analysis from clinical practice did not confirm any benefit of frontline nilotinib treatment for OS and PFS; however, it did demonstrate higher FFS and EFS in the nilotinib cohort.

Background European guidelines recommend that susceptibility tests be routinely performed, even before prescribing first‐line treatment of Helicobacter pylori infection. However, empirical treatments are the rule in France, and susceptibility‐guided treatments are the exception. Objective We aimed to report our experience of systematic antibiotic susceptibility testing before first‐line treatment. Methods Prospective registration of all esofagogastroduodenoscopies performed in a community hospital from December 2023 to December 2024. Antral and fundic biopsies were performed, at the discretion of the endoscopist, for histological examination, polymerase chain reaction (PCR) and culture without any freezing. Results Overall, 3566 adults underwent esofagogastroduodenoscopy, 1785 (50.1%) were tested and H. pylori infection was diagnosed in 308 (17.3%) [95% confidence interval (CI): 15.5%–19.0%] individuals. The sensitivity of PCR for the diagnosis of H. pylori infection was 99.7%, significantly higher than those of histology (94.1%) and culture (95.2%) (p < 0.01). Clarithromycin resistance was observed in 22.6% [95% CI: 17.9%–27.3%] and levofloxacin resistance in 18.6% [95% CI: 14.1%–23.2%] of cases. Among 285 patients treated, susceptibility‐guided triple therapy was prescribed in 84.9% of cases (73.3% amoxicillin‐clarithromycin, 11.6% amoxicillin‐levofloxacin) and quadruple bismuth therapy in 14.4% of cases. The eradication rates were 98.1% [95% CI: 96.0%–100%] for triple therapy amoxicillin‐clarithromycin and 100% [95% CI: 100%–100%] for amoxicillin‐levofloxacin, significantly higher than 81.3% [95% CI: 67.7%–94.8%] for quadruple bismuth therapy (p < 0.01 and p = 0.03, respectively). Overall, of 218 (70.8%) patients evaluated by the C13 urea breath test, H. pylori was eradicated in 209 (95.9%) [95% CI: 93.2%–98.5%] patients. The PCR‐based diagnostic and therapeutic strategy was more cost‐effective than the immunohistochemistry‐based strategy. Conclusion A PCR‐based susceptibility‐guided strategy is easy to implement in routine clinical practice. In more than 7 in 10 patients, PCR enabled the offer of a susceptibility‐guided triple therapy that was more effective and less costly than empirical quadruple bismuth therapy. Culture enabled one additional patient in 10 to be offered a susceptibility‐guided triple therapy. Key Summary Summarise the established knowledge on this subject ◦ Owing to an increase in antibiotic resistance, the eradication rate of Helicobacter pylori with empirical therapy has declined. ◦ European guidelines recommend that susceptibility tests are routinely performed, even before prescribing first‐line treatment. ◦ Evidence for the superiority of susceptibility‐guided therapy over empirical therapy is still limited and varies by region and treatment regimen. ◦ Almost all studies evaluating the efficacy of a susceptibility‐guided tailored first‐line treatment have been carried out in Asia, with very few in Europe. What are the significant and/or new findings of this study? ◦ A PCR‐based susceptibility‐guided strategy is easy to implement in routine clinical practice. ◦ In more than seven in 10 patients, PCR enabled susceptibility‐guided triple therapy to be proposed that was more effective and less costly than empirical quadruple bismuth therapy. ◦ Culture enabled one additional patient in 10 to be offered a susceptibility‐guided triple therapy. ◦ The PCR‐based diagnostic and therapeutic strategy was more cost‐effective than immunohistochemistry‐based strategy.

Objectives HER2 alterations are identified in 2%–4% of lung adenocarcinoma, indicating poor clinical outcomes. Chemotherapy alone (C) or in combination with bevacizumab (BC), immune checkpoint inhibitors (IC), or both (IBC) are standard options in the first‐line setting; however, optimal therapy and beneficiary populations remain unclear. Methods Patients with Stage IV HER2‐altered lung adenocarcinoma from four cancer centers in China were retrospectively analyzed. The patients received C, BC, IC, or IBC as the first‐line treatments. Clinical outcomes, including progression‐free survival (PFS) and overall survival (OS), were evaluated. The tumor immune microenvironment (TIME) characteristics were analyzed to explore the beneficiary populations with different treatments. Results IBC treatment generated the longest mPFS and OS among four schemes. Subgroup analyses showed that IBC resulted in longer PFS in patients with brain or bone metastases compared to IC. IBC generated significant benefits in younger patients, nonsmokers, and those with oligometastases versus BC. In patients with low density of PD‐1+CD8+ T‐cells or high density of CD163+ macrophages in the TIME, IBC treatment resulted in the longest PFS, followed by BC treatment. Conclusions IBC treatment generated optimal efficacy as first‐line therapy for HER2‐altered lung adenocarcinoma. Patients with low PD1+CD8+ T‐cell or high CD163+ macrophage infiltration benefited more from IBC treatment. Chemotherapy combination with bevacizumab and immune checkpoint inhibitors (IBC) generated optimal efficacy as first‐line therapy for HER2‐altered lung adenocarcinoma. Patients with low PD1+CD8+ T‐cell or high CD163+ macrophage infiltration benefited more from IBC treatment.