Durvalumab With or Without Tremelimumab in Combination With Chemotherapy in First-Line Metastatic NSCLC: Five-Year Overall Survival Outcomes From the Phase 3 POSEIDON Trial.

INTRODUCTION: The primary analysis (median follow-up 34.9 mo across all arms) of the phase 3 POSEIDON study revealed a statistically significant overall survival (OS) improvement with first-line tremelimumab plus durvalumab and chemotherapy (T+D+CT) versus CT in patients with EGFR and ALK wild-type metastatic NSCLC (mNSCLC). D+CT had a trend for OS improvement versus CT that did not reach statistical significance. This article reports prespecified OS analyses after long-term follow-up (median >5 y). METHODS: A total of 1013 patients were randomized (1:1:1) to T+D+CT, D+CT, or CT, stratified by tumor cell programmed cell death ligand-1 (PD-L1) expression (≥50% versus <50%), disease stage (IVA versus IVB), and tumor histologic type (squamous versus nonsquamous). Serious adverse events were collected during follow-up. RESULTS: After a median follow-up of 63.4 months across all arms, T+D+CT had sustained OS benefit versus CT (hazard ratio [HR] = 0.76, 95% confidence interval [CI]: 0.64-0.89; 5-y OS: 15.7% versus 6.8%). OS improvement with D+CT versus CT (HR = 0.84, 95% CI: 0.72-1.00; 5-y OS: 13.0%) was consistent with the primary analysis. OS benefit with T+D+CT versus CT remained more pronounced in nonsquamous (HR = 0.69, 95% CI: 0.56-0.85) versus squamous (HR = 0.85, 95% CI: 0.65-1.10) mNSCLC. OS benefit with T+D+CT versus CT was still evident regardless of PD-L1 expression, including patients with PD-L1 tumor cell less than 1%, and remained evident in STK11-mutant (nonsquamous), KEAP1-mutant, and KRAS-mutant (nonsquamous) mNSCLC. No new safety signals were identified. CONCLUSIONS: After a median follow-up of more than 5 years, T+D+CT had durable long-term OS benefit versus CT, supporting its use as first-line treatment in mNSCLC, including in patient subgroups with harder-to-treat disease.

Development of a Mental Health Apps Recommender Platform.

INTRODUCTION: The aim of the paper is to establish the requirements and methodology for the development and implementation of a recommender system for mental health apps to support patients in self-managing their mental health while awaiting formal treatment. METHODS: The system was developed using an algorithm-based approach, including: (1) user needs assessment through literature review and interviews with various stakeholders, (2) software modelling and prototype creation, and (3) bench testing of the prototype with health experts and users. RESULTS: Based on initial exploration of users' requirements, relevant standards and regulations, a library of trusted mental health apps was compiled and a recommendation engine was built to generate accurate user profiles and deliver personalised health recommendations, which will be further tested to ensure quality. CONCLUSION: Developing a constructive mental health recommendation system requires the establishment of clear and comprehensive requirements, as well as a robust methodology adressing concerns related to data security, confidentiality, safety, and reliability. Subsequent research may compare various indicators of mental health outcomes at the start and end of patients' waiting period to gain more insights into how the recommender system could be further improved to enhance user experience and their overall well-being.

Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC.

BACKGROUND: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC). METHODS: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR-mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review. RESULTS: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR-related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib. CONCLUSIONS: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR-mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).

Mutation profile in liquid biopsy tested by next generation sequencing in Mexican patients with non-small cell lung carcinoma and its impact on survival.

Background: Lung cancer represents a significant global health concern, often diagnosed in its advanced stages. The advent of massive DNA sequencing has revolutionized the landscape of cancer treatment by enabling the identification of target mutations and the development of tailored therapeutic approaches. Unfortunately, access to DNA sequencing technology remains limited in many developing countries. In this context, we emphasize the critical importance of integrating this advanced technology into healthcare systems in developing nations to improve treatment outcomes. Methods: We conducted an analysis of electronic clinical records of patients with confirmed advanced non-small cell lung cancer (NSCLC) and a verified negative status for the epidermal growth factor receptor (EGFR) mutation. These patients underwent next-generation sequencing (NGS) for molecular analysis. We performed descriptive statistical analyses for each variable and conducted both univariate and multivariate statistical analyses to assess their impact on progression-free survival (PFS) and overall survival (OS). Additionally, we classified genetic mutations as actionable or non-actionable based on the European Society for Medical Oncology Scale of Clinical Actionability of Molecular Targets (ESCAT) guidelines. Results: Our study included a total of 127 patients, revealing the presence of twenty-one distinct mutations. The most prevalent mutations were EGFR (18.9%) and Kirsten rat sarcoma viral oncogene homolog (KRAS) (15.7%). Notably, anaplastic lymphoma kinase (ALK) [hazard ratio (HR): 0.258, P<0.001], tumor mutation burden (TMB) (HR: 2.073, P=0.042) and brain magnetic resonance imaging (MRI) (HR: 0.470, P=0.032) demonstrated statistical significance in both the univariate and multivariate analyses with respect to PFS. In terms of OS, ALK (HR: 0.285, P<0.001) and EGFR (HR: 0.482, P=0.024) exhibited statistical significance in both analyses. Applying the ESCAT classification system, we identified actionable genomic variations (ESCAT level-1), including EGFR, ALK, breast cancer (BRAF) gene, c-ros oncogene 1 (ROS1), and rearranged during transfection (RET) gene, in 32.3% of the patients. Conclusions: Our findings from massive DNA sequencing underscore that 32.3% of patients who test negative for the EGFR mutation possess other targetable mutations, enabling them to receive personalized, targeted therapies at an earlier stage of their disease. Implementing massive DNA sequencing in developing countries is crucial to enhance survival rates among NSCLC patients and guide more effective treatment strategies.

Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON).

OBJECTIVES: In the phase 3 POSEIDON study, first-line tremelimumab plus durvalumab and chemotherapy significantly improved overall survival and progression-free survival versus chemotherapy in metastatic non-small-cell lung cancer (NSCLC). We present patient-reported outcomes (PROs). PATIENTS AND METHODS: Treatment-naïve patients were randomized 1:1:1 to tremelimumab plus durvalumab and chemotherapy, durvalumab plus chemotherapy, or chemotherapy. PROs (prespecified secondary endpoints) were assessed using the European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire version 3 (QLQ-C30) and its 13-item lung cancer module (QLQ-LC13). We analyzed time to deterioration (TTD) of symptoms, functioning, and global health status/quality of life (QoL) from randomization by log-rank test and improvement rates by logistic regression. RESULTS: 972/1013 (96 %) patients randomized completed baseline QLQ-C30 and QLQ-LC13 questionnaires, with scores comparable between treatment arms. Patients receiving tremelimumab plus durvalumab and chemotherapy versus chemotherapy had longer median TTD for all PRO items. Hazard ratios for TTD favored tremelimumab plus durvalumab and chemotherapy for all items except diarrhea; 95 % confidence intervals did not cross 1.0 for global health status/QoL, physical functioning, cognitive functioning, pain, nausea/vomiting, insomnia, constipation, hemoptysis, dyspnea, and pain in other parts. For durvalumab plus chemotherapy, median TTD was longer versus chemotherapy for all items except nausea/vomiting and diarrhea. Hazard ratios favored durvalumab plus chemotherapy for all items except appetite loss; 95 % confidence intervals did not cross 1.0 for global health status/QoL, physical functioning, role functioning, dyspnea, and pain in other parts. For both immunotherapy plus chemotherapy arms, improvement rates in all PRO items were numerically higher versus chemotherapy, with odds ratios > 1. CONCLUSIONS: Tremelimumab plus durvalumab and chemotherapy delayed deterioration in symptoms, functioning, and global health status/QoL compared with chemotherapy. Together with significant improvements in survival, these results support tremelimumab plus durvalumab and chemotherapy as a first-line treatment option in metastatic NSCLC.

Influence of nutritional counseling on treatment results in patients with head and neck cancers.

OBJECTIVES: Nutritional intervention, including nutritional counseling (NC), plays a significant role in the comprehensive management of patients with head and neck cancer (HNC). The aim of this study was to investigate the effects of NC combined with oral nutritional supplements during radical treatment on weight loss and survival outcomes in patients with HNC. METHODS: The study included 310 patients who received radical treatment for HNC. Among these patients, 119 underwent NC along with oral nutritional supplements (NCONS); 191 were supported with oral nutritional supplements only (ONS). The study aimed to investigate the effects of sex, disease stage, treatment modality, and tumor site on weight loss. Additionally, the Kaplan-Meier method assessed the influence of NC on overall survival and disease-free survival. RESULTS: The present study suggested that the NC independently prevented weight loss, regardless of sex and disease stage (female: -1.6%, P = 0.001; male: -2.3 %, P = 0.003; T stage (0-2): -1.7%, P = 0.008; T stage (3-4): -2.7%, P = 0.003; N stage (0-1): 2.5%, P = 0,027; N stage (3-4): 2.9%, P < 0.001). The protective effect was most significant in patients with oral cancer and oropharyngeal cancer and in patients treated with chemotherapy (oral: -1.7%, P = 0.03; oropharynx: -3.3%, P < 0.001; radiochemotherapy: -3%, P = 0.028; induction chemotherapy preceded radiochemotherapy: -6%, P < 0.001). Furthermore, the 3-year overall survival rates were 93.4% and 85.4% in the NC along with oral nutritional supplements (NCONS) and oral nutritional supplement (ONS) groups, respectively (P = 0.031). CONCLUSIONS: Patients with HNC who received NC during radical treatment experienced reduced weight loss. This effect was particularly pronounced in patients with oral cavity or oropharyngeal cancer and those undergoing chemotherapy. Additionally, NC was associated with improved overall survival in this patient cohort. Nevertheless, further studies are required to validate and support these findings.

The Real-World Evidence on the Fragility and Its Impact on the Choice of Treatment Regimen in Newly Diagnosed Patients with Multiple Myeloma over 75 Years of Age.

Fragility scales are intended to help in therapeutic decisions. Here, we asked if the fragility assessment in MM patients ≥ 75 years old qualified for treatment by the local physician correlates with the choice of treatment: a two- or three-drug regimens. Between 7/2018 and 12/2019, we prospectively enrolled 197 MM patients at the start of treatment from the 13 Polish Myeloma Group centers. The data to assess fragility were prospectively collected, but centrally assessed fragility was not disclosed to the local center. The activity of daily living (ADL) could be assessed in 192 (97.5%) and was independent in 158 (80.2%), moderately impaired in 23 (11.7%), and 11 (5.6%) in completely dependent. Patients with more than three comorbidities made up 26.9% (53 patients). Thus, according to the Palumbo calculator, 43 patients were in the intermediate fitness group (21.8%), and the rest belonged to the frailty group (153, 77.7%). Overall, 79.7% of patients (157) received three-drug regimens and 20.3% (40) received two-drug regimens. In each ECOG group, more than three out of four patients received three-drug regimens. According to the ADL scale, 82.3% of the independent 65.2% of moderately impaired, and 81.8% of the dependent received three-drug regimens. Out of 53 patients with at least four comorbidities, 71.7% received three-drug regimens, and the rest received two-drug regimens. Thirty-four patients from the intermediate fit group (79.0%), and 123 (79.9%) from the frail group received three-drug regimens. Early mortality occurred in 25 patients (12.7%). No one discontinued treatment due to toxicity. To conclude, MM patients over 75 are mainly treated with triple-drug regimens, not only in reduced doses, regardless of their frailty scores. However, the absence of prospective fragility assessment did not negatively affect early mortality and the number of treatment discontinuations, which brings into question the clinical utility of current fragility scales in everyday practice.

Epirubicin, cisplatin plus ifosfamide versus standard chemotherapeutic regimens for advanced/unresectable primary thoracic sarcomas.

PURPOSE: Thoracic sarcomas are rare malignancies, with limited data for unresectable/advanced scenarios. Our goal is to provide insights of a three-drug chemotherapy regimen improving patient survival compared to standard regimens. METHODS: Retrospective cohort analysis of patients diagnosed with unresectable/advanced primary thoracic sarcoma divided between primary pulmonary sarcomas (PPS) and chest wall sarcomas (CWS) comparing chemotherapeutical regimens efficacy. Not true soft tissue sarcomas (STS) for PPS were excluded from the analysis. Univariate and multivariate analysis performed via Cox-regression model. Progression-free survival (PFS) and overall survival (OS) analysis via Kaplan-Meier with hazard ratio (HR) obtained via Mantel-Haenszel or log rank. RESULTS: 157 total cases were included, from which 50 cases were PPS and 107 cases CWS. For PPS, 4 cases were excluded from the analysis as they were not true STS. The most common histology was undifferentiated sarcomas, 63% of cases were treated with E/C/I and 37% with another regimen. The E/C/I regimen demonstrated a benefit for both OS (p = 0.020) and PFS (p = 0.010) when compared to any other regimen as well as when compared to non-platinum regimens (p = 0.016 and p = 0.001). Regarding CWS, the most common histology was synovial and undifferentiated sarcomas, 55.1% were treated with E/C/I and 44.9% treated with another regimen. The E/C/I regimen did not demonstrate a benefit for OS or PFS compared to any other regimen, neither when compared to other non-platinum regimens. However, a benefit was observed in favor of E/C/I when compared to other platinum regimens in both OS (p = 0.049) and PFS (0.015). Both analyses for PPS and CWS demonstrated a benefit in favor of cisplatin therapies compared to carboplatin in both OS and PFS. CONCLUSION: This study demonstrates that platinum therapy alone does not work, and that cisplatin must be the agent of choice and it's used in combination could increase treatment response. The E/C/I regimen demonstrated a in PPS but not for CWS, this is due do their rarity of PPS and that no standard treatment is established yet. The regimen proposed here could represent a possible new standard of treatment for PPS as long as it is validated in a prospective study.

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study.

PURPOSE: The open-label, phase III POSEIDON study evaluated tremelimumab plus durvalumab and chemotherapy (T + D + CT) and durvalumab plus chemotherapy (D + CT) versus chemotherapy alone (CT) in first-line metastatic non-small-cell lung cancer (mNSCLC). METHODS: Patients (n = 1,013) with EGFR/ALK wild-type mNSCLC were randomly assigned (1:1:1) to tremelimumab 75 mg plus durvalumab 1,500 mg and platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression and one additional tremelimumab dose; durvalumab plus chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression; or chemotherapy for up to six 21-day cycles (with or without maintenance pemetrexed; all arms). Primary end points were progression-free survival (PFS) and overall survival (OS) for D + CT versus CT. Key alpha-controlled secondary end points were PFS and OS for T + D + CT versus CT. RESULTS: PFS was significantly improved with D + CT versus CT (hazard ratio [HR], 0.74; 95% CI, 0.62 to 0.89; P = .0009; median, 5.5 v 4.8 months); a trend for improved OS did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.02; P = .0758; median, 13.3 v 11.7 months; 24-month OS, 29.6% v 22.1%). PFS (HR, 0.72; 95% CI, 0.60 to 0.86; P = .0003; median, 6.2 v 4.8 months) and OS (HR, 0.77; 95% CI, 0.65 to 0.92; P = .0030; median, 14.0 v 11.7 months; 24-month OS, 32.9% v 22.1%) were significantly improved with T + D + CT versus CT. Treatment-related adverse events were maximum grade 3/4 in 51.8%, 44.6%, and 44.4% of patients receiving T + D + CT, D + CT, and CT, respectively; 15.5%, 14.1%, and 9.9%, respectively, discontinued treatment because of treatment-related adverse events. CONCLUSION: D + CT significantly improved PFS versus CT. A limited course of tremelimumab added to durvalumab and chemotherapy significantly improved OS and PFS versus CT, without meaningful additional tolerability burden, representing a potential new option in first-line mNSCLC.

High-dose alectinib for RET fusion-positive non-small cell lung cancer in the Blood First Assay Screening Trial.

Introduction: This paper presents results from Cohort B (rearranged during transfection [RET], fusion-positive) of the Blood First Assay Screening Trial in patients with advanced non-small cell lung cancer (NSCLC) screened for genetic alterations using blood-based next-generation sequencing. Material and methods: Adults with advanced RET fusion-positive NSCLC received alectinib 900 mg twice daily (BID) in Phase I. Enrolment closed prematurely with Phase II uninitiated. Results: Among eight treated patients, confirmed best overall responses in evaluable patients were stable disease (4/5) and progressive disease (1/5). One dose-limiting toxicity (death, unknown cause) was considered by the investigator to be related to treatment and underlying disease. Serious adverse events (SAEs) occurred in five patients, and SAEs that may be related to treatment occurred in two patients. Conclusions: Alectinib showed limited activity in advanced RET fusion-positive NSCLC, and further investigation was not conducted due to the development of selective RET inhibitors pralsetinib and selpercatinib. No new safety signals were observed, and the safety profile of alectinib was in line with previous reports at the 600 mg BID dose.

Microfibril Associated Protein 5 (MFAP5) Is Related to Survival of Ovarian Cancer Patients but Not Useful as a Prognostic Biomarker.

Ovarian cancer (OC) is usually diagnosed late due to its nonspecific symptoms and lack of reliable tools for early diagnostics and screening. OC studies concentrate on the search for new biomarkers and therapeutic targets. This study aimed to validate the MFAP5 gene, and its encoded protein, as a potential prognostic biomarker. In our previous study, we found that patients with high-grade serous OC who had higher MFAP5 mRNA levels had shorter survival, as compared with those with lower levels. Here, we used the Kaplan-Meier Plotter and CSIOVDB online tools to analyze possible associations of MFAP5 expression with survival and other clinico-pathological features. In these analyses, higher MFAP5 mRNA expression was observed in the more advanced FIGO stages and high-grade tumors, and was significantly associated with shorter overall and progression-free survival. Next, we analyzed the expression of the MFAP5 protein by immunohistochemistry (IHC) in 108 OC samples and tissue arrays. Stronger MFAP5 expression was associated with stronger desmoplastic reaction and serous vs. non-serous histology. We found no significant correlation between IHC results and survival, although there was a trend toward shorter survival in patients with the highest IHC scores. We searched for co-expressed genes/proteins using cBioPortal and analyzed potential MFAP5 interaction networks with the STRING tool. MFAP5 was shown to interact with many extracellular matrix proteins, and was connected to the Notch signaling pathway. Therefore, although not suitable as a prognostic biomarker for evaluation with a simple diagnostic tool like IHC, MFAP5 is worth further studies as a possible therapeutic target.

Final results from TAIL: updated long-term efficacy of atezolizumab in a diverse population of patients with previously treated advanced non-small cell lung cancer.

In patients with previously treated advanced or metastatic non-small cell lung cancer (NSCLC), atezolizumab therapy improves survival with manageable safety. The open-label, single-arm phase III/IV TAIL study (NCT03285763) evaluated atezolizumab monotherapy in patients with previously treated NSCLC, including those with Eastern Cooperative Oncology Group performance status of 2, severe renal impairment, prior anti-programmed death 1 therapy, autoimmune disease, and age ≥75 years. Patients received atezolizumab intravenously (1200 mg) every 3 weeks. At data cut-off for final analysis, the median follow-up was 36.1 (range 0.0-42.3) months. Treatment-related (TR) serious adverse events (SAEs) and TR immune-related adverse events (irAEs) were the coprimary endpoints. Secondary endpoints included overall survival (OS), progression-free survival (PFS), overall response rate, and duration of response. Safety and efficacy in key patient subgroups were also assessed. TR SAEs and TR irAEs occurred in 8.0% and 9.4% of patients, respectively. No new safety signals were documented. In the overall population, median OS and PFS (95% CI) were 11.2 months (8.9 to 12.7) and 2.7 months (2.3 to 2.8), respectively. TAIL showed that atezolizumab has a similar risk-benefit profile in clinically diverse patients with previously treated NSCLC, which may guide treatment decisions for patients generally excluded from pivotal clinical trials.

Survival prognostic factors in unresectable/advanced primary thoracic sarcomas.

Background: Primary thoracic sarcomas (PTS) including primary pulmonary and chest wall sarcomas (CWS), are aggressive lung malignancies with limited information specially in an advanced/unresectable setting. Unfortunately, prognostic factors for these malignancies are not well identified. Methods: Retrospective cohort analysis of patients diagnosed with unresectable/advanced soft tissue PTS from a third level reference institute. Univariate and multivariate analysis performed via Cox-regression model. Progression-free survival (PFS) and overall survival (OS) analysis via Kaplan-Meier method. Results: A total of 157 patients were identified, 55.4% female, mean age 51.8 years (range, 18-90 years), 19.1% tobacco exposure and 10.8% asbestos exposure. The most common performance status was Eastern Cooperative Oncology Group (ECOG) 1 (38.9%), most common clinical presentation cough (58.4%) and thoracic pain (55.4%). Undifferentiated sarcoma (37.6%) followed by synovial sarcoma (34.4%) were the most common histologies. Most patients received five chemotherapeutic cycles (37.6%), 57.3% of patients obtained a partial response and 61.1% an overall response rate (ORR). Median PFS was 9 months [95% confidence interval (CI): 8.717-9.283 months]. The multivariable analysis identified ECOG ≥2, a poorer response to chemotherapy (less number of chemotherapy cycles) and an increase Response Evaluation Criteria in Solid Tumors (RECIST) to be associated with a shorter progression-free period. Median OS was 11 months (95% CI: 10.402-11.958 months) with an ECOG ≥2 and a poorer response to chemotherapy (less number of chemotherapy cycles) associated with a shorter survival. Conclusions: Age, gender, comorbidities, tobacco and asbestos exposure, clinical presentation and histopathological diagnosis are not useful prognostic factors in unresectable/advanced PTS, however, an adequate initial ECOG, RECIST and a better response to chemotherapy should be used as prognostic factors in the management of these tumors.

Impact of renin-angiotensin system inhibitors on the survival of patients with rectal cancer.

BACKGROUND: Renin-angiotensin system inhibitors (RASIs) are widely used in the treatment of hypertension. However, their impact on the outcome of the combined treatment of rectal cancer is poorly understood. The aim of this study was to assess the effect of RASIs on the survival of rectal cancer patients with associated hypertension after neoadjuvant treatment and radical resection. METHODS: Between 2008 and 2016, 242 radical (R0) rectal resections for cancer were performed after neoadjuvant treatment in patients with associated hypertension. At the time of treatment, 158 patients were on RASIs, including 35 angiotensin-receptor antagonists (ARB) users and 123 angiotensin-converting enzyme inhibitors (ACEI) users. Eighty-four patients were on drugs other than RASIs (non-RASI users). The survival analysis was performed using the Kaplan-Meier estimator with the log-rank test and the Cox proportional hazards model. RESULTS: The log-rank test showed a significantly worse overall survival (OS) in the group of ACEI users compared to ARB users (p = 0.009) and non-RASI users (p = 0.013). Disease-free survival (DFS) was better in the group of ARB users compared to ACEI users. However, the difference was not statistically significant (p = 0.064). The Multivariate Cox analysis showed a significant beneficial effect of ARBs on OS (HR: 0.326, 95% CI: 0.147-0.724, p = 0.006) and ARBs on DFS (HR: 0.339, 95% CI: 0.135-0.850, p = 0.021) compared to ACEIs. Other factors affecting OS included age (HR: 1.044, 95% CI: 1.016-1.073, p = 0.002), regional lymph node metastasis (ypN +) (HR: 2.157, 95% CI: 1.395-3.334, p = 0.001) and perineural invasion (PNI) (HR: 3.864, 95% CI: 1.799-8.301, p = 0.001). Additional factors affecting DFS included ypN + (HR: 2.310, 95% CI: 1.374-3.883, p = 0.002) and PNI (HR: 4.351, 95% CI: 1.584-11.954, p = 0.004). CONCLUSIONS: The use of ARBs instead of ACEIs may improve the outcome of the combined therapy for rectal cancer patients with associated hypertension.

The role of thyroid sonographic malignancy risk features when the fine needle aspiration biopsy result is indeterminate.

INTRODUCTION: Although the role of the thyroid ultrasound is well established in the initial thyroid nodule work up, it is still equivocal whether the thyroid ultrasound pattern could have an impact on refining malignancy risk after an indeterminate cytopathology result. We aim to assess the possible supportive role of the thyroid nodule ultrasound malignancy risk features listed in the Polish guidelines when a biopsy result is indeterminate. MATERIAL AND METHODS: We retrospectively reviewed thyroid ultrasound scans from 175 adult patients with thyroid nodules and indeterminate cytopathology results, who underwent thyroid surgery. Sonographic malignancy risk features were reported in accordance with the guidelines of the Polish National Societies Diagnostics and Treatment of Thyroid Carcinoma and included the following: solid structure, hypoechogenicity, microcalcifications, taller than wide shape, irregular margins, features of extrathyroidal expansion, suspicious cervical lymph nodes. RESULTS: The malignancy risk in relevant cytological categories, estimated on the basis of histological verification, was 10.9% for Bethesda III category, 12.1% for Bethesda IV, and 71.4% for Bethesda V. The predominant type of thyroid malignancy was papillary thyroid carcinoma (79%). Thyroid nodules sonographic malignancy risk features provided high specificity but low sensitivity in selected groups of indeterminate thyroid nodules. Microcalcifications was the only characteristic that solely had a clinically relevant positive likelihood ratio (> 10) to suggest malignancy in the analysed cohort, but it was not observed in thyroid nodules eventually verified as follicular thyroid carcinoma. An accumulation of more than one sonographic risk feature yielded significant increase in malignancy risk only in Bethesda V category thyroid nodules. CONCLUSIONS: The impact of sonographic malignancy risk features on refining post-biopsy probability of thyroid cancer in thyroid nodule with indeterminate cytopathology, may be inadequate to sort patients (without any doubt) between those who require thyroid surgery and those who only require surveillance. There is an urgent need to search for new tools in the diagnostics of indeterminate thyroid nodules and to standardize thyroid ultrasound reports.

p38 Mediates Resistance to FGFR Inhibition in Non-Small Cell Lung Cancer.

FGFR signalling is one of the most prominent pathways involved in cell growth and development as well as cancer progression. FGFR1 amplification occurs in approximately 20% of all squamous cell lung carcinomas (SCC), a predominant subtype of non-small cell lung carcinoma (NSCLC), indicating FGFR as a potential target for the new anti-cancer treatment. However, acquired resistance to this type of therapies remains a serious clinical challenge. Here, we investigated the NSCLC cell lines response and potential mechanism of acquired resistance to novel selective FGFR inhibitor CPL304110. We found that despite significant genomic differences between CPL304110-sensitive cell lines, their resistant variants were characterised by upregulated p38 expression/phosphorylation, as well as enhanced expression of genes involved in MAPK signalling. We revealed that p38 inhibition restored sensitivity to CPL304110 in these cells. Moreover, the overexpression of this kinase in parental cells led to impaired response to FGFR inhibition, thus confirming that p38 MAPK is a driver of resistance to a novel FGFR inhibitor. Taken together, our results provide an insight into the potential direction for NSCLC targeted therapy.

Heat shock factor 1 (HSF1) cooperates with estrogen receptor α (ERα) in the regulation of estrogen action in breast cancer cells.

Heat shock factor 1 (HSF1), a key regulator of transcriptional responses to proteotoxic stress, was linked to estrogen (E2) signaling through estrogen receptor α (ERα). We found that an HSF1 deficiency may decrease ERα level, attenuate the mitogenic action of E2, counteract E2-stimulated cell scattering, and reduce adhesion to collagens and cell motility in ER-positive breast cancer cells. The stimulatory effect of E2 on the transcriptome is largely weaker in HSF1-deficient cells, in part due to the higher basal expression of E2-dependent genes, which correlates with the enhanced binding of unliganded ERα to chromatin in such cells. HSF1 and ERα can cooperate directly in E2-stimulated regulation of transcription, and HSF1 potentiates the action of ERα through a mechanism involving chromatin reorganization. Furthermore, HSF1 deficiency may increase the sensitivity to hormonal therapy (4-hydroxytamoxifen) or CDK4/6 inhibitors (palbociclib). Analyses of data from The Cancer Genome Atlas database indicate that HSF1 increases the transcriptome disparity in ER-positive breast cancer and can enhance the genomic action of ERα. Moreover, only in ER-positive cancers an elevated HSF1 level is associated with metastatic disease.

About 70% of breast cancers rely on supplies of a hormone called estrogen ­ which is the main hormone responsible for female physical characteristics ­ to grow. Breast cancer cells that are sensitive to estrogen possess proteins known as estrogen receptors and are classified as estrogen-receptor positive. When estrogen interacts with its receptor in a cancer cell, it stimulates the cell to grow and migrate to other parts of the body. Therefore, therapies that decrease the amount of estrogen the body produces, or inhibit the receptor itself, are widely used to treat patients with estrogen receptor-positive breast cancers. When estrogen interacts with an estrogen receptor known as ERα it can also activate a protein called HSF1, which helps cells to survive under stress. In turn, HSF1 regulates several other proteins that are necessary for ERα and other estrogen receptors to work properly. Previous studies have suggested that high levels of HSF1 may worsen the outcomes for patients with estrogen receptor-positive breast cancers, but it remains unclear how HSF1 acts in breast cancer cells. Vydra, Janus, Kus et al. used genetics and bioinformatics approaches to study HSF1 in human breast cancer cells. The experiments revealed that breast cancer cells with lower levels of HSF1 also had lower levels of ERα and responded less well to estrogen than cells with higher levels of HSF1. Further experiments suggested that in the absence of estrogen, HSF1 helps to keep ERα inactive. However, when estrogen is present, HSF1 cooperates with ERα and enhances its activity to help cells grow and migrate. Vydra, Janus, Kus et al. also found that cells with higher levels of HSF1 were less sensitive to two drug therapies that are commonly used to treat estrogen receptor-positive breast cancers. These findings reveal that the effect HSF1 has on ERα activity depends on the presence of estrogen. Therefore, cancer therapies that decrease the amount of estrogen a patient produces may have a different effect on estrogen receptor-positive tumors with high HSF1 levels than tumors with low HSF1 levels.

Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial.

BACKGROUND: Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19. METHODS: In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT04421027. FINDINGS: Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of -2·7 percentage points (95% CI -7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41-0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47-0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups. INTERPRETATION: Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19. FUNDING: Eli Lilly and Company. TRANSLATIONS: For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

A comparative study of immunotherapy as second-line treatment and beyond in patients with advanced non-small-cell lung carcinoma.

BACKGROUND: Immunotherapy has demonstrated an improved overall survival (OS) and progression-free survival (PFS) as second-line treatment and subsequent lines compared with chemotherapy. MATERIALS & METHODS: This was a retrospective review among eight medical centers comprising 100 patients with a confirmed diagnosis of non-small-cell lung carcinoma, in their second-line treatment or beyond with immune checkpoints inhibitors treatment. The current study aimed to analyze effectiveness of immunotherapy in second-line treatment or further in the Mexican population, using PFS rate, OS rate and the best objective response to treatment by RECIST 1.1 as a surrogate of effectiveness. RESULTS: In total, 100 patients met the criteria for enrollment in the current study. From the total study population, 49 patients (49.0%) were male and 51 (51.0%) were female, with an average age of 60 years and stage IV as the most prevalent clinical stage at the beginning of the study. A total of 61 patients (61.0%) had partial response; 11 (11.0%) stable disease; 2 (2.0%), complete response, 4 (4.0%), progression; and 22 (22.0%) were nonevaluable. We found a median PFS of 4 months (95% CI: 3.2-4.7 months) and an OS of 9 months (95% CI: 7.2-10.7 months). CONCLUSION: The response to immunotherapy is similar, with an improvement in OS and PFS, independent of which drug is used. Patients using nivolumab had a better survival, although that was not statistically significant.